Metal chelator combination therapy for treatment of cancer

Abstract

To provide a novel and improved method for cancer treatment and risk assessment.SOLUTION: A method of treating a disease in a mammalian subject comprises the step for administering to the subject: (i) one or more metal chelators; (ii) an anti-cancer therapy; and (iii) optionally, at least one antioxidant, vitamin, or essential mineral, in a therapeutically effective amount.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application is hereby incorporated by reference in its entirety as if set forth herein. U.S. Provisional Application No. 62 / 797,7 filed January 28, 2019, which is incorporated by reference. Priority is claimed to specification No. 52. [Background technology]

[0002] 1. Field of the invention The present invention relates generally to the fields of molecular biology and medicine. More specifically, it relates to cancer The present invention relates to compositions and methods for treating 2. Description of Related Technology Currently, there are no drugs for the treatment or prevention of cancer, cancer maintenance therapy, cancer prevention, or acute and chronic diseases. There are no standard treatment protocols for broad-spectrum metal detoxification or metal rebalancing. remains a significant clinical problem. Summary of the Invention [Problem to be solved by the invention]

[0003] There is a need for new and improved methods for cancer treatment and risk assessment. [Means for solving the problem]

[0004] The present invention relates to the use of various combination therapies that include metal chelators to treat, for example, leukemia, This is based in part on the observation that it may be particularly beneficial in the treatment of various cancers. In some embodiments, the one, two, or more chelating agents are administered to a mammal having cancer. When administered to a subject (e.g., a human patient), copper (Cu), arsenic (As), cesium (Cs), and / or selectively binds to one or more metals, such as lead (Pb).

[0005] In one embodiment, a therapeutically effective amount of (i) a metal chelator; (ii) chemotherapy, epigenetics, (iii) a cancer therapy that is a therapeutic agent, an immunotherapy, or a targeted cancer therapy; and At least one of, and more preferably at least one of, lead, selenium, magnesium, and / or vitamin C At least two, more preferably at least three, and even more preferably all, of the Also provided is a method for treating a disease, preferably cancer, in a mammalian subject, comprising the step of: In some embodiments, vitamin C is administered in combination with another antioxidant, such as amifostine. or reducing agents. In some embodiments, multiple chelating agents may be substituted. may be used. When the chelating agent is dexrazoxane or another chelating agent Alternatively, the method may include administering a second metal chelator to the subject. In some embodiments, one or more metal chelators are administered to a subject, where one or The metal chelator is not dexrazoxane. In certain embodiments, the subject is a human.

[0006] In some aspects, the cancer is leukemia or a hematological malignancy. Leukemia is classified into acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CL), and In certain embodiments, the cancer is chronic myeloid leukemia (CLL), or chronic myeloid leukemia (CML). The elephant has myelodysplastic syndrome (MDS). In some embodiments, the cancer has recurred or , or is resistant to previous treatment.

[0007] In certain embodiments, the metal chelator is a dithiol chelator. So, the dithiol chelating agent is dimercaptosuccinic acid (DMSA), 2,3-dimer Capryl-1-propanesulfonic acid (DMPS) or dimercaprol (BAL) In some embodiments, the chelating agent is dimercaptosuccinic acid (DMSA), 2, 3-Dimercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercapto Propyl)-phthalamic acid (DMPA), pentetic acid calcium trisodium (Ca- In some embodiments, the method is , dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propanesulfone In some embodiments, the method includes administering to the subject both a DMPS and a chiral acid. The chelating agent may be a gadolinium chelating agent, such as a bifunctional gadolinium(III) chelating agent. In certain embodiments, the metal chelator is calcium-EDTA (Ca-ED In some embodiments, the metal chelate is calcium disodium EDTA. In certain embodiments, the metal chelator is deferasirox. , deferiprone, or deferoxamine. In some embodiments, the metal chelator The agent is N-acetyl-cysteine ​​(NAC). In some embodiments, the metal chelating agent In certain embodiments, the copper chelator is trientine or tetrahydrofuran. In certain embodiments, the metal chelator is dexrazoxane. In some embodiments, the chelator is a metal chelator complex.

[0008] In an additional aspect, the method comprises administering to the subject a therapeutically effective amount of dexrazoxane. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of amifostine. In some embodiments, the method further comprises the step of: The method includes administering to the subject one, two, three, or all of the following: In some embodiments, the method includes administering to the subject zinc, selenium, magnesium, and vitamin C. The method includes the step of administering.

[0009] In some embodiments, the cancer therapy is chemotherapy. In certain embodiments, the chemotherapy is One of the following: Ilotarg, cladribine, idarubicin, cytarabine, and CPX-351 In certain embodiments, the chemotherapy is selected from Mylotarg, Cladribine, Ida In certain embodiments, the chemotherapy is Mylotarg, Cladosine, or Cytarabine. Lipoic acid, idarubicin, and cytarabine (CLIA-M). Therapy consisted of Mylotarg, cladribine, idarubicin, cytarabine (CLIA-M), and and CPX-351.

[0010] In a further aspect, the method further comprises administering amifostine to the subject.

[0011] In some embodiments, the cancer is leukemia, preferably AML; zinc, selenium, magnesium, and vitamin C are all administered to the subject. In some embodiments, vitamin C is used in combination with another antioxidant, such as amifostine, or It is expected that it may be substituted with a reducing agent.

[0012] In certain embodiments, chemotherapy is anthracycline, Berlin-Frankfurt-Munich Benign pulmonary (BFM) chemotherapy, (cyclophosphamide, vincristine, doxorubicin Hyper-CVAD chemotherapy including cyclosporine, cyclosporine, and dexamethasone; hypomethylation therapy (e.g., dexamethasone); cytabine or azacitidine), cytarabine, clofarabine, or cladribine.

[0013] In some embodiments, the cancer therapy is immunotherapy. In certain embodiments, the immunotherapy is Monoclonal antibodies or immune checkpoint inhibitors, rituximab, ofatumumab, or The drugs are blinatumomab, inotuzumab, gemtuzumab ozogamicin, nivolumab, and ipilimumab. It is an immune checkpoint inhibitor that targets mabs or PD-1 / PD-L1. In some embodiments, the cancer therapy is a targeted therapy. In some embodiments, the targeted therapy is a FL T3 inhibitors, BCR-ABL tyrosine kinase inhibitors, JAK-2 inhibitors, IDH1 or In some embodiments, the targeting Therapy includes FLT3 inhibitors, BCR-ABL tyrosine kinase inhibitors, JAK-2 inhibitors, IDH1 or IDH2 inhibitors, gemtuzumab ozogamicin, BCL2-inhibitors or BC L-2 targeted therapy, RAS / MEK inhibitors, CDK inhibitors, glasdegib and / or another In some preferred embodiments, the subject is In some embodiments, the method comprises detecting one or more mutations or cellular changes in the cancer. In some embodiments, the cancer treatment method includes the step of: Pygenetic or targeted therapy.

[0014] Other objects, features and advantages of the present invention will become apparent from the following detailed description. However, various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. As will be apparent to those skilled in the art, the detailed description and specific examples illustrate preferred embodiments of the invention. However, it should be understood that they are provided by way of example only.

[0015] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The present invention is not limited to the disclosed embodiments, and may be modified in any manner without departing from the spirit and scope of the present invention. The present invention may be better understood by reference to one or more of these drawings. . [Brief description of the drawings]

[0016] [Figure 1] Lower magnesium levels below 33049.03 ppb were associated with poor survival in patients with AML. [Diagram 2] Excessive copper levels above 1130.69 ppb were associated with poor survival in patients with AML. [Diagram 3] Lower zinc (Zn), below 546.02 ppb, was associated with poor survival in AML. [Figure 4] Higher arsenic (As) levels, ≥1.06 ppb, were associated with poor survival in AML. [Diagram 5] Higher antimony (Sb) levels above 0.57 ppb were associated with poor survival in AML. [Figure 6] Higher cesium (Cs) levels, above 0.71 ppb, were associated with poor survival in AML. [Figure 7] Higher lead (Pb) levels, ≥0.91 ppb, were associated with poor survival in AML. [Figure 8] Kaplan-Meier curves comparing overall survival in patients with AML with high (>2.43 mmol / L) and low (<2.43 mmol / L) serum calcium levels. [Figure 9]Kaplan-Meier curves comparing overall survival in patients with AML with high (≥0.750 mmol / L) and low (<0.750 mmol / L) serum cadmium levels. [Figure 10] Kaplan-Meier curves comparing overall survival in patients with AML with high (≥0.692 mmol / L) and low (<0.692 mmol / L) serum selenium levels. [Figure 11] Overall survival by metal score grouping is shown for patients treated in the study of Example 2. Patients with higher metal scores had significantly worse survival. [Figure 12] Overall survival by metal score grouping is shown for patients treated in the second study of Example 2, conducted at a different hospital. Patients with higher metal scores had significantly worse survival. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In some aspects, the present application provides methods and compositions for treating cancer. Thus, overcoming limitations in the prior art. In some embodiments, (i) one or more (ii) one or more antioxidants, vitamins, or minerals, and iii) Combination with chemotherapy, epigenetic therapy, immunotherapy, or targeted therapy for the treatment and / or maintenance of cancer, leukemia, or other hematological malignancies , Compositions and Method Protocols.

[0018] In certain embodiments, the present disclosure provides a method for providing essential minerals and antioxidants during cancer treatment and prevention. New treatments include broad-spectrum detoxification of toxic and / or essential metals while replacing This novel approach provides a method for the detection of significantly elevated levels of toxic metals and essential metals. Imbalances and Deficiencies, and Metal Chelators and Antioxidants / Minerals During AML / MDS Treatment Supported by clinical and laboratory data demonstrating favorable clinical outcomes in treated AML / MDS patients Further provided herein is a method for treating a patient's chronic condition by administering a medicament for treating a patient's chronic condition. It's a combination that can be individually tailored to specific metal anomalies.

[0019] Further embodiments of the present invention are described below.

[0020] Embodiment 1. A method of treating a disease in a mammalian subject; or Undetectable levels of one or more toxic metals in the serum and / or bone marrow of subjects with cancer Provided herein is a method for reducing the level of The method includes administering a therapeutically effective amount of (i) one or more metal chelators; (ii) at least one antioxidant, vitamin, or mineral (preferably an essential mineral); ); and (iii) optionally, at least one anti-cancer therapy The method includes administering to a subject.

[0021] Embodiment 2. The method of embodiment 1, further comprising the step of administering an anti-cancer therapy to the subject.

[0022] Embodiment 3. Provided herein is a method of treating cancer in a mammalian subject; or Undetectable levels of one or more toxic metals in the serum and / or bone marrow of subjects with cancer Also provided is a method for reducing the level of The method includes administering a therapeutically effective amount of (i) one or more metal chelators; (ii) at least one anticancer therapy; and (iii) optionally, at least one antioxidant, vitamin, or mineral (preferably an essential The method includes administering to a subject a dietary supplement (essential minerals).

[0023] Embodiment 4. At least one antioxidant, vitamin, and / or mineral (preferably The method of embodiment 3, further comprising the step of administering to the subject a nutrient source of essential minerals.

[0024] Embodiment 5. One or more metal chelators are broad spectrum metal chelators The method of any one of embodiments 1 to 4, wherein, for example, one or more metal chelates are At least one of the agents is capable of chelating at least two metals and / or one or more wherein the metal chelator is capable of chelating potentially toxic / non-essential metals.

[0025] Embodiment 6. One or more metal chelators reduce the levels of at least two metals. and / or an amount effective to reduce the levels of potentially toxic / non-essential metals. The method of embodiment 5, wherein the amount of

[0026] Embodiment 7. At least two chelating agents are administered, the chelating agents being administered simultaneously or sequentially. The method of either embodiment 5 or 6, wherein

[0027] Embodiment 8. The one or more metal chelators are EDTA, dimercaptosuccinic acid ( DMSA), 2,3-dimercapto-1-propanesulfonic acid (DMPS), BAL, N -Acetylcysteine ​​(NAC), deferasirox, deferiprone, deferoxamine , calcium trisodium pentetate (Ca-DPTA), zinc trisodium pentetate (Zn-DTPA), trientine, tetrathiomolybdate, and dexrazoxane The method of any of embodiments 1-7, wherein the method is selected from the group consisting of:

[0028] Embodiment 9. The one or more metal chelators are EDTA, dimercaptosuccinic acid ( DMSA), 2,3-dimercapto-1-propanesulfonic acid (DMPS), BAL, N -Acetylcysteine ​​(NAC), deferasirox, deferiprone, deferoxamine Calcium trisodium pentetate (Ca-DPTA), trientine, tetrathiophene The method of any one of embodiments 1 to 7, wherein the aryl ester is selected from molybdate and dexrazoxane. .

[0029] Embodiment 10. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3-dimercaptosuccinic acid (DMSA), Mercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropionyl Dimethyl phthalamic acid (DMPA), calcium trisodium pentetate (Ca-DTP A), and dimercaprol (BAL). Law.

[0030] Embodiment 11. The method of any one of embodiments 1 to 7, wherein the metal chelator is a dithiol chelator. Either way.

[0031] Embodiment 12. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3-dimercaptosuccinic acid. Mercapto-1-propanesulfonic acid (DMPS) and N-(2,3-dimercaptopropanesulfonic acid) or a metal; The chelating agent is dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propanol. Pansulfonic acid (DMPS), N-(2,3-dimercaptopropyl)-phthalamic acid (DMPA), and dexrazoxane.

[0032] Embodiment 13. The method of any one of embodiments 1 to 7, wherein the metal chelator is a dithiol chelator. Either way.

[0033] Embodiment 14. The metal chelator is deferasirox, deferiprone, or defe The method of embodiment 13, wherein the amine is loxamine.

[0034] Embodiment 15. The metal chelator is N-acetylcysteine ​​(NAC); gadolinium(III) chelators, The method of any one of embodiments 1 to 7.

[0035] Embodiment 16. Any of embodiments 1 to 7, wherein the metal chelator is a copper chelator. How to.

[0036] Embodiment 17. The copper chelator is trientine or tetrathiomolybdate. The method of embodiment 16.

[0037] Embodiment 18. Any of embodiments 1 to 7, wherein the metal chelator is dexrazoxane. Some way.

[0038] Embodiment 19. The chelated metal is arsenic (As), aluminum (Al), arsenic (Ar), Sb, barium (Ba), boron (B), cadmium (Cd), cerium (C e), Chromium (Cr), Lead (Pb), Mercury (Hg), Neodymium (Nd), Nickel ( Ni), selenium (Se), tin (Sn), titanium (Ti), uranium (U), and vanadium The method of any of embodiments 1-18, wherein the compound (V) is selected from the group consisting of:

[0039] Embodiment 20. The chelated metal is arsenic (As), antimony (Sb), boron (B), Cadmium (Cd), Lead (Pb), Mercury (Hg), Neodymium (Nd), Tin (S n), titanium (Ti), uranium (U), vanadium (V), Any of 18 methods.

[0040] Embodiment 21. The chelated metal is cadmium (Cd), lead (Pb), ammonium (Au), or ammonium phosphate. 19. The method of any of the preceding claims, wherein the cation is selected from the group consisting of antimony (Sb), arsenic (As), and arsenic (As). .

[0041] Embodiment 22. The chelated metal is antimony (Sb), cadmium (Cd), Any of embodiments 1 to 18, wherein the cation is selected from mercury (Hg), arsenic (As), and uranium (U). Either way.

[0042] Embodiment 23. The chelated metals are mercury (Hg), antimony (Sb), and lead (Pb). The method of any of the preceding embodiments, wherein the aryl group is selected from (Pb).

[0043] Embodiment 24. Any of embodiments 19 to 23, wherein two or more metals are chelated. Some way.

[0044] Embodiment 25. The antioxidant, vitamin or essential mineral is zinc, selenium, magnesium 25. The method of any of embodiments 1-24, wherein the selenium ionizing agent is selected from the group consisting of selenium, rubidium, and vitamin C; or Contains antioxidants, vitamins or essential minerals such as zinc, selenium, magnesium, rubidium, Ascorbic acid (vitamin C), α-tocopherol (vitamin E), glutathione, arachidonic acid, uric acid, carotenoids (e.g., β-carotene, lycopene), flavonoids (e.g., , quercetin), retinol, ubiquinol (coenzyme Q), taurine, N-acetylglucosamine Any of embodiments 1 to 24, wherein the ameliorantha is selected from the group consisting of ameliorantha, ... Law.

[0045] Embodiment 26. A method for the preparation of a medicament for the treatment of a disease comprising administering to the patient at least one of zinc, selenium, magnesium, rubidium, and vitamin C. 26. The method of embodiment 25, wherein one or more of the following is administered:

[0046] Embodiment 27. A method of administering at least one of zinc, selenium, magnesium, rubidium, and vitamin C to a patient having a pulmonary circulation disorder. 26. The method of embodiment 25, wherein two or more are administered.

[0047] Embodiment 28. A method comprising administering to a patient a composition comprising at least one of zinc, selenium, magnesium, rubidium, and vitamin C. 26. The method of embodiment 25, wherein three or more are administered.

[0048] Embodiment 29. At least three of zinc, selenium, magnesium, and vitamin C are administered. The method of embodiment 25,

[0049] Embodiment 30. Zinc, selenium, magnesium, rubidium, rubidium, and vitamins The method of embodiment 25, wherein C is administered.

[0050] Embodiment 31. An embodiment in which zinc, selenium, magnesium, and vitamin C are administered 25 ways.

[0051] Embodiment 32 The method of any one of embodiments 1 to 31, wherein the disease is a proliferative disease.

[0052] Embodiment 33. The disease is cancer, myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MD) S), bone marrow disease; bone marrow failure; and cytopenia.

[0053] Embodiment 34 The method of embodiment 33, wherein the disease is cancer.

[0054] Embodiment 35. An embodiment in which the cancer has recurred or is resistant to previous treatment. Method 34.

[0055] Embodiment 36 The method of embodiment 35, wherein the cancer is a hematological malignancy.

[0056] Embodiment 37 The method of embodiment 36, wherein the cancer is leukemia.

[0057] Embodiment 38. The leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia (AL), or LL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML) , The method of embodiment 37.

[0058] Embodiment 39 The method of embodiment 38, wherein the leukemia is AML.

[0059] Embodiment 40. The method of embodiment 33, wherein the disease is myelodysplastic syndrome (MDS).

[0060] Embodiment 41. The method of embodiment 33, wherein the disease is a myeloproliferative neoplasm (MPN).

[0061] Embodiment 42 The method of embodiment 33, wherein the disease is a bone marrow disease or bone marrow failure.

[0062] Embodiment 43 The method of embodiment 33, wherein the disease is cytopenia.

[0063] Embodiment 44 The method of embodiment 43, wherein the cytopenia is idiopathic cytopenia.

[0064] Embodiment 45. A method according to claim 1, further comprising administering to the subject a therapeutically effective amount of an anti-cancer therapy. The method of any one of embodiments 1, 2, and 5 to 44.

[0065] Embodiment 46. The anti-cancer therapy is chemotherapy, epigenetic therapy, immunotherapy, or targeted therapy. 46. ​​The method of any of embodiments 1-45, wherein the therapeutic agent is selected from the group consisting of targeted cancer therapies.

[0066] Embodiment 47. The method of embodiment 45, wherein the anti-cancer therapy is an anti-cancer pharmacological therapy.

[0067] Embodiment 48. The anticancer pharmacological therapy is Mylotarg, Cladribine, Idarubicin, and The method of embodiment 47, comprising one or more agents selected from cytarabine.

[0068] Embodiment 49. The anticancer pharmacological therapy is Mylotarg, Cladribine, Idarubicin, and The method of embodiment 47, comprising cytarabine ("CLIA-M").

[0069] Embodiment 50 The method of embodiment 46, wherein the anti-cancer therapy is immunotherapy.

[0070] Embodiment 51. The immunotherapy comprises a monoclonal antibody and an immune checkpoint inhibitor. The method of embodiment 50, wherein

[0071] Embodiment 52. The immunotherapy is rituximab, ofatumumab, or blinatumumab, in Notuzumab, gemtuzumab ozogamicin, ipilumumab, and PD-1 / PD-L1 The method of embodiment 50, wherein the therapeutic agent is selected from an immune checkpoint inhibitor that targets

[0072] 53. The immune checkpoint inhibitor targeting PD-1 / PD-L1 is Select from volumab, pembrolizumab, atezolizumab, avelumab, and durvalumab 53. The method of embodiment 52,

[0073] Embodiment 54 The method of embodiment 46, wherein the anti-cancer therapy is a targeted therapy.

[0074] Embodiment 55. The targeted therapy is an FLT3 inhibitor, a BCR-ABL tyrosine kinase inhibitor. agents, JAK-2 inhibitors, IDH1 or IDH2 inhibitors, BCL-2 inhibitors, and Gemtuzumab 55. The method of embodiment 54, wherein the compound is selected from mab ozogamicin.

[0075] Embodiment 56. The disease is leukemia; the cancer treatment is chemotherapy; and zinc, selenium, magnesium The method of embodiment 1, wherein all of the calcium phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate phosphate

[0076] Embodiment 57 The method of embodiment 56, wherein the leukemia is AML.

[0077] Embodiment 58. The chemotherapy comprises cladribine, idarubicin, and cytarabine ("CLI"). 58. The method of embodiment 57, comprising:

[0078] Embodiment 59. The chemotherapy comprises Mylotarg, Cladribine, Idarubicin, and Cytara. 59. The method of embodiment 58, comprising a bin ("CLIA-M").

[0079] Embodiment 60. The method of any one of embodiments 47 to 60, further comprising administering amifostine to the subject. Any of 59 methods.

[0080] Embodiment 61. The method of any one of embodiments 1 to 60, wherein the subject is a human.

[0081] Embodiment 62. A human subject comprising: a) have cancer; b) have elevated levels of one or more metals compared to healthy subjects; 62. The method of any of embodiments 61.

[0082] Embodiment 63. Elevated levels of one or more metals are measured in bone marrow or serum , The method of embodiment 62.

[0083] Embodiment 64. Elevated levels of one or more metals are measured in bone marrow and serum. , The method of embodiment 62.

[0084] Embodiment 65. The human subject has elevated levels of two or more metals. How to.

[0085] 66. The metal is arsenic (As), aluminum (Al), antimony (Sb), Barium (Ba), Boron (B), Cadmium (Cd), Cerium (Ce), Chromium (C r), lead (Pb), mercury (Hg), neodymium (Nd), nickel (Ni), tin (S n), titanium (Ti), uranium (U), and vanadium (V). Any of the methods from 62 to 65.

[0086] Embodiment 67. A human subject is taking calcium (Ca), magnesium (Mg), selenium (S e), zinc (Zn), and rubidium (Rb) The method of embodiment 62,

[0087] Embodiment 68. The elevated and / or decreased levels are relative to the median values ​​in a non-diseased population. The method of any of embodiments 64 to 66, wherein

[0088] Embodiment 69. The method comprises reducing one or more mutations or cytogenetic abnormalities in a cancer. or elimination.

[0089] Embodiment 70. A therapeutically effective amount of (i) one or more metal chelators; (ii) at least one antioxidant, vitamin, or essential mineral; The method of claim 1, further comprising administering to the subject one or more of the following to the subject: Methods for reducing or eliminating mutations or cytogenetic abnormalities:

[0090] Embodiment 71. The method of embodiment 70, further comprising administering an anti-cancer therapy to the subject. method.

[0091] Embodiment 72. A therapeutically effective amount of (i) one or more metal chelators; (ii) at least one anticancer therapy The method of claim 1, further comprising administering to the subject one or more of the following to the subject: Methods for reducing or eliminating mutations or cytogenetic abnormalities:

[0092] Embodiment 73. A method for treating a chronic condition comprising administering to a patient a therapeutically effective amount of at least one antioxidant, vitamin, and / or essential mineral. 73. The method of embodiment 72, further comprising administering to

[0093] Embodiment 74. The one or more metal chelators are broad spectrum metal chelators. The method of any one of embodiments 70 to 73, for example, wherein one or more metal chips are At least one of the chelating agents is capable of chelating at least two metals and / or one or more A method in which multiple metal chelators are capable of chelating potentially toxic / non-essential metals.

[0094] Embodiment 75. One or more metal chelators regulate the levels of at least two metals. An amount effective to reduce and / or to reduce the levels of potentially toxic / non-essential metals The method of embodiment 5, wherein the compound is administered in an effective amount.

[0095] Embodiment 76. At least two chelating agents are administered, and the chelating agents are administered simultaneously or sequentially. The method of embodiment 6, wherein

[0096] Embodiment 77. The one or more metal chelators are EDTA, dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propanesulfonic acid (DMPS), BAL, N-acetylcysteine ​​(NAC), deferasirox, deferiprone, deferoxa amine, calcium trisodium pentetate (Ca-DPTA), trientine, tetrathiophene Any of embodiments 70 to 76, wherein the compound is selected from omolybdate and dexrazoxane. How to.

[0097] Embodiment 78. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3-dimercaptosuccinic acid. Mercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropionyl Dimethyl phthalamic acid (DMPA), calcium trisodium pentetate (Ca-DTP Any of embodiments 70 to 76, wherein the compound is selected from A), and dimercaprol (BAL). How to.

[0098] Embodiment 79. The metal chelator is a dithiol chelator. Any of 6 methods.

[0099] Embodiment 80. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3-dimercaptosuccinic acid. Mercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropionyl The method of embodiment 79, wherein the phthalamic acid is selected from the group consisting of dimethylaminopropyl (DMPA);

[0100] Embodiment 81. The metal chelator is a dithiol chelator, according to any one of embodiments 70 to 7. Any of 6 methods.

[0101] Embodiment 82. The metal chelator is deferasirox, deferiprone, or defe The method of embodiment 81, wherein the amine is loxamine.

[0102] Embodiment 83. The metal chelator is N-acetylcysteine ​​(NAC); gadolinium(III) chelators, The method of any one of embodiments 70 to 76.

[0103] Embodiment 84. Any of embodiments 70 to 76, wherein the metal chelator is a copper chelator. Either way.

[0104] Embodiment 85. The copper chelator is trientine or tetrathiomolybdate. The method of embodiment 84.

[0105] Embodiment 86. Any of embodiments 70 to 76, wherein the metal chelator is dexrazoxane. Either way.

[0106] Embodiment 87. The chelated metal is arsenic (As), aluminum (Al), arsenic (Ar), Sb, barium (Ba), boron (B), cadmium (Cd), cerium (C e), Chromium (Cr), Lead (Pb), Mercury (Hg), Neodymium (Nd), Nickel ( Ni), selenium (Se), tin (Sn), titanium (Ti), uranium (U), and vanadium The method of any of embodiments 70 to 86, wherein the compound (V) is selected from the group consisting of:

[0107] Embodiment 88. The chelated metal is arsenic (As), antimony (Sb), boron (B), Cadmium (Cd), Lead (Pb), Mercury (Hg), Neodymium (Nd), Tin (S n), titanium (Ti), uranium (U), vanadium (V). ~Any of 86 methods.

[0108] Embodiment 89. The chelated metal is cadmium (Cd), lead (Pb), ammonium phosphate (Au) or ammonium phosphate (Ab). Any of embodiments 70 to 86, wherein the cation is selected from antimony (Sb), and arsenic (As). Law.

[0109] Embodiment 90. The chelated metal is antimony (Sb), cadmium (Cd), 87. The method of claim 70 to 86, wherein the cation is selected from mercury (Hg), arsenic (As), and uranium (U). Either way.

[0110] Embodiment 91. The chelated metals are mercury (Hg), antimony (Sb), and lead. The method of any of embodiments 70-86, wherein the compound is selected from (Pb).

[0111] Embodiment 92. Any of embodiments 87 to 91, wherein two or more metals are chelated. Some way.

[0112] Embodiment 93. The antioxidant, vitamin or essential mineral is zinc, selenium, magnesium , rubidium, and vitamin C; Or antioxidants, vitamins or essential minerals such as zinc, selenium, magnesium, rubidium , ascorbic acid (vitamin C), α-tocopherol (vitamin E), glutathione, Lipoic acid, uric acid, carotenoids (e.g., β-carotene, lycopene), flavonoids (e.g., For example, quercetin, retinol, ubiquinol (coenzyme Q), taurine, N-acetylglucosamine, Any of embodiments 70 to 92, wherein the anti-inflammatory agent is selected from stearate (NAC), and amifostine. How to.

[0113] Embodiment 94. A method for the preparation of a medicament for the treatment of a disease comprising administering to the patient at least one of zinc, selenium, magnesium, rubidium, and vitamin C. 94. The method of embodiment 93, wherein one or more of the following is administered:

[0114] Embodiment 95. A method for the preparation of a medicament for the treatment of a disease comprising administering to the patient at least one of zinc, selenium, magnesium, rubidium, and vitamin C. 94. The method of embodiment 93, wherein two or more are administered.

[0115] Embodiment 96. A method for treating a patient having a disease comprising administering at least one of zinc, selenium, magnesium, rubidium, and vitamin C to a patient having a disease comprising administering at least one of zinc, selenium, magnesium, rubidium, and vitamin C to a patient having a disease comprising administering at least one of said ... vitamin C to a patient having a disease. 94. The method of embodiment 93, wherein three or more are administered.

[0116] Embodiment 97. At least three of zinc, selenium, magnesium, and vitamin C are administered. The method of embodiment 93, wherein

[0117] Embodiment 98. Zinc, selenium, magnesium, rubidium, rubidium, and vitamins The method of embodiment 93, wherein C is administered.

[0118] Embodiment 99. An embodiment in which zinc, selenium, magnesium, and vitamin C are administered. 93 ways.

[0119] Embodiment 100. The method of any of embodiments 70-99, wherein the disease is a proliferative disease.

[0120] Embodiment 101. The disease is cancer, myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or DS), bone marrow disease; bone marrow failure; and cytopenia. Law.

[0121] Embodiment 102. The method of embodiment 101, wherein the disease is cancer.

[0122] Embodiment 103. The cancer is recurrent or resistant to previous treatment. Method of form 102.

[0123] Embodiment 104. The method of embodiment 103, wherein the cancer is a hematological malignancy.

[0124] Embodiment 105. The method of embodiment 104, wherein the cancer is leukemia.

[0125] Embodiment 106. The leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia (AML), and acute myeloid leukemia (AML). ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML) The method of embodiment 105.

[0126] Embodiment 107. The method of embodiment 106, wherein the leukemia is AML.

[0127] Embodiment 108. The method of embodiment 100, wherein the disease is myelodysplastic syndrome (MDS).

[0128] Embodiment 109. The method of embodiment 100, wherein the disease is a myeloproliferative neoplasm (MPN).

[0129] Embodiment 110. The method of embodiment 100, wherein the disease is a bone marrow disease or bone marrow failure.

[0130] Embodiment 111. The method of embodiment 100, wherein the disease is cytopenia.

[0131] Embodiment 112 The method of embodiment 111, wherein the cytopenia is idiopathic cytopenia.

[0132] Embodiment 113. The method further comprising administering a therapeutically effective amount of an anti-cancer therapy to the subject. The method of any one of embodiments 70, 71, and 74 to 112.

[0133] Embodiment 114. The anti-cancer therapy is chemotherapy, epigenetic therapy, immunotherapy, or The method of any of embodiments 70-113, wherein the therapeutic agent is selected from a targeted cancer therapy.

[0134] Embodiment 115. The method of embodiment 113, wherein the anti-cancer therapy is an anti-cancer pharmacological therapy.

[0135] Embodiment 116. The anticancer pharmacological therapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and and cytarabine.

[0136] Embodiment 117. The anticancer pharmacological therapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and and cytarabine ("CLIA-M").

[0137] Embodiment 118. The method of embodiment 114, wherein the anti-cancer therapy is immunotherapy.

[0138] Embodiment 119. The immunotherapy is selected from monoclonal antibodies and immune checkpoint inhibitors. The method of embodiment 118, wherein the method is selected from the group consisting of:

[0139] Embodiment 120. The immunotherapy is rituximab, ofatumumab, or blinatumumab, Inotuzumab, gemtuzumab ozogamicin, ipilumumab, and PD-1 / PD-L1 119. The method of embodiment 118, wherein the immune checkpoint inhibitor is selected from an immune checkpoint inhibitor that targets

[0140] Embodiment 121. The immune checkpoint inhibitor targeting PD-1 / PD-L1 is From nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab The method of embodiment 120, which is selected

[0141] Embodiment 122. The method of embodiment 114, wherein the anti-cancer therapy is a targeted therapy.

[0142] Embodiment 123. The targeted therapy is an FLT3 inhibitor, a BCR-ABL tyrosine kinase inhibitor. inhibitors, JAK-2 inhibitors, IDH1 or IDH2 inhibitors, BCL-2 inhibitors, and Gemtu inhibitors 123. The method of embodiment 122, wherein the anti-inflammatory agent is selected from zumab ozogamicin.

[0143] Embodiment 124. The disease is leukemia; the cancer treatment is chemotherapy; zinc, selenium, The method of embodiment 70, wherein all of the magnesium and vitamin C are administered to the subject.

[0144] Embodiment 125. The method of embodiment 124, wherein the leukemia is AML.

[0145] Embodiment 126. Chemotherapy is a combination of cladribine, idarubicin, and cytarabine ("CL IA”)).

[0146] Embodiment 127. Chemotherapy is performed using Mylotarg, Cladribine, Idarubicin, and Cytarabine. The method of embodiment 126, comprising administering to the patient a therapeutically effective amount of rabin ("CLIA-M").

[0147] Embodiment 128. The method of embodiment 11 further comprising administering amifostine to the subject. Any method from 4 to 127.

[0148] Embodiment 129. The method of any of embodiments 70 to 128, wherein the subject is a human.

[0149] Embodiment 130. A human subject comprising: a) have cancer; b) have elevated levels of one or more metals compared to healthy subjects; Any of the methods of embodiment 129.

[0150] Embodiment 131. Elevated levels of one or more metals are measured in bone marrow or serum. The method of embodiment 130.

[0151] Elevated levels of one or more metals are measured in bone marrow and serum. The method of embodiment 130.

[0152] Embodiment 133. The method of embodiment 1, in which the human subject has elevated levels of two or more metals. 30 ways.

[0153] Embodiment 134. The metal is arsenic (As), aluminum (Al), antimony (Sb) , barium (Ba), boron (B), cadmium (Cd), cerium (Ce), chromium ( Cr), lead (Pb), mercury (Hg), neodymium (Nd), nickel (Ni), tin ( Sn), titanium (Ti), uranium (U), and vanadium (V). Any of the methods listed in item 130 to 65.

[0154] Embodiment 135. A human subject is taking calcium (Ca), magnesium (Mg), selenium ( having reduced levels of at least one of the following elements: The method of embodiment 62,

[0155] Embodiment 136. The elevated and / or decreased levels are relative to the median of a non-diseased population. The method of any one of embodiments 64 to 66,

[0156] EMBODIMENT 137. i) measuring the levels of two or more metals in one or more samples of serum or bone marrow from a subject; and ii) The levels of each of two or more metals in a sample were compared with the same concentrations obtained from healthy patients. comparing to each of two or more corresponding median reference values ​​for the metal; iii) If the levels of two or more metals in the sample are higher than the median reference value, classifying the subject as having a chelation therapy responsive proliferative disorder; A method for diagnosing a subject having a chelation therapy responsive proliferative disease, comprising:

[0157] EMBODIMENT 138. i) measuring the levels of two or more metals in one or more samples of serum or bone marrow from a subject; and ii) The levels of each of two or more metals in a sample were compared with the same concentrations obtained from healthy patients. comparing to each of two or more corresponding median reference values ​​for the metal; iii) If the levels of two or more metals in the sample are higher than the median reference value, exclude the subject. classifying the subject as having a chelation therapy responsive proliferative disorder; iv) a therapeutically effective amount of (a) one or more metal chelators; (b) at least one anticancer therapy; and (b) optionally administering to the subject at least one antioxidant and / or essential mineral; Top and A method for diagnosing and treating a subject having a chelation therapy responsive proliferative disease, comprising:

[0158] EMBODIMENT 139. v) determining the levels of one or more essential minerals in one or more samples of serum or bone marrow from the subject; measuring the bell; vi) determining the respective levels of one or more essential minerals in the samples from healthy subjects; The results are compared with each of two or more corresponding median reference values ​​for the same essential mineral. Top and iii) If the level of one or more essential minerals in the sample is higher than the reference value, and classifying the elephant as having a chelation therapy responsive proliferative disorder. Any of the methods set forth in 137 to 138.

[0159] Embodiment 140. The metal is arsenic (As), aluminum (Al), antimony (Sb) , barium (Ba), boron (B), cadmium (Cd), cerium (Ce), chromium ( Cr), Lead (Pb), Mercury (Hg), Neodymium (Nd), Nickel (Ni), Selenium (Se), tin (Sn), titanium (Ti), uranium (U), and vanadium (V). The method of any one of embodiments 137 to 139, wherein

[0160] Embodiment 141. The metal is arsenic (As), antimony (Sb), boron (B), cadmium (Cd), or arsenic (As). Cd, Pb, Hg, Nd, Sn, Ti Any of embodiments 137 to 139, wherein the cation is selected from the group consisting of uranium (U), vanadium (V), and titanium (Ti). Either way.

[0161] Embodiment 142. The chelated metal is cadmium (Cd), lead (Pb), arsenic (Au), or mercury (Mg). Any of embodiments 137 to 139, wherein the cations are selected from antimony (Sb), arsenic (As), and arsenic (As). Some way.

[0162] Embodiment 143. The metal is antimony (Sb), cadmium (Cd), mercury (Hg), 139. Any of embodiments 137 to 139, wherein the arsenic (As) and uranium (U) are selected from the group consisting of arsenic (As), uranium (U), and uranium (U). method.

[0163] Embodiment 144. The metal is selected from mercury (Hg), antimony (Sb), and lead (Pb). The method of any one of embodiments 137 to 139, wherein

[0164] Embodiment 145. The essential minerals to be measured and compared are calcium (Ca), magnesium (Mg), and Mg, Selenium (Se), Zinc (Zn), and Rubidium (Rb). , any one of embodiments 137 to 144.

[0165] Embodiment 146. In one or more samples of serum or bone marrow of a subject, three, four, five Any of embodiments 137 to 145, in which one, six, seven or more metals are measured. How to.

[0166] Elevated levels of one or more metals are measured in bone marrow and serum. The method of embodiment 146,

[0167] Embodiment 148. A method for treating a chronic inflammatory condition comprising administering to a patient a composition comprising at least one antioxidant, vitamin, and / or essential mineral. The method of any of embodiments 138-147, further comprising administering to an elephant.

[0168] Embodiment 149. The one or more metal chelators are broad spectrum metal chelators. The method of any of embodiments 138 to 148, wherein at least one of the chelating agents is capable of chelating at least two metals; and / or One or more metal chelators are capable of chelating potentially toxic / non-essential metals. Law.

[0169] Embodiment 150. The one or more metal chelators are and / or an amount effective to reduce the levels of potentially toxic / non-essential metals. The method of embodiment 149, wherein an effective amount is administered.

[0170] Embodiment 151. At least two chelating agents are administered, and the chelating agents are administered simultaneously or The method of embodiment 150, wherein the compounds are administered sequentially.

[0171] Embodiment 152. The one or more metal chelators are EDTA, dimercaptosuccinic acid. Acid (DMSA), 2,3-dimercapto-1-propanesulfonic acid (DMPS), BAL , N-acetylcysteine ​​(NAC), deferasirox, deferiprone, deferoxacin Samine, Calcium Trisodium Pentetate (Ca-DPTA), Trientine, Tetra Any of embodiments 138 to 151, wherein the thiomolybdate and dexrazoxane are selected from Either way.

[0172] Embodiment 152. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3- Dimercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropanesulfonic acid) pyridinium phthalamate (DMPA), calcium trisodium pentetate (Ca-DT Any of embodiments 138 to 151, wherein the aryl ester is selected from the group consisting of aryl esters (PA) and dimercaprol (BAL). Either way.

[0173] Embodiment 153. The metal chelator is a dithiol chelator. ~One of 151 methods.

[0174] Embodiment 154. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3- Dimercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropanesulfonic acid) The method of embodiment 153, wherein the aryl phthalate is selected from the group consisting of dimethylaminopropyl (DMPA);

[0175] Embodiment 155. The metal chelator is a dithiol chelator. ~One of 151 methods.

[0176] Embodiment 156. The metal chelator is deferasirox, deferiprone, or deferasirox. The method of embodiment 155, wherein the compound is eroxamine.

[0177] Embodiment 157. The metal chelator is N-acetylcysteine ​​(NAC); gadolinium chelating agents, such as functional gadolinium(III) chelating agents. The method of any one of embodiments 138 to 151,

[0178] Embodiment 158. The method of any one of embodiments 138 to 151, wherein the metal chelator is a copper chelator. Either way.

[0179] Embodiment 159. The copper chelator is trientine or tetrathiomolybdate. , The method of embodiment 16.

[0180] Embodiment 160. The metal chelator of any of embodiments 138-15, wherein the metal chelator is dexrazoxane. Either way 1.

[0181] Embodiment 161. The chelated metal is arsenic (As), aluminum (Al), Antimony (Sb), Barium (Ba), Boron (B), Cadmium (Cd), Cerium ( Ce), Chromium (Cr), Lead (Pb), Mercury (Hg), Neodymium (Nd), Nickel (Ni), selenium (Se), tin (Sn), titanium (Ti), uranium (U), and vanadium The method of any of embodiments 138-160, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl and aryl groups.

[0182] Embodiment 162. The chelated metal is arsenic (As), antimony (Sb), boron (B), or arsenic (As). B, Cadmium (Cd), Lead (Pb), Mercury (Hg), Neodymium (Nd), Tin ( Sn), titanium (Ti), uranium (U), vanadium (V), Any of the methods from 38 to 160.

[0183] Embodiment 163. The chelated metal is cadmium (Cd), lead (Pb), arsenic (Au), or mercury (Mg). Any of embodiments 138 to 160, wherein the cations are selected from antimony (Sb), and arsenic (As). Some way.

[0184] Embodiment 164. The chelated metal is antimony (Sb), cadmium (Cd) , mercury (Hg), arsenic (As), and uranium (U). Any of 60 ways.

[0185] Embodiment 165. The chelated metal is selected from the group consisting of mercury (Hg), antimony (Sb), and 161. The method of any of embodiments 138-160, wherein the metal ion is selected from lead (Pb).

[0186] Embodiment 166. The method of any one of embodiments 138 to 165, in which two or more metals are chelated. Either way.

[0187] Embodiment 167. The administered antioxidant, vitamin or essential mineral is zinc, selenium, According to embodiments 138 to 166, the compound is selected from magnesium, rubidium, and vitamin C. or antioxidants, vitamins or essential minerals such as zinc, selenium, magnesium Calcium, rubidium, ascorbic acid (vitamin C), α-tocopherol (vitamin E) , glutathione, lipoic acid, uric acid, carotenoids (e.g., β-carotene, lycopene), Lavonoids (e.g., quercetin), retinol, ubiquinol (coenzyme Q), taurine , N-acetylcysteine ​​(NAC), and amifostine; Any of the methods from 8 to 166.

[0188] Embodiment 168. A dietary supplement containing at least zinc, selenium, magnesium, rubidium, and vitamin C. The method of embodiment 167, wherein both are administered.

[0189] Embodiment 169. A dietary supplement containing at least zinc, selenium, magnesium, rubidium, and vitamin C. The method of embodiment 167, wherein both are administered.

[0190] Embodiment 170. A dietary supplement containing at least zinc, selenium, magnesium, rubidium, and vitamin C. The method of embodiment 167, wherein all three are administered.

[0191] Embodiment 171. At least three of zinc, selenium, magnesium, and vitamin C are administered. The method of embodiment 167,

[0192] Embodiment 172. Zinc, selenium, magnesium, rubidium, rubidium, and vitamin The method of embodiment 167, wherein anti-inflammatory drug C is administered.

[0193] Embodiment 173. An embodiment in which zinc, selenium, magnesium, and vitamin C are administered. Method of attitude 167.

[0194] Embodiment 174. The method of any one of embodiments 138 to 173, wherein the disease is a proliferative disease. .

[0195] Embodiment 175. The disease is cancer, myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or DS), bone marrow disease; bone marrow failure; and cytopenia. Law.

[0196] Embodiment 176. The method of embodiment 175, wherein the disease is cancer.

[0197] Embodiment 177. Cancer is recurrent or resistant to previous treatment. Method of Form 176.

[0198] Embodiment 178. The method of embodiment 177, wherein the cancer is a hematological malignancy.

[0199] Embodiment 179. The method of embodiment 178, wherein the cancer is leukemia.

[0200] Embodiment 180. The leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia (AML), and acute myeloid leukemia (AML). ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML) The method of embodiment 179.

[0201] Embodiment 181. The method of embodiment 180, wherein the leukemia is AML.

[0202] Embodiment 182. The method of embodiment 175, wherein the disease is myelodysplastic syndrome (MDS).

[0203] Embodiment 183. The method of embodiment 175, wherein the disease is a myeloproliferative neoplasm (MPN).

[0204] Embodiment 184. The method of embodiment 175, wherein the disease is a bone marrow disease or bone marrow failure.

[0205] Embodiment 185. The method of embodiment 175, wherein the disease is cytopenia.

[0206] Embodiment 186. The method of embodiment 185, wherein the cytopenia is idiopathic cytopenia.

[0207] Embodiment 187. The anti-cancer therapy is chemotherapy, epigenetic therapy, immunotherapy, or The method of any of embodiments 138-186, wherein the therapeutic agent is selected from a targeted cancer therapy.

[0208] Embodiment 188. The method of embodiment 187, wherein the anti-cancer therapy is an anti-cancer pharmacological therapy.

[0209] Embodiment 189. The anticancer pharmacological therapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and and cytarabine.

[0210] Embodiment 190. The anticancer pharmacological therapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and and cytarabine ("CLIA-M").

[0211] Embodiment 191. The method of embodiment 187, wherein the anti-cancer therapy is immunotherapy.

[0212] Embodiment 192. The immunotherapy is selected from monoclonal antibodies and immune checkpoint inhibitors. 192. The method of embodiment 191, wherein the method is selected from the group consisting of:

[0213] Embodiment 193. The immunotherapy is rituximab, ofatumumab, or blinatumumab, Inotuzumab, gemtuzumab ozogamicin, ipilumumab, and PD-1 / PD-L1 192. The method of embodiment 191, wherein the immune checkpoint inhibitor is selected from an immune checkpoint inhibitor that targets

[0214] Embodiment 194. The immune checkpoint inhibitor targeting PD-1 / PD-L1 is From nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab The method of embodiment 193, wherein

[0215] Embodiment 195. The method of embodiment 187, wherein the anti-cancer therapy is a targeted therapy.

[0216] Embodiment 196. The targeted therapy is an FLT3 inhibitor, a BCR-ABL tyrosine kinase inhibitor. inhibitors, JAK-2 inhibitors, IDH1 or IDH2 inhibitors, BCL-2 inhibitors, and Gemtu inhibitors 196. The method of embodiment 195, wherein the anti-inflammatory agent is selected from zumab ozogamicin.

[0217] Embodiment 197. The disease is leukemia; the cancer treatment is chemotherapy; zinc, selenium, The method of embodiment 138, wherein all of the magnesium and vitamin C are administered to the subject.

[0218] Embodiment 198. The method of embodiment 197, wherein the leukemia is AML.

[0219] Embodiment 199. Chemotherapy is a combination of cladribine, idarubicin, and cytarabine ("CL 199. The method of embodiment 198, comprising:

[0220] Embodiment 200. The chemotherapy comprises Mylotarg, Cladribine, Idarubicin, and Cytarabine. 200. The method of embodiment 199, comprising administering to the patient a therapeutically effective amount of rabin ("CLIA-M").

[0221] Embodiment 201. The method of embodiment 19 further comprising administering amifostine to the subject. Any of the methods from 7 to 200.

[0222] Embodiment 202. The method of any of embodiments 138-201, wherein the subject is a human.

[0223] Embodiment 203. The method comprises: reducing one or more mutations or cytogenetic abnormalities in a cancer. The method of any one of embodiments 138 to 202, resulting in reduction or elimination.

[0224] EMBODIMENT 204. (i) one or more metal chelators; (ii) at least one antioxidant, vitamin, or essential mineral, and (iii) a pharma- ceutically acceptable excipient; 20. A pharmaceutical composition or pharmaceutical combination comprising:

[0225] Embodiment 205. The method of embodiment 204, further comprising at least one anticancer pharmacological therapy. Pharmaceutical compositions or combinations.

[0226] EMBODIMENT 206. (i) one or more metal chelators; (ii) at least one anticancer pharmacological therapy; and (iii) a pharma- ceutically acceptable excipient; 20. A pharmaceutical composition or pharmaceutical combination comprising:

[0227] Embodiment 207. The method further comprises the steps of: 207. The pharmaceutical composition or pharmaceutical combination of embodiment 206.

[0228] Embodiment 208. A metal chelate for use in a method for treating cancer in a mammalian subject. a metal ionizing agent, the method comprising administering to the subject a cancer therapy; Rate regulator.

[0229] Embodiment 209. An anti-cancer therapy for use in a method for treating cancer in a mammalian subject. wherein the method comprises administering to the subject a metal chelator.

[0230] Embodiment 210. The method comprises administering a metal chelator and / or a cancer therapy. Zinc, selenium, magnesium, rubidium and bicarbonate for use in a method for treating cancer. Antioxidants and / or minerals, preferably essential minerals, selected from vitamin C.

[0231] Embodiment 211. A metal chelator for use in a method for treating cancer in a mammalian subject. wherein the metal chelator is for administration in combination with a cancer therapy. , metal chelates.

[0232] Embodiment 212. A cancer therapy for use in a method for treating cancer in a mammalian subject. wherein the cancer therapy is for administration in combination with a metal chelator; Treatment.

[0233] Embodiment 213. Zinc, selenium, magnesium, for use in a method for treating cancer. Antioxidants and / or minerals selected from rubidium, and vitamin C, preferably The antioxidant and / or mineral is a metal chelator and / or An antioxidant and / or mineral for administration in combination with a cancer therapy.

[0234] Embodiment 214. The vitamin or mineral is zinc, selenium, magnesium, rubidium. For use according to any of the embodiments 204 to 213, wherein the medicament is selected from the group consisting of vitamin C, vitamin D, and vitamin B. Pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or methods of use or antioxidants, vitamins or essential minerals such as zinc , selenium, magnesium, rubidium, ascorbic acid (vitamin C), α-tocopherol Vitamin E, glutathione, lipoic acid, uric acid, carotenoids (e.g., β-carotene lycopene), flavonoids (e.g., quercetin), retinol, ubiquinol (coenzymes), Enzyme Q), taurine, N-acetylcysteine ​​(NAC), and amifostine The method of any one of embodiments 204 to 213,

[0235] Embodiment 215. The anti-cancer therapy is chemotherapy, epigenetic therapy, immunotherapy, or For use in any of embodiments 204 to 214, selected from targeted cancer therapy; Pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or methods of use Antioxidants and / or minerals.

[0236] Embodiment 216. For the use of embodiment 215, wherein the anti-cancer therapy is an anti-cancer pharmacological therapy. , pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or uses - Patents.com Antioxidants and / or minerals for.

[0237] Embodiment 217. The anticancer pharmacological therapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and and cytarabine, Pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or methods of use Antioxidants and / or minerals.

[0238] Embodiment 218. The anticancer pharmacological therapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and and cytarabine ("CLIA-M") or cladribine, idarubicin, and cytarabine ( The pharmaceutical compositions, pharmaceutical combinations, and methods for use in embodiment 216, including the use of chelating agents, cancer treatment methods for use, or antioxidants and / or mineral Ru.

[0239] Embodiment 219. The pharmaceutical composition of embodiment 215, wherein the anti-cancer therapy is an immunotherapy. Compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or methods for use of antioxidants and / or minerals.

[0240] Embodiment 220. The immunotherapy is selected from monoclonal antibodies and immune checkpoint inhibitors. The pharmaceutical composition, pharmaceutical combination, metal killer, etc. for use in embodiment 219, selected from the group consisting of a nutrient, a cancer treatment for use, or an antioxidant and / or mineral for use.

[0241] Embodiment 221. The immunotherapy is rituximab, ofatumumab, or blinatumomab, ibuprofen Notuzumab, gemtuzumab ozogamicin, ipilumumab, and immune checkpoint inhibitors For use of embodiment 219, the inhibitor is selected from the group consisting of PD-1 / PD-L1 targeting inhibitors. Pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or methods of use Antioxidants and / or minerals.

[0242] Embodiment 222. The immune checkpoint inhibitor targeting PD-1 / PD-L1 is From nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab The pharmaceutical compositions, pharmaceutical combinations, metal chelates, etc. for use in embodiment 220 are selected. a mitigating agent, a cancer treatment for use, or an antioxidant and / or mineral for use.

[0243] Embodiment 223. The method of claim 215, wherein the anticancer therapy is a targeted therapy. Pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or Antioxidants and / or minerals.

[0244] Embodiment 224. The targeted therapy is an FLT3 inhibitor, a BCR-ABL tyrosine kinase inhibitor. inhibitors, JAK-2 inhibitors, IDH1 or IDH2 inhibitors, BCL-2 inhibitors, and Gemtu inhibitors 223. The pharmaceutical composition, the medicine, for use in embodiment 223, selected from azumab ozogamicin. Drug combination, metal chelator, cancer therapy for use, or antioxidant for use and / or minerals.

[0245] Embodiment 225. The one or more metal chelators are broad spectrum metal chelators. For example, at least one of the one or more metal chelators is at least two The metal chelator or agents are capable of chelating metals and / or are potentially toxic / non-toxic. A pharmaceutical composition for use according to any of the embodiments 204 to 224, which is capable of chelating essential metals. Pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or Antioxidants and / or minerals.

[0246] Embodiment 226. One or more metal chelators chelating at least two metal levels and / or an amount effective to reduce the levels of potentially toxic / non-essential metals. The pharmaceutical composition, pharmaceutical combination, for use in embodiment 225, administered in an effective amount. Metal chelators, cancer treatments for use, or antioxidants and / or mineral oils for use Ral.

[0247] Embodiment 227. At least two chelating agents are administered, the chelating agents being administered simultaneously or The pharmaceutical composition, pharmaceutical combination, metal cation, and / or amine salts for use in embodiment 226, which are administered sequentially, rating agents, cancer treatments for use, or antioxidants and / or minerals for use.

[0248] Embodiment 228. The one or more metal chelators are selected from the group consisting of EDTA, dimercaptosuccinic acid, Acid (DMSA), 2,3-dimercapto-1-propanesulfonic acid (DMPS), BAL , N-acetylcysteine ​​(NAC), deferasirox, deferiprone, deferoxacin Samine, Calcium Trisodium Pentetate (Ca-DPTA), Trientine, Tetra Any of embodiments 204 to 227, wherein the thiomolybdate and dexrazoxane are selected from Pharmaceutical compositions, pharmaceutical combinations, metal chelators, and methods for use thereof Antioxidants and / or minerals for use in cancer treatment methods.

[0249] Embodiment 229. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3- Dimercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropanesulfonic acid) pyridinium phthalamate (DMPA), calcium trisodium pentetate (Ca-DT Any of embodiments 204 to 227, wherein the aryl ester is selected from aryl esters (PA) and dimercaprol (BAL). Pharmaceutical compositions, pharmaceutical combinations, metal chelators, and methods for use thereof Antioxidants and / or minerals for use in cancer treatment methods.

[0250] Embodiment 230. The metal chelator is a dithiol chelator. 227 for use in any one of pharmaceutical compositions, pharmaceutical combinations, and metal chelators. A cancer treatment for use, or an antioxidant and / or mineral for use.

[0251] Embodiment 231. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3- Dimercapto-1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropanesulfonic acid) For use of embodiment 230, the aryl phthalamic acid (DMPA) is selected from Pharmaceutical compositions, pharmaceutical combinations, metal chelators, cancer treatment methods for use, or methods of use Antioxidants and / or minerals.

[0252] Embodiment 232. The method of any of embodiments 204 to 227, wherein the metal chelator is an iron chelator. A pharmaceutical composition, a pharmaceutical combination, a metal chelator, and / or minerals for use in cancer treatment.

[0253] Embodiment 233. The metal chelator is deferasirox, deferiprone, or deferasirox. The pharmaceutical composition, pharmaceutical combination, gold, for use in embodiment 232, wherein the compound is eroxamine. chelating agents, cancer treatment methods for use, or antioxidants and / or mineral Ru.

[0254] Embodiment 234. The metal chelator is N-acetylcysteine ​​(NAC); gadolinium chelating agents, such as functional gadolinium(III) chelating agents. A pharmaceutical composition, pharmaceutical combination, or the like, for use in any one of embodiments 204 to 227. , metal chelators, cancer treatments for use, or antioxidants and / or amines for use Neral.

[0255] Embodiment 235. The method of any one of embodiments 204 to 227, wherein the metal chelator is a copper chelator. A pharmaceutical composition, a pharmaceutical combination, a metal chelator, and / or minerals for use in cancer treatment.

[0256] Embodiment 236. The copper chelator is trientine or tetrathiomolybdate. The pharmaceutical composition, pharmaceutical combination, metal chelator, use of embodiment 235 or for use as a cancer treatment, or as an antioxidant and / or mineral.

[0257] Embodiment 237. The metal chelator is dexrazoxane. 7. A pharmaceutical composition, a pharmaceutical combination, a metal chelator, and a method of use thereof or antioxidants and / or minerals for use in cancer treatments.

[0258] Embodiment 238. The pharmaceutical composition or pharmaceutical combination is for oral, subcutaneous, or intravenous administration. The pharmaceutical composition of any one of embodiments 204 to 207 and 214 to 237, Pharmaceutical compositions, pharmaceutical combinations.

[0259] Embodiment 239. The pharmaceutical composition or combination is formulated for oral administration. The pharmaceutical composition or pharmaceutical combination of embodiment 238.

[0260] Embodiment 240. The pharmaceutical composition or combination is formulated for subcutaneous administration. The pharmaceutical composition or pharmaceutical combination of embodiment 238.

[0261] Embodiment 241. The pharmaceutical composition or pharmaceutical combination is formulated for intravenous administration. The pharmaceutical composition or pharmaceutical combination of embodiment 238.

[0262] The following embodiments are also provided:

[0263] Embodiment P1. A therapeutically effective amount of (i) metal chelators; (ii) is a chemotherapy, epigenetic therapy, immunotherapy, or targeted cancer therapy, Cancer treatment; and (iii) at least one of zinc, selenium, magnesium, and / or vitamin C; Preferably at least two, more preferably at least three, and even more preferably all 1. A method of treating a disease in a mammalian subject, comprising administering to the subject The method, wherein the disease is preferably cancer.

[0264] Embodiment P2. When the chelating agent is dexrazoxane, the method further comprises adding a second metal chelator. The method of embodiment P1, comprising administering to the subject a toning agent.

[0265] Embodiment P3. The method of embodiment P1, wherein the cancer is leukemia or a hematological malignancy.

[0266] Embodiment P3. The leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia (AL), LL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). The method of embodiment P3.

[0267] Embodiment P4. The method of embodiment P4, wherein the subject has myelodysplastic syndrome (MDS).

[0268] Embodiment P5. The cancer has recurred or is resistant to previous treatment. Method of state P4.

[0269] Embodiment P6. The metal chelator is a dithiol chelator, preferably a dimercapto Tosuccinic acid (DMSA), 2,3-dimercapto-1-propanesulfonic acid (DMPS) , N-(2,3-dimercaptopropyl)-phthalamic acid (DMPA), Method of state P1.

[0270] Embodiment P7. The chelating agent is dimercaptosuccinic acid (DMSA), 2,3-dimer DMPS, N-(2,3-Dimercaptopropyl) -D-phthalamic acid (DMPA), calcium trisodium pentetate (Ca-DTPA) The method of embodiment P1, wherein the glycerol is glycerol, or dimercaprol (BAL).

[0271] Embodiment P8. The method comprises the steps of: -1-propanesulfonic acid (DMPS) to a subject. Method of state P8.

[0272] Embodiment P9. The metal chelator is calcium-EDTA (Ca-EDTA) or The method of embodiment P1, wherein the EDTA is calcium disodium EDTA.

[0273] Embodiment P10. The method of embodiment P10, wherein the metal chelator is an iron chelator.

[0274] Embodiment P11. The metal chelator is deferasirox, deferiprone, or deferasirox. The method of embodiment P11, wherein the compound is eroxamine.

[0275] Embodiment P12. The metal chelator is N-acetylcysteine ​​(NAC); or a bifunctional Gadolinium chelators, such as functional gadolinium(III) chelators. Method of form P1.

[0276] Embodiment P13. The method of embodiment P1 wherein the metal chelator is a copper chelator.

[0277] Embodiment P14. The copper chelator is trientine or tetrathiomolybdate , The method of embodiment P14.

[0278] Embodiment P15. The method of embodiment P1 wherein the metal chelator is dexrazoxane.

[0279] Embodiment P16. The method comprises administering to the subject a therapeutically effective amount of dexrazoxane. The method of any one of embodiments P1 to P15, further comprising:

[0280] Embodiment P17. The method further comprises administering to the subject a therapeutically effective amount of amifostine. The method of any one of embodiments P1 to P15, comprising:

[0281] Embodiment P18. The method comprises administering to a subject zinc, selenium, magnesium, and vitamin C. The method of embodiment P17, comprising the step of:

[0282] Embodiment P19. The method comprises administering to a subject zinc, selenium, magnesium, and vitamin C. The method of any one of embodiments P1 to P16, comprising the step of:

[0283] Embodiment P20. Any one of embodiments P1 to P16, in which the cancer treatment method is chemotherapy. There are two ways.

[0284] Embodiment P21. The chemotherapy is Mylotarg, Cladribine, Idarubicin, or Cyta The method of embodiment P21, wherein the rabin is rabin.

[0285] Embodiment P22. The chemotherapy comprises Mylotarg, Cladribine, Idarubicin, and Cytarabine. The method of embodiment P22, wherein the RAVIN (CLIA-M) is

[0286] Embodiment P23. The method further comprises administering amifostine to the subject. Method of form P21.

[0287] Embodiment P24. The cancer is leukemia, preferably AML; and the cancer therapy is chemotherapy. In an embodiment, zinc, selenium, magnesium, and vitamin C are all administered to the subject. P1 method.

[0288] Embodiment P25. The chemotherapy comprises anthracycline, Berlin-Frankfurt-Munich Benign pulmonary (BFM) chemotherapy, (cyclophosphamide, vincristine, doxorubicin Hyper-CVAD chemotherapy including cyclosporine, cyclosporine, and dexamethasone; hypomethylation therapy (e.g., dexamethasone); cytabine or azacitidine), cytarabine, clofarabine, or cladribine; The method of embodiment P25.

[0289] Embodiment P26. The method of embodiment P1, wherein the cancer therapy is immunotherapy.

[0290] Embodiment P27. The immunotherapy is a monoclonal antibody or an immune checkpoint inhibitor. The method of embodiment P27.

[0291] Embodiment P28. The immunotherapy is rituximab, ofatumumab, or blinatumomab, Inotuzumab, gemtuzumab ozogamicin, nivolumab, ipilumumab, or PD-1 / The method of embodiment P27, wherein the therapeutic agent is an immune checkpoint inhibitor that targets PD-L1.

[0292] Embodiment P29. The method of embodiment P1, wherein the cancer therapy is a targeted therapy.

[0293] Embodiment P30. The targeted therapy is an FLT3 inhibitor, a BCR-ABL tyrosine kinase inhibitor. inhibitors, JAK-2 inhibitors, IDH1 or IDH2 inhibitors, gemtuzumab ozogamicin The method of embodiment P30.

[0294] Embodiment P31. The method of any one of embodiments P1-P16, wherein the subject is a human.

[0295] Embodiment P32. The method comprises: reducing one or more mutations or cytogenetic abnormalities in a cancer. The method of any one of embodiments P1 to P32, resulting in a reduction or elimination.

[0296] Embodiment P33. (i) a metal chelator and (ii) zinc, selenium, magnesium, and / or vitamin C, more preferably at least two, even more preferably at least three Preferably all of the above, and a pharmaceutical composition comprising a pharma- ceutically acceptable excipient.

[0297] Embodiment P34. The metal chelator is dimercaptosuccinic acid (DMSA), 2,3- Dimercapto-1-propanesulfonic acid (DMPS), dimercaprol (BAL), Calcium-EDTA (Ca-EDTA), Calcium trisodium pentetate (Ca-D TPA), N-(2,3-dimercaptopropyl)-phthalamic acid (DMPA), or The pharmaceutical composition of embodiment P34, which is calcium disodium EDTA.

[0298] Embodiment P35. The pharmaceutical composition is formulated for oral or intravenous administration. The pharmaceutical composition according to any one of forms P34 to P35.

[0299] I. Combination Therapies and Methods A. Metal Chelators The methods and compositions of the present invention include broad spectrum metal chelators or specific metal chelators. The composition may include one or more metal chelators, such as calcium ethylenediamine tetraacetate. acetic acid (EDTA), dithiol chelators, iron chelators, and copper chelators. Metal chelation methods known in the art, including but not limited to: When two or more metal chelators are administered to a subject, The additives may be co-administered simultaneously (e.g., in a single formulation or in separate formulations); Or they may be administered sequentially (eg, in a single formulation or in separate formulations).

[0300] Metal chelators are used to treat acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and ), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and other leukemias; bone marrow Dysplastic syndromes (MDS); myeloproliferative neoplasms (MPN); bone marrow disorders; bone marrow failure; and Proliferative diseases, including cancer, selected from cytopenias (including idiopathic cytopenias) and the like may be administered to treat the diseases disclosed herein. Examples of leukemia include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CRL). Cancers such as chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML) Therapy may be administered for the treatment of leukemia, including induction or consolidation therapy and / or maintenance therapy. Treatment may be administered during the course of treatment for a myeloproliferative neoplasm or aplastic anemia. It may be administered in

[0301] EDTA, such as calcium EDTA or calcium disodium EDTA, is used to remove It is a broad spectrum chelating agent that can remove heavy metals and minerals. EDTA (e.g. , calcium EDTA) may be administered intravenously. Ca-EDTA is usually administered in the form of normal saline. 1g / m in water 2 or may be administered in other multiple doses as described above. (Calcium disodium versenate, 2013). Calcium ED The dose of TA is approximately 1 g / m2, 2 g / m2 2 , 3g / m 2 , 4g / m 2 , or 5 g / m 2 N Which is about 0.5g / m 2 ~about 5g / m 2 , preferably about 1 g / m 2 It may be. Umium EDTA may be administered in saline.

[0302] Metal chelators include, for example, dimercaptosuccinic acid (DMSA; also known as succiner). (which have been reported) and / or 2,3-dimercapto-1-propanesulfonic acid (DMPS) Any dithiol chelator may be used. Oral D administered at about 30 mg / kg / day MSA may provide an effective antidote for lead poisoning; however, wide inter- and intra-individual variability is present in its use. (Bradberry et al., 2009; Package Insert DMPS-DMSA is administered at a dose of approximately 200-400 mg per day depending on the clinical situation. g of DMPS (Bose-O'Rei lly et al., 2003). DMSA is approximately 10 mg / kg / day and 20 mg / kg / day. g / day, 30 mg / kg / day, 40 mg / kg / day, or 50 mg / kg / day It may be administered orally at a dose of preferably about 30 mg / kg / day, such as 50 mg / kg / day. DMPS is about 200mg / day, 250mg / day, 300mg / day, 350mg / day, or Dimercapto may be administered orally at a dose of 200 to 400 mg / day, such as 400 mg / day. The roll (also known as the British Anti-Lewisite or BAL) is It is an organic dithiol compound (Flora and Pachauri, 2010).

[0303] BAL is usually administered by deep intramuscular injection. BAL is administered as follows: 2.5 mg / kg body weight 4 times daily for 2 days, then 2 times on the 3rd day, and then for 10 days. once daily (FDA, Dimercaprol Injection). Alternatively, BAL should be administered at 3 mg / kg. may be administered every 4 hours for 2 days, 4 times on the third day, then twice daily for 10 days. Alternatively, BAL may be administered at 5 mg / kg initially, followed by 10 mg / kg for 10 days. BAL may also be administered as follows: May be administered as a single dose of 4 mg / kg body weight followed by edema at 4-hour intervals. Calcium disodium acetate injection USP (administered at a separate site) After the initial administration, the dose may be reduced to 3 mg / kg. In one embodiment, the treatment is This is maintained for 2-7 days depending on efficacy.

[0304] Any iron chelator may be used in the methods and compositions of the present invention. Exemplary Iron Chelates Antioxidants include, but are not limited to, deferasirox (Exjade; Jadenu), deferiprone (Ferriprox), and deferoxamine (De Deferasirox or dexrazoxane is approximately 10 mg / kg / day, 20mg / kg / day, 30mg / kg / day, 40mg / kg / day, or 50mg g / kg / day, such as 10 to 50 mg / kg / day, preferably about 20 to 40 mg / kg / day Deferiprone may be administered at an exemplary dose of 20 to 90 mg / kg. It may be administered (e.g., orally) at an exemplary dose of 0-100 mg / kg. Infusion of oxamine may be administered at an exemplary dose of 1-2 g for up to 5-7 days, or by overnight infusion. The iron chelator may be administered subcutaneously, intravenously, or intramuscularly. Some chelating agents may be administered orally.

[0305] Another exemplary metal chelator that may be used in the methods and compositions of the present invention is N-acetylglutamate. Cetyl-cysteine ​​(NAC). NAC may be administered intravenously or orally. The recommended intravenous dose is about 100 to 300 mg / mL, especially 200 mg / mL. Exemplary oral doses of NAC are, for example, 500 mg, 600 mg, or 700 mg. For example, the tablets may contain 250-1000 mg tablets, such as one tablet per day. In certain embodiments, they may be administered once or twice daily. NAC may be administered both intravenously and orally.

[0306] Gadolinium chelators may be used in the methods of the invention. For example, some In embodiments, a bifunctional gadolinium(III) chelator may be administered to a subject. (e.g., Frullano, 2011).

[0307] Calcium trisodium pentetate (Ca-DTPA) and zinc trisodium pentetate Ca-(Zn-DTPA) is a chelating agent that may be used in the methods of the present invention. DTPA contains the sodium salt of calcium diethylenetriaminepentaacetate. Also known as calcium trisodium thiamine pentaacetate. Ca-DTPA and Zn-DPTA can be administered intravenously (by slow IV or infusion) or via inhalation. In addition, the same doses and dose schedules as for Ca-DTPA are used for Zn-DTPA. For chelation therapy, they used 1 g in 100-250 cc of D5W or NS for 30 min. or 5 cc of 5% dextrose in water (D5W) or 0.9% sodium chloride as a slow intravenous infusion of 1 g over 3-4 minutes in thorium (normal saline, NS) or Absorption of 1 g of sterile water or NS diluted 1:1 through the riser for 15-20 min. The drug may be administered either as an infusion or as a bolus.

[0308] Copper chelators that may be used in the methods of the present invention include trientine (Sypri ne), tetrathiomolybdate, and dexrazoxane. Trientine is administered at an exemplary dose of 750 to 1250 mg / day. It may be administered two, three, or four times daily. It may be administered orally, for example in 0 mg or 500 mg tablets. Dosage adjustments will be made as necessary. The serum ceruloplasmin level may be maintained at 5 to 15 mg / dL. Molybdate is administered in divided doses, such as 4 divided doses, in doses of 100-200 mg, such as 180 mg. Exemplary doses may be administered and adjusted to maintain copper levels between 5-15 mg / dL. Dexrazoxane may be administered in combination with an anthracycline. Dexrazoxane (Totect; Savene) has a maximum daily dose of 1000-2 000 mg / m2, at an exemplary intravenous dose of 500-1000 mg / m2. It is possible.

[0309] B. Antioxidants, Minerals, and Vitamins Many embodiments herein are administered in combination with anti-cancer therapies and / or chelating agents. The antioxidants, vitamins, and / or essential minerals that are bioactive include: Antioxidant vitamins include certain compounds that are also classified as vitamins. These include scorbic acid (vitamin C) and α-tocopherol (vitamin E). Other antioxidant compounds include glutathione, lipoic acid, uric acid, and carotenoids (e.g., β -Carotene, lycopene), flavonoids (e.g., quercetin), retinol, ubiquitin coenzyme Q, taurine, N-acetylcysteine ​​(NAC), and amifostine Antioxidants Antioxidants may be generally hydrophilic or generally lipophilic; In embodiments, either one may be appropriate.

[0310] Essential minerals are those minerals that the body needs for proper functioning. They are i) Many minerals such as sodium, chloride, potassium, calcium, phosphorus, magnesium, and sulfur and iron, zinc, iodine, selenium, copper, manganese, fluoride, and molybdenum. In certain embodiments, the microminerals may be classified as: Essential minerals include zinc, selenium, magnesium, calcium, rubidium, and copper. One such subset of minerals may include zinc, selenium, magnesium, a further subset includes zinc, selenium, magnesium, Sium, and calcium.

[0311] In some embodiments, the vitamins zinc, selenium, magnesium, and / or vitamin C are At least one, more preferably two, more preferably three, of the following: amines and minerals; More preferably, all are administered to the subject; preferably, these compounds are The subject is administered the compound in combination with an additional anti-cancer therapy, such as that described in US Pat. Examples of ranges of dosages and forms of zinc, selenium, magnesium, and vitamin C that may be used include: Examples of supplements that may be included include, but are not limited to, zinc (e.g., 25 to 75 mg, e.g., 50 mg) zinc sulfate, zinc citrate, or zinc glycinate) , vitamin C (e.g., orally or intravenously, 1000 mg to 50 grams), malate Magnesium (e.g., orally or intravenously, 3 g of magnesium sulfate IV, 100 mg g to 3 g), and selenium (e.g., 100 to 200 μg orally daily) onin or equivalent).

[0312] In some embodiments, zinc, selenium, magnesium, rubidium, and / or vitamin All of the vitamins and minerals in Vitamin C are administered to the subject; preferably, these compounds are , is administered to the subject in combination with an additional anti-cancer therapy as described herein.

[0313] C.Treatment Certain embodiments of the present disclosure use metal chelators to treat cancers such as leukemia and other cancers. The present invention provides a method for treating and / or preventing a disease comprising administering to a patient a metal chelator comprising the steps of: or in combination with antioxidants, minerals, vitamins, and / or free radical scavengers. Additional combination therapies include chemotherapy, immunotherapy, and targeted therapy. Can be obtained.

[0314] The method of treating cancer includes administering metal chelation during treatment, either as a maintenance therapy or as cancer prevention. administration of antioxidants, antioxidants, minerals, vitamins, free radical scavengers, and / or chemotherapy In some embodiments, magnesium, selenium, zinc, and and trace mineral supplements such as vitamin C are useful during cancer treatment, cancer maintenance therapy, or disease prevention. It may be administered for the following reasons.

[0315] Metal chelation therapy may be used to detoxify healthy subjects for the maintenance of health. Rate therapy includes antioxidants, minerals, vitamins, and free radical scavengers for rebalancing. It may be combined with an agent.

[0316] The chelating agents disclosed herein may be used alone or in combination with an anti- The chiral agent may be administered to a subject in combination with an oxidant, vitamin, and / or mineral. These are examples of agonists and antagonists. They may be administered simultaneously or sequentially. In some embodiments, One or more of the following chelating agents: The antioxidants are preferably combined with antioxidants / minerals, vitamins, and additional cancer therapies. (e.g. chemotherapy / epigenetic changes during cancer treatment, cancer maintenance therapy, or cancer prevention therapy) Chelating agents + antioxidants / minerals / The vitamin combination may include one or more chelating agents, cancer treatment, During cancer maintenance therapy or prevention, chemotherapy / epigenetic therapy / immunotherapy / targeted therapy These chelating agents may be utilized in the presence or absence of therapy. or schedules, including, but not limited to, may be administered.

[0317] Calcium-EDTA (Ca-EDTA): used for broad spectrum chelation As an example, Ca-EDTA can be used at 1 g / m2 in saline or as described above. Other doses may be administered as described below (Calcium disodium v ersenate, 2013).

[0318] DMSA and / or DMPS: As an example, oral D administered at about 30 mg / kg / day MSA may provide an effective antidote to lead poisoning; however, there is wide inter- and intra-individual variability. The movement can be used (Bradberry et al., 2009; Package I DMPS-DMSA is administered at doses of approximately 200-400 mg / day, depending on the clinical situation. It may be used alternately with or substituted for DMPS at an exemplary dose of 0.100 mg (Bos e-O'Reilly et al., 2003).

[0319] In some embodiments, the iron chelator is administered to a patient, for example, as follows: .

[0320] Deferasirox: May be administered at a dose of 20-40 mg / kg per day. Deferiprone can be administered orally daily at doses of approximately 40-90 mg / kg. Good (Cermak et al., 2011; Cermak et al., 2013 Deferoxamine can be administered subcutaneously (sc), intravenously (iv), or intramuscularly (im .) at a dose of about 1-2 g for up to about 5-7 days, or sc. If administered intravenously, it may be infused sc overnight (sc may be administered 5-7 times a week). Dexrazoxane is an anthracycline (e.g., idarucizumab) that is administered intravenously. It may be combined with bicine to prevent cardiotoxicity during the induction and consolidation phases of treatment. Or in the case of adult leukemia, dexrazoxane is combined with idarubicin for cardioprotection. may be used (Vachhani et al., 2017; Schloemer et al. al.,2017;Walker et al.,2013;Woodlock et al. al., 1998). Dexrazoxane also acts as an antioxidant / mineral / vitamin and Administered with a maintenance phase of treatment with a low-dose anthracycline (e.g., idarubicin). Dexrazoxane may be administered with idarubicin as follows or as prescribed by package insert: It is administered according to the instructions (Dexrazoxane, 2014). It is administered together with idarubicin. When administered daily, dexrazoxane may be administered with idarubicin as follows: Surazoxane was administered in a 50:1 dexrazoxane:idarubicin ratio (e.g., idarubicin Dose 10mg / m 2 500 mg / m 2 ) IV 30 minutes before idarubicin administration It can be administered.

[0321] N-acetyl-cysteine: N-acetyl-cysteine ​​(NAC) is, for example, about 20 Acetadote can be administered intravenously at a dose of 0 mg / mL. N-acetyl-cysteine, for example, on days when patients did not receive intravenous NAC, NAC may be administered orally in a dosage of about 600 mg tablets twice daily.

[0322] In some embodiments, the copper chelator is administered to a patient, for example, as follows: .

[0323] Trientine: Daily dose of trientine is preferably adjusted based on clinical response or toxicity. (Fu et al., 2012). If free serum copper is persistently above 15 μg / mL, If symptoms persist, the dose may need to be increased (Prod Info Syprine (Registered Trademark, 1998). Maintenance doses may be weekly initially, then at 1-3 month intervals, or as determined by a physician. For example, oral trientine should be administered at approximately 50 mg once daily. 0 mg four times a day (two with meals and two without meals) and may be administered as needed. Dose adjusted accordingly to maintain serum ceruloplasmin levels between 5 and 15 mg / dL .

[0324] Trientine should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal, and after all medications. (Prod Info Syprine®, 1998). The capsules must be swallowed whole with water and are usually not opened or chewed. It should not be.

[0325] Tetrathiomolybdate (TM): Initial TM administration is recommended for copper levels between 5 and 15 mg / dL. The daily dose of TM may be approximately 180 mg in 4 divided doses until the blood sugar level drops to the target range (Ch Once copper levels are within the target range of 5-15 mg / dL, Patients are switched to a lower dose of TM, 100 mg daily in divided doses.

[0326] Amifostine: Amifostine is a cytoprotective adjuvant that may be administered in cancer treatment. Amifostine is used to treat bone marrow disorders, bone marrow failure, myeloproliferative neoplasms, MDA and / or chemotherapy for MPN, AML, or ALL (in a particular embodiment, AML or ALL) It is administered before the act, during low or high intensity regiments, and to prevent toxicity. Toxicity (e.g., mucositis, organ toxicity) is prevented during the maintenance phase if necessary to prevent This may also be the case.

[0327] Repurposed uses of amifostine include, but are not limited to, the treatment of cancer and leukemia. Free radical scavenging therapy with amifostine as prophylaxis; as maintenance therapy for cancer / leukemia or free radical scavenging therapy with amifostine for the treatment and prevention of chronic diseases Free radical scavenging therapy with amifostine may be included. Up to 1300 mg / m 2 may be administered about 15-30 minutes prior to chemotherapy or without chemotherapy.

[0328] The metal chelators may be used alone or in combination with antioxidants, minerals, and / or vitamins. Other conditions that may also be treated include, but are not limited to, diabetes Cardiovascular diseases (e.g., Parkinson's disease and Alzheimer's disease), blood disorders (e.g., aplastic anemia) anemia and myeloproliferative neoplasms), autoimmune / rheumatic diseases (e.g., rheumatoid arthritis) and systemic lupus erythematosus (SLE), infectious diseases (e.g. fungal infections ), renal disease (e.g., renal dysfunction, acute tubular necrosis, and acute renal failure), immune disease (immune deficiency), psychiatric disorders, ADHD, autism, musculoskeletal disorders, skin disorders, eye disorders (e.g. macular degeneration), liver disorders These include chronic conditions (e.g., hepatic steatosis), and gastrointestinal disorders.

[0329] In another embodiment, the treatment of prevention of osteoporosis tion}, the method comprising adding metal chelators, antioxidants, minerals, vitamins, and / or or by administering a free radical scavenger.

[0330] Further embodiments provide for the analysis of metallomic profiles by molecular, genomic, proteomic, and The subject is a healthy patient, Patients seeking medical care, including those with cancer and leukemia, and those with acute and chronic diseases During the medical evaluation of patients with The subject may be administered a dietary supplement to improve nutritional status, microbiome, and metabolism during cancer treatment or for disease prevention. Panel on dietary status, trace mineral status, and / or oxidative stress status / antioxidant status Subjects may be evaluated for cancer treatment or general medical follow-up (e.g., risk assessment). Environmental exposures (including metal levels) may be monitored during the assessment process (for risk assessment). toxic chemicals, such as counseling on eliminating mattresses that contain toxic chemicals Interventions may be undertaken in the presence of such exposure.

[0331] The methods described herein are useful for treating cancer. The term "cancer" refers to a disease in mammals that is typically characterized by uncontrolled cell proliferation. More specifically, the term refers to or describes a physiological state associated with the methods provided herein. Cancers that may be treated in conjunction with other cancers include, but are not limited to, solid tumors, hematological In certain embodiments, the cancer may be a primary malignancy, a metastatic cancer, or a non-metastatic cancer. , lungs, kidneys, bladder, blood, bones, bone marrow, brain, breast, colon, esophagus, duodenum, small intestine, large intestine, Intestines, rectum, anus, gums, head, liver, nasopharynx, neck, ovaries, pancreas, prostate, skin, stomach, semen It may occur in the nest, tongue, or uterus.

[0332] The cancer or related condition may specifically be of the following histological types, but is not limited to: i:malignant neoplasm;carcinoma;non-small cell lung cancer;kidney cancer;renal cell carcinoma;renal clear cell carcinoma; Lymphoma;blastoma;sarcoma;anaplastic carcinoma;meningioma;brain cancer;oropharyngeal cancer;nasopharyngeal cancer; Bile duct cancer; pheochromocytoma; islet cell carcinoma; Li-Fraumeni tumor; thyroid cancer; parathyroid pituitary tumor; adrenal tumor; osteogenic sarcoma tumor; neuroendocrine tumor; breast cancer; lung cancer; head and neck Neck cancer; Prostate cancer; Esophageal cancer; Tracheal cancer; Liver cancer; Bladder cancer; Stomach cancer; Pancreatic cancer; Egg uterine cancer;cervical cancer;testicular cancer;colon cancer;rectal cancer;skin cancer;giant cell and Spindle cell carcinoma;Small cell carcinoma;Small cell lung cancer;Papillary carcinoma;Oral cavity cancer;Oropharyngeal cancer; Nasopharyngeal cancer; Respiratory cancer; Genitourinary cancer; Squamous cell carcinoma; Lymphoepithelial carcinoma; Basal cell carcinoma;calcifying epithelial carcinoma;transitional cell carcinoma;papillary transitional cell carcinoma;adenocarcinoma;stomach Intestinal cancer; malignant gastrinoma; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; Trabecular adenocarcinoma; Adenoid cystic carcinoma; Adenocarcinoma in carcinomatous polyps; Adenocarcinoma, familial colorectal adenocarcinoma pulmonary tumor; solid carcinoma; malignant carcinoid tumor; branching duct alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe Cancer;Esinophilic carcinoma;Acinophilic adenocarcinoma;Basophilic carcinoma;Clear cell adenocarcinoma;Granular cell carcinoma ;Follicular adenocarcinoma;Papillary and follicular adenocarcinoma;Non-encapsulated sclerosing carcinoma;Adrenal cortical carcinoma;Endoplasmic renal cell carcinoma Endometroid carcinoma; skin adnexal carcinoma; apocrine gland carcinoma; sebaceous gland ear canal adenocarcinoma;mucoepidermoid tumor;cystadenocarcinoma;papillary cystadenocarcinoma;papillary serous cystadenocarcinoma carcinoma;mucinous cystadenocarcinoma;mucinous adenocarcinoma;signet ring cell carcinoma;invasive ductal carcinoma;medullary carcinoma ;lobular carcinoma;inflammatory carcinoma;Paget's disease of the breast;acinic cell carcinoma;adenosquamous carcinoma;squamous Adenocarcinoma with squamous metaplasia;Malignant thymoma;Malignant ovarian stromal tumor;Malignant theca tumor;Malignant granulosa cell Tumor; Malignant androblastoma; Sertoli cell carcinoma; Malignant Leydig cell tumor; Malignant Lipid cell tumor; Malignant paraganglioma; Malignant extramammary paraganglioma; Pheochromocytoma; Hemangiosarcoma ;Malignant melanoma;Amelanotic melanoma;Superficial diffuse melanoma;Malignant melanoma in giant pigmented nevus; Lentigo maligna melanoma; Acral lentigo melanoma; Nodular melanoma; Epithelioid cell melanoma; Malignant blue nevus ;Sarcoma;Fibrosarcoma;Malignant fibrous histiocytoma;Myxosarcoma;Liposarcoma;Leiomyosarcoma;Rhabdomyosarcoma ;embryonal rhabdomyosarcoma;alveolar rhabdomyosarcoma;stromal sarcoma;malignant mixed tumor;Mullerian mixed tumor; Nephroblastoma; Hepatoblastoma; Carcinosarcoma; Malignant mesenchymal tumor; Malignant Brenner tumor; Malignant phyllodes tumor tumor; synovial sarcoma; malignant mesothelioma; dysgerminoma; embryonal carcinoma; malignant teratoma; malignant ovarian thyroid Adenoma;choriocarcinoma;malignant mesonephroma;angiosarcoma;malignant hemangioendothelioma;Kaposi's sarcoma;malignant hemangiopericytoma Lymphangiosarcoma; Osteosarcoma; Parosteal osteosarcoma; Chondrosarcoma; Malignant chondroblastoma; Mesenchymal chondrosarcoma tumor; giant cell tumor of bone; Ewing's sarcoma; malignant odontogenic tumor; ameloblastic odontosarcoma; malignant enamel ameloblastoma;ameloblastic fibrosarcoma;endocrine or neuroendocrine or hematopoietic carcinoma;malignant Pinealoma; Chordoma; Central or peripheral nervous system tissue cancer; Malignant glioma; Ependymoma; Astrocytoma tumor; plasmid astrocytoma; fibrous astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; Oligodendroglioblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma Cell tumor; Olfactory nerve tumor; Malignant meningioma; Neurofibrosarcoma; Malignant schwannoma; Malignant granular cell tumor; B cell tumor Follicular lymphoma; Malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; Low-grade / follicular non-Hodgkin's Lymphoma; granulomatous; malignant lymphoma, small lymphocytic; malignant lymphoma, diffuse large cell; ;follicular lymphoma;mycosis fungoides;mantle cell lymphoma;Waldenström lymphoma globulinemia;other specified non-Hodgkin's lymphoma;malignant histiocytosis;multiple myeloma; Mast cell sarcoma; Immunoproliferative small intestinal disease; Leukemia; Lymphoid leukemia; Plasma cell leukemia; Erythroleukemia lymphosarcoma; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia Hematologic malignancies; Mast cell leukemia; Megakaryoblastic leukemia; Myeloid sarcoma; Chronic lymphocytic leukemia (CLL) ;acute lymphoblastic leukemia (ALL);hairy cell leukemia;chronic myeloblastic leukemia;hereditary Breast and ovarian cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome, Sézary syndrome and other cutaneous lymphomas, and hereditary (equivalently, familial or genetic) including Lynch syndrome. myelodysplastic syndrome; and / or myeloproliferative neoplasms Organism.

[0333] Additional hematological malignancies that may be treated include, but are not limited to, , multiple myeloma; acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Acute myeloid leukemia (CML), chronic myeloid leukemia (CML), and large granular lymphocytic leukemia acute and chronic leukemias, including myelofibrosis (MF, primary and secondary) Myeloproliferative disorders, including polycythemia vera (PV), and essential thrombocytopenia (ET) Myelodysplastic syndromes (MDS); MDS / MPN; Hodgkin lymphoma and lymphomas, including non-Hodgkin's lymphoma (low, intermediate, and high grade).

[0334] Regarding the treatment of neoplastic conditions (e.g., cancer), depending on the stage of the neoplastic condition, Treatment of the condition involves one or a combination of the following therapies: surgery to remove the tumorous tissue; Radiation therapy, and chemotherapy. The administration of anticancer drugs includes, for example, therapeutic compositions and chemotherapeutic agents. It may be combined with any other therapeutic regimen. For example, treatment with such anti-cancer agents The treated patient may also undergo radiation therapy and / or surgery.

[0335] In the case of non-small cell lung cancer, patients may undergo surgery to remove cancerous tissue. The surgery may be a pneumonectomy, lobectomy, segmentectomy, wedge resection, or sleeve resection. stomach.

[0336] The patient may also receive radiation therapy, such as external beam radiation therapy or brachytherapy. radiofrequency ablation, which uses high-energy radio waves to heat tumors and destroy cancer cells You may accept it.

[0337] The patient may be treated with pharmacological or biological anti-cancer therapy. These include cytotoxic therapy, hormonal therapy, and targeted therapy.

[0338] Non-limiting examples of anti-cancer therapeutic agents include: 1) Inhibition of proteins involved in one or more of the following DNA damage repair (DDR) pathways: Adverse Agents or Regulators: a. Including, but not limited to, olaparib, niraparib, and rucaparib not PARP1 / 2; b.UCN-01, AZD7762, PF477736, SCH900776, MK-8 776, LY2603618, V158411, and EXEL-9844 but not limited to checkpoint kinase 1 (CHK1); c.PV1019, NSC109555, and VRX0466617, among others. including but not limited to checkpoint kinase 2 (CHK2); d.XL-844, AZD7762, and PF-473336, among others. Not limited to dual CHK1 / CHK2; Including but not limited to e.MK-1775 and PD0166285 Not WEE1; f.ATMs, including but not limited to KU-55933; g. Including but not limited to NU7441 and M3814 NA-dependent protein kinase; and h. additional proteins involved in DDR; 2) One or more immune checkpoints, including but not limited to: Cpoint inhibitors or modulators: a. Nivolumab (OPDIVO), pembrolizumab (Keytruda), pidilizumab ( CT-011), cemiplimab (LIBTAYO), spartalizumab (PDR001) , camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS001), and AMP-224 (AMPLI PD-1 inhibitors such as MMUNE); b. Atezolizumab (TECENTRIQ), avelumab (Bavencio), and dur Valmab (Imfinzi), MPDL3280A (Tecentriq), BMS-9 PD-L1 inhibitors such as 36559, and MEDI4736; c. Ipilimumab (YERVOY) and CP-675,206 (TREMELIMUMA B) anti-CTLA-4 antibodies such as; dT-cell immunoglobulin and mucin domain 3 dmucin domain 3 (Tim-3) inhibitor; eV-domain Ig suppressor of T cell activation inhibitors of ation (Vista); Inhibition of f.band T lymphocyte attenuator (BTLA) Agent; g. Lymphocyte activation gene 3 (LAG3) inhibitor ); and hT cell immunoglobulin and immunorecept or tyrosine-based inhibitory motif domai n (TIGIT) inhibitors; 3) telomerase inhibitors or telomeric DNA binding compounds; 4) Chlorambucil (LEUKERAN), oxaliplatin (ELOXATIN), Treptozocin (ZANOSAR), dacarbazine, ifosfamide, lomustine (CC NU), procarbazine (MATULAN), temozolomide (TEMODAR), and Alkylating agents, including but not limited to thiotepa; 5) Carmustine, chlorambucil (LEUKERAN), carboplatin (PARAP LATIN), cisplatin (PLATIN), busulfan (MYLERAN), ALKERAN, MITOMYCIN (MITOSOL), AND CYCLOPHOSPHA DNA crosslinking agents, including but not limited to ENDOXAN Agent; 6) Cladribine (LEUSTATIN), Cytarabine (AR AC), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine ( GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELO DA), leucovorin (FUSILEV), methotrexate (RHEUMATREX) antimetabolites, including but not limited to, raltitrexed, ; 7) Taxanes such as docetaxel (TAXITERE), paclitaxel (ABRAXA NE, TAXOL), vinca alkaloids such as vincristine (ONCOVIN), These include vinblastine, vindesine, and vinorelbine (NAVELBINE) , but not limited to, plant alkaloids and terpenoids, or their Antimitotic drugs, often derivatives; 8) Amsacrine, camptothecin (CTP), genistein, ibuprofen Rinotecan (CAMPTOSAR), Topotecan (HYCAMTIN), Doxorubicin (ADRIAMYCIN), DAUNORUBICIN (CERUBIDINE) AND DAUNORUBICIN combinations thereof, such as cyclosporine (VYXEOS), epirubicin (ELLEN CE), ICRF-193, teniposide (VUMON), mitoxantrone (NOVAN including, but not limited to, cyclosporine (TRONE), and etoposide (EPOSIN) Not a topoisomerase inhibitor; 9) Fludarabine (FLUDARA), Aphidicolin, Ganciclovir, and Cidofovir DNA replication inhibitors, including but not limited to: 10) Ribonucleosides, including but not limited to hydroxyurea dodiphosphate reductase inhibitors; 11) Actinomycin D (Dactinomycin, COSMEGEN) and Plicamycin transcription inhibitors, including but not limited to (mithramycin); 12) Bleomycin (BLENOXANE), idarubicin, and other DNA cleaving agents, including but not limited to 13) Actinomycin D (COSMEGEN), among others Cytotoxic antibiotics, including but not limited to: 14) Aminoglutethimide, Anastrozole (ARIMIDEX), Letrozole (F EMARA, vorozole (RIVIZOR), and exemestane (AROMASIN ), including but not limited to aromatase inhibitors; 15) Genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN ), including but not limited to, angiogenesis inhibitors; 16) Aminoglutethimide (CYTADREN), bicalutamide (CASODEX), Cytopenic acid Proteron, flutamide (EULEXIN), nilutamide (NILANDRON), etc. including, but not limited to, antisteroids and antiandrogens; 17) Imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib { lapatinib} (TYKERB), sorafenib (NEXAVAR), and Tyrosine kinase inhibitors, including but not limited to citinib (INLYTA) Kinase inhibitors; 18) Everolimus, temsirolimus (TORISEL), and other including, but not limited to, mTOR inhibitors; 19) Trastuzumab (HERCEPTIN) and rituximab (RITUXAN) including, but not limited to, monoclonal antibodies; 20) Apoptosis inducers such as cordycepin; 21) Clindamycin, chloramphenicol, streptomycin, anisomycin Proteins including, but not limited to, cycloheximide Synthetic inhibitors; 22) Drugs including, but not limited to, metformin and phenformin No antidiabetic drugs; 23) Antibiotics, including but not limited to: Tetracyclines, including but not limited to doxycycline hmm; b. Erythromycin, including but not limited to azithromycin hmm; C. Antibiotics, including but not limited to tigecyline Not glycylglycine; d. Anthelmintics, including but not limited to pyrvinium pamoate; e. Drugs including, but not limited to, penicillins and cephalosporins β-lactams; f. including, but not limited to, daunorubicin and doxorubicin No anthracycline antibiotics; g. Antibiotics, including chloramphenicol, mitomycin C, and actinomycin , including but not limited to other antibiotics; 24) Muromonab CD3, infliximab (REMICADE), adalimumab (HU MIRA), omalizumab (XOLAIR), daclizumab (ZENAPAX), Rituki Simab (RITUXAN), ibritumomab (ZEVALIN), tositumomab (BEX XAR), cetuximab (ERBITUX), trastuzumab (HERCEPTIN), ADCETRIS, alemtuzumab (CAMPATH-1H), Lym-1 (ONCOL YM), ipilimumab (YERVOY), vitaxin, bevacizumab (AVASTIN) These include, but are not limited to, abciximab (REOPRO) and cefotaxime (CEFO). No antibody therapeutics; 25) Gemtuzumab ozogamicin (MYLOTARG) and inotuzumab ozogamicin conjugated antibody therapeutics such as BESPONSA; 26) BCL-2 targeted therapy (e.g., oblimersen, venetoclax, and navitox) laxatives), FLT3 inhibitors (e.g., midostaurin and gilteritinib), BCR-A BL tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib rtinib}, bosutinib, ponatinib {posatinib}, and bafetinib) , JAK-2 inhibitors (e.g., fedratinib, gandotinib, and pacritinib), I DH1 inhibitors (e.g., ivosidenib) or IDH2 inhibitors (e.g., enasidenib) Targeted therapies not classified above, including 27) Bacille Calmette-Guerin (BCG) vaccine; Buserelin (ETILAMIDE); Chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates Fonate; Colchicine; Demethoxyviridin; Dichloroacetate; Estramustine; Filgrastim (NEUPOGEN); Fludrocortisone (FLORINEF); Serene (ZOLADEX); Interferon; Leucovorin; Leuprolide (LUP RON); Levamisole; Lonidamine; Mesna; Metformin; Mitotane (o,p'-D DD, LYSODREN); nocodazole; octreotide (Sandostatin); Peripheral steroids Syn; Porfimer (especially in combination with phototherapy and radiation therapy); Suramin; Tamoxifen Fen; Titanocene dichloride; Tretinoin; Fluoxymesterone (HALOTESTI Anabolic steroids such as estradiol and diethylstilbestrol (DES). estrogens such as dienestrol, medroxyprogesterone acetate (MPA ) and progestins such as megestrol; and other agents such as testosterone.

[0339] Patients were randomly assigned to receive cisplatin, carboplatin, paclitaxel, or albumin-bound paclitaxel. Cel, docetaxel, gemcitabine, vinorelbine, irinotecan, etoposide, vinbustat In addition, the patient may receive chemotherapy with one or more of the following: Bevacizumab, ramucirumab, or necitumumab is used. If the patient's cancer expresses increased levels of EGFR, the patient may also be treated with erlotinib. Even if treated with nivolumab, afatinib, gefitinib, osimertinib, or dacomitinib If the patient's cancer has a rearrangement of the ALK gene, the patient should be treated with crizotinib, ceritinib, or rituximab. The patient's cancer may be treated with rivaroxaban, alectinib, brigatinib, or lorlatinib. If the patient expresses an altered BRAF protein, the patient may also be treated with dabrafenib or trametinib. In certain embodiments, patients may be treated with Mylotarg, Cladribine, Invivo. Patients may be treated with one or more of the following: darubicin, cytarabine, and any combination of these. In certain embodiments, the patient is administered cladribine. Patients may be treated with one or more of the following: cytarabine, idarubicin, and cytarabine, all of which are The combination is known as "CLIA."

[0340] In the treatment of a disease, the appropriate dosage of the therapeutic composition is determined according to the disease to be treated as defined above. type of disease, severity and course of disease, previous treatment, patient history and response to medication, and medical history. The drug is administered appropriately to the patient at one time or over a series of treatments. This may also be the case.

[0341] D. Combination Therapy Methods and compositions involving combination therapy may enhance the therapeutic or protective effect and / or enhance the therapeutic or protective effect of another anti-inflammatory agent. Increasing the therapeutic efficacy of cancer therapy or anti-hyperproliferative therapy. are effective in achieving a desired effect, such as killing cancer cells and / or inhibiting hyperproliferation of cells. The tissue, tumor, or cells may be provided with one or more agents in a combined amount effective to treat the disease. The tissue, tumor, and / or tissues may be contacted with one or more compositions or pharmacological preparations, including by contacting the cells with two or more different compositions or formulations. Combination therapy may be used in combination with radiation therapy, surgery, immunotherapy; or with targeted therapy. It is also envisioned that such a method may be used.

[0342] Coadministration can refer to the simultaneous administration of two or more drugs in the same dosage form, or in separate dosage forms. This may include administering a therapeutic composition to a subject and administering another therapeutic composition separately. The therapeutic agents may be formulated together in the same dosage form and administered simultaneously. The composition and another therapeutic agent may be administered simultaneously, again with both agents being in separate formulations. In another alternative, a therapeutic agent may be administered immediately after the other therapeutic agent, or vice versa. In another administration protocol, the subject therapeutic composition and another therapeutic agent are administered within a few minutes. The doses may be administered at intervals of several hours or several days.

[0343] The first-line anticancer treatment may be administered before, during, or after the second anticancer treatment, or in various combinations. Administration may be at the same time or at intervals ranging from minutes to days to weeks. In embodiments in which the first treatment is administered to the patient separately from the second treatment, the two compounds may still Generally, each delivery is performed in a manner that provides a beneficial combined effect on the patient. In such cases, it is ensured that there is no significant period of time between them. The first and second treatments may be administered within 24 or 72 hours of each other, more specifically within about 6 to 12 hours of each other. It is contemplated that a first and second treatment may be provided to the patient. Between doses, there may be a few days (2, 3, 4, 5, 6, 7) to a few weeks (1, 2, 3, 4, 5, 6, 7, 8), it may be desirable to extend the treatment period significantly.

[0344] In certain embodiments, a course of treatment may last from 1 to 90 days or more (such ranges may include intervening One drug may be administered on any day between day 1 and day 90 (including days on which the drug is administered). or any combination thereof, and may be administered in combination with another drug Any day between day 1 and day 90 of the drug administration (such ranges include intervening days) or It is envisaged that the drug may be administered in any combination within one day (24 hours). The anti-cancer treatment may be administered multiple times to the patient. During this period, the patient's prognosis, physical strength, health condition, and other aspects of the patient's condition will be monitored. Depending on the condition, 1-7 days and / or 1-5 weeks and / or 1-12 months or more (this Such treatment cycles may continue for up to 12 days (including any intervening days). Treatment cycles may be repeated as necessary. It is expected that this will be done.

[0345] In some embodiments, the metal chelator may be administered simultaneously with the anti-cancer therapy. In some embodiments, the metal chelator may be administered sequentially in combination with an anti-cancer therapy. Various combinations may be employed. The following examples show combinations of metal chelators: The treatment is "A" and another anti-cancer therapy is "B": A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / A B / B / A / A B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / A A / A / B / A

[0346] Administration of any compound or treatment of the invention to a patient should be considered with consideration of the toxicity, if any, of the agent. The general protocol for administration of such compounds will be followed. In some embodiments, the method includes monitoring for toxicity attributable to the combination therapy. .

[0347] Combination therapy may consist of one or more of chemotherapy, epigenetic therapy, immunotherapy, and targeted therapy. may include multiple.

[0348] Chemotherapy may be induction chemotherapy and / or consolidation chemotherapy after remission is achieved. For example, metal chelation can be used to treat anthracyclines during induction or consolidation therapy for AML, etc. Alongside chemotherapy such as cyclosporine, it is often combined with antioxidants, minerals, and / or vitamins. Chemotherapy may be performed using high-intensity chemotherapy such as idarubicin or cytarabine, or Fulda. It may be a nucleoside analogue such as rabine, chlorfarabine, or cladribine. Targeted therapies include FLT3 inhibitors, BCR-ABL tyrosine kinase inhibitors, or JAK It may contain a -2 inhibitor.

[0349] Another combination for ALL is metal chelation and chemotherapy such as anthracyclines. The method may include the step of adding antioxidants, minerals, and / or vitamins in combination with the method. The most common treatments are cyclophosphamide, vincristine, doxorubicin, and dexamethasone. Combination therapy may be hyper-CVAD chemotherapy, including rituximab, off-label chemotherapy, or combination chemotherapy. Immunotherapies such as rituximab, blinatumomab, or other monoclonal antibodies Combination therapy is the extended Berlin-Frankfurt-Münster (BFM) chemotherapy regimen. may include.

[0350] Chemotherapy, such as for treating AML, is a type of treatment that uses hypomethylating therapies (e.g., decitabine or arginine). Zacitidine), low-dose cytarabine, low-dose clofarabine, or low-dose cladribine Low-intensity chemotherapy, such as low-dose anthracyclines, combined with low-intensity AML therapy The targeted therapy may be an FLT3 inhibitor, a BCR-ABL tyrosine kinase inhibitor, or the like. The therapeutic agent may include a vasopressinase inhibitor, or a JAK-2 inhibitor.

[0351] Combination therapies such as those for treating ALL include metal chelation and hyper-CVAD chemotherapy. Antioxidants, minerals, or vitamin supplements combined with low-intensity chemotherapy or immunotherapy such as rituximab The immunotherapy may include rituximab, ofatumumab, or blinatumomab. may be also possible.

[0352] In maintenance therapy, such as to prevent relapse of AML or MDS, metal chelation alone is or in combination with antioxidants, minerals, vitamins, and / or low-dose chemotherapy. Other combination agents include hypomethylating agents, immunotherapy, low-dose cytarabine, or The combination therapy may include targeted therapy. POMP combination therapy chemotherapy may be used in combination therapy. stomach.

[0353] The other component of the combination therapy may be amifostine. Amifostine is used to reduce toxicity. It may be administered to prevent. 2 Amifostine doses up to It may be administered 15 minutes, 30 minutes before the procedure, or without chemotherapy.

[0354] II. Pharmaceutical Compositions The pharmaceutical compositions of the present invention may contain, for example, metal chelators, vitamins, minerals, and / or A useful agent, such as a chemotherapeutic agent, or an additional agent dissolved or dispersed in a pharma- ceutically acceptable carrier. "Pharmaceutically or pharmacologically acceptable" means a compound or compounds of the present invention in an effective amount. The phrase "a compound that does not cause any adverse or allergic reactions when administered to an animal, such as a human, is also used, as appropriate. The term refers to molecular entities and compositions that do not produce aggressive or other adverse reactions. Remington: The Science and Prac tice of Pharmacy, 21st Ed., Lippincott Wi At least as illustrated by Illiams and Wilkins (2005), The preparation of pharmaceutical compositions containing another therapeutic compound or additional active ingredients can be readily achieved in light of the present disclosure. Further, for animal (e.g., human) administration, the formulation may be , typically the FDA Office of Biological Standards s., does not meet the standards of sterility, pyrogenicity, general safety and purity. It will be understood that this should not be the case.

[0355] As used herein, a "pharmaceutically acceptable carrier" refers to a compound that is suitable for use in a pharmaceutical composition or composition combination according to the ordinary skill in the art. Any and all solvents, dispersion media, coatings, interfaces, etc., as known to those skilled in the art. Active agents, antioxidants, preservatives (e.g., antibacterial and antifungal agents), isotonicity agents, absorption delaying agents, salts, Preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, Dyes, such similar materials, and combinations thereof (see, for example, Remington's Pharmaceutical Sc iences,18th Ed.Mack Printing Company,199 0, pp. 1289-1329). Except where compatible, its use in pharmaceutical compositions is contemplated.

[0356] The therapeutic compounds described herein may be administered in any form, whether solid, liquid, aerosol, or aerosol form. Depending on what is being given and whether it must be sterile for routes of administration such as injection Depending on the circumstances, different types of carriers may be included. The present invention relates to intravenous, intradermal, transdermal, spinal cord, and intrathecal administration. Intracavitary, intra-arterial, intra-articular, intraperitoneal, intranasal, intravaginal, intrarectal, topical, intramuscular, subcutaneous, transmucosal , oral, topical, localized, inhaled (e.g., aerosolized), injected, infused, or infused; targeted cell The cells can be directly injected into the catheter, through a lavage fluid, into a cream, or into a lipid composition (e.g., lipase). or by local perfusion, as known to those of ordinary skill in the art. Other methods such as those described in Remington's Methods, incorporated herein by reference. s Pharmaceutical Sciences,18th Ed.Mack P Printing Company, 1990), or any combination of the foregoing. The drug may be administered by combination of the above.

[0357] The therapeutic compounds may be in free base, neutral or salt form, or in complex form (e.g., Ca-E DTA or Zn-dexrazoxane (metal-ligand complex) Pharmaceutically acceptable salts include, for example, salts obtained by reacting the free amino groups of the proteinaceous composition with the or by inorganic acids such as hydrochloric acid or phosphoric acid, is formed by organic acids such as acetic acid, oxalic acid, tartaric acid or mandelic acid Salts formed with free carboxyl groups also include, for example, hydroxyl groups. Sodium, potassium, ammonium, calcium, or dihydrogen hydroxide Inorganic bases such as iron, isopropylamine, trimethylamine, histidine, or proline It may also be derived from an organic base of caine. When formulated, the solution may be mixed in a manner compatible with the dosage form. The formulation may be administered in a therapeutically effective amount in the form of a solution formulated for parenteral administration, such as an injection. or for administration to the digestive system, such as aerosols for delivery to the lungs, or drug-releasing capsules These drugs are easily administered in a variety of dosage forms, including those formulated in

[0358] Further, in accordance with the present invention, the compositions of the present invention suitable for administration may contain or may not contain an inert diluent. In some embodiments, the composition is provided in a pharma- ceutical acceptable carrier, preferably a non-medicinal agent. The carrier must be assimilable and may be a liquid, semi-solid, i.e. Any conventional vehicle, agent, diluent or carrier may be used in the preparation of the pharmaceutical composition of the present invention. or the therapeutic efficacy of the compositions contained therein. Its use in administrable compositions for use in the practice is appropriate. Examples of diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, and binders. , fillers, etc., or combinations thereof. The compositions may also contain various antioxidants. The oxidation of one or more components may be retarded. Non-limiting examples of such compounds include parabens (e.g., methylparaben, propylparaben, etc.) chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof Preservatives such as various antibacterial and antifungal agents, including but not limited to sodium phosphate esters, sodium lauryl sulfate, sodium phosphate esters, and sodium phosphate esters.

[0359] In accordance with the present invention, the compositions can be formulated in any convenient and practical manner, i.e., as a solution, suspension, emulsion, or the like. The compound may be combined with a carrier by, for example, mixing, encapsulation, absorption, etc. This is routine for those skilled in the art.

[0360] In certain embodiments of the present invention, the composition is thoroughly combined with a semi-solid or solid carrier. or mixed. Mixing can be carried out in any convenient manner, such as by grinding. Loss of therapeutic activity Stabilizers are also added to the mixing process to protect the composition from denaturation in the stomach. Examples of stabilizers that may be used in the composition include buffers; aldehydes such as lysine and lysine; amino acids; dextrose, mannose, galactose, fructose, lactose, sucrose Examples of carbohydrates include maltose, sorbitol, and mannitol.

[0361] In a further embodiment, the present invention provides a method for the treatment of a disease comprising administering to a subject a therapeutic compound, one or more lipids, comprising administering to a subject a therapeutic compound ... The present invention may also relate to the use of pharmaceutical lipid vehicle compositions comprising a lipid, a lipid polymer, and an aqueous solvent. In the present invention, the term "lipid" refers to a substance that is characteristically insoluble in water and extractable with an organic solvent. This broad class of compounds may be defined to include any of a wide variety of substances. It is well known that the term "lipid" as used herein does not refer to any particular structure. Non-limiting examples include compounds containing long chain aliphatic hydrocarbons and their derivatives. Lipids can be naturally occurring or synthetic (i.e., designed or manufactured by man). However, the lipid is usually a biological substance. These are well known in the art and include, for example, neutral lipids, phospholipids, phosphoglycerides, steroids, Terpenes, lysolipids, sphingoglycolipids, glycolipids, sulfatides s}, ether-containing lipids, and ester-linked fatty acids, and polymerizable lipids, and Of course, the lipids herein are understood by those skilled in the art to be lipids. Compounds other than those specifically described are also encompassed by the compositions and methods of the present invention.

[0362] Those of ordinary skill in the art will appreciate that the compositions used to disperse the compositions in lipid vehicles are For example, therapeutic compounds may be prepared by methods known to those skilled in the art. The lipid-containing solution is dispersed in the lipid-containing solution, dissolved in the lipid, or dissolved in the lipid by any means known in the art. Emulsified, mixed with lipids, combined with lipids, covalently bonded to lipids, suspended in lipids, The compound may be contained in or complexed with a micelle or liposome, or may be otherwise The composition may be bound to a lipid or lipid structure. and / or an emulsifier (e.g., lecithin). The dispersion may result in the formation of liposomes. It does not have to be brought about by this.

[0363] The actual dosage of the compositions of the present invention administered to an animal subject will depend on physical and physiological factors, such as body weight. factors, severity of the condition, type of disease being treated, previous or concurrent therapeutic interventions, patient Depending on the dosage and route of administration, the preferred dosage may vary. The amount and / or frequency of administration of an effective amount may vary depending on the subject's response. The practitioner responsible for administration will be responsible for determining the concentration of active ingredient(s) in the composition and the appropriate dose for the individual subject. Solubility, bioavailability, biological half-life, route of administration, product shelf life Factors such as the drug's life expectancy, dosage form, and other pharmacological considerations influence the ability of the skilled artisan to prepare such formulations. It is thus envisioned that different dosages and treatment regimens may be desirable accordingly.

[0364] A. Digestive System Compositions and Formulations In some embodiments, therapeutic compounds (e.g., vitamins, minerals, and / or The drug (or chelating agent) is administered via the digestive system. All possible routes of administration in which the composition is in direct contact with the digestive tract are included. The pharmaceutical compositions disclosed herein may be administered orally, bucally, rectally, or sublingually. Thus, these compositions may be formulated with an inert diluent or an assimilable edible carrier. or they may be enclosed within hard or soft shell gelatin capsules. They may be compressed into tablets or they may be incorporated directly into the diet.

[0365] B. Parenteral Compositions and Formulations In further embodiments, the compounds of the invention can be administered via parenteral routes. For example, in some embodiments, two, three, or four treatments may be administered in the same formulation. It may be desirable to administer a compound of formula (I) or (II) to a patient to treat the cancer. In the present law, the term "parenteral" includes routes that avoid the digestive tract. The pharmaceutical compositions disclosed herein can be administered, for example, but not limited to, intravenously. The drug may be administered intradermally, intramuscularly, intra-arterially, intra-articularly, intrathecally, subcutaneously, or intraperitoneally. No. 6,7537,514, U.S. Pat. No. 6,613,308, U.S. Pat. No. 5,466,468; U.S. Pat. No. 5,543,158; U.S. Pat. Nos. 5,399,363 (each of which is incorporated herein by reference) the entire contents of which are specifically incorporated herein by reference).

[0366] A solution of the active compound as a free base or a pharmacologically acceptable salt is added to the hydroxypropyl Dispersions may also be prepared in water suitably mixed with a surfactant such as cellulose. Also in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations will prevent the growth of microorganisms. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions. and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (the entire contents of which are No. 5,466,468, which is specifically incorporated herein by reference. Generally, solutions are preferably sterile and fluid to the extent that easy syringability exists. It is preferably stable under the conditions of manufacture and storage and can withstand microorganisms such as bacteria and fungi. The carrier must be protected from the effects of biological contamination. ols (i.e., glycerol, propylene glycol, and liquid polyethylene glycol) and / or vegetable oils, suitable mixtures thereof, and / or a solvent or dispersion medium. For example, the use of a coating such as lecithin can reduce the amount of water required for dispersions. Proper fluidity may be maintained by maintaining particle size and by the use of surfactants. The prevention of the action of microorganisms can be achieved by using, for example, paraben, chlorobutanol, phenol, sorbic acid, This can be caused by a variety of antibacterial and antifungal agents, such as thiol, thiourea, thiol ... It may be preferable to include isotonic agents, such as sugars or sodium chloride. Sustained absorption of the composition can be achieved by using absorbent agents such as aluminum monostearate and gelatin. This may be brought about by using an agent in the composition that retards harvest.

[0367] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary. The liquid diluent must first be made isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this connection, sterile aqueous media that can be used will be known to those of skill in the art in light of the present disclosure. For example, , one dose is dissolved in isotonic NaCl solution and subcutaneous injection is added or proposed It may be injected into the injection site (e.g., "Remington's Pharmacy" tical Sciences”15th Edition, pages 1035-1 (See US Pat. Nos. 038 and 1570-1580.) Some variation in dosage may be required depending on the This will necessarily depend on the condition of the subject being treated. In some embodiments, a chelating agent, While fixed ratio combinations of vitamins and minerals may be administered to a subject, Nevertheless, the individual responsible for administration must make the final determination of the appropriate dose for an individual subject. Additionally, for human administration, the formulation must comply with the requirements of the Office of Biologics of the U.S. Food and Drug Administration. They must meet the standards of sterility, pyrogenicity, general safety and purity as specified in .

[0368] The active compound, in the required amount, may be mixed with various other ingredients as listed above in appropriate amounts, as required. Sterile injectable solutions can be prepared by incorporating the compound in a suitable solvent followed by filtered sterilization. Dispersions generally contain the various sterilized active ingredients in a basic dispersion medium and the required amount from those enumerated above. It is prepared by incorporating it into a sterile vehicle containing the other ingredients. In the case of sterile powders for preparation of the composition, the preferred method of preparation is to mix the active ingredient with a previously sterile filtered powder. Vacuum drying and freeze drying techniques are used to produce a powder with any additional desired ingredients from the dried solution. The powder composition may be dissolved in water or saline, for example, with or without a stabilizer. Combined with a liquid carrier.

[0369] C. Other Pharmaceutical Compositions and Formulations In some embodiments, the active compound or combination therapy is administered, for example, topically or transdermally, by mucosal administration, or by other route. and various other routes, such as intranasal, intravaginal, etc., and / or via inhalation. In some embodiments, the composition may be formulated to contain antioxidants and / or minerals (e.g., For example, zinc, selenium, magnesium, and vitamin C may be administered orally, and iron chelates may be administered orally. The toxigenic agent may be administered orally or intravenously.

[0370] III. Pharmaceutical Combinations Also disclosed herein are pharmaceutical combinations, i.e. kits. In the package, at least one of the active ingredients, together with instructions for use and optionally one or more other active ingredients, is Each of the compositions may contain one or more pharma- ceutically active ingredients. For example, some of the pharma- ceutically active ingredients disclosed herein may be In one embodiment, the pharmaceutical combination comprises at least one anticancer pharmacological therapy and one or more and optionally at least one antioxidant, vitamin, or essential mineral. In other embodiments disclosed herein, the pharmaceutical combination comprises one or a plurality of metal chelators and at least one antioxidant, vitamin, or essential mineral; and optionally at least one anti-cancer pharmacological therapy. The kit may be used to administer the agents simultaneously or in combination. The instructions may be sequential; the intent of the kit is that they are used together.

[0371] IV. Definition As used herein, the following terms have the meanings indicated.

[0372] As used herein and throughout the specification, "a" or "an" means one or more. As used herein in the claims, when used in conjunction with the word "comprises," the word " The terms "a" or "an" may mean one or more than one.

[0373] Although the disclosure supports definitions that refer only to alternatives and "and / or," Use of the term "or" in any context is expressly intended to refer to alternatives only. Unless otherwise specified or alternatives are mutually exclusive, "and / or" is used to mean As used herein, "another" means at least one other. Good too.

[0374] Throughout this application, the term "about" is used to indicate that a value is within the inherent error margin of error for a device. to include the methods used to determine the Used.

[0375] The phrase "therapeutically effective" refers to the treatment of a disease or disorder, or to the achievement of a clinical endpoint, etc. The amount of active ingredient or combination of active ingredients used to determine the effect of a measurable parameter of When the individual active ingredients are not present in a therapeutically effective amount, e.g., metal ions, Combination of a rate-increasing agent with an active ingredient such as an anti-cancer therapy or an antioxidant, or both. The combined amount may be therapeutically effective.

[0376] As used herein, for example, the term "metal" in the context of chelation includes gold. Metal ions and metal salts, sequestered metal ions, bound metal ions, and other metal ions present in the mammalian body This includes all forms of metals that are likely to be

[0377] As used herein, the terms "cancer therapy" and "anti-cancer therapy" are synonymous.

[0378] As used herein, the terms "anti-cancer pharmacological therapy" and "chemotherapy" are synonymous. .

[0379] As used herein, the term "subject" or, equivalently, "patient" refers to a subject on whom the method is performed. Generally, a patient is a human, but as will be understood by those of skill in the art, The patient may also be an animal. Thus, rodents (mice, rats, hamsters and including Lumots); cats; dogs; rabbits; cows, horses, goats, sheep, pigs, etc. and pets such as primates (including monkeys, chimpanzees, orangutans and gorillas). Other animals, including mammals, are included in the definition of patient.

[0380] "Therapy" and "treat" refer to any treatment or therapy for the purpose of obtaining a therapeutic benefit for a disease or health-related condition. refers to the administration or application of a therapeutic agent to a subject, or the performance of a procedure or modality on a subject, For example, treatment may involve administration of chemotherapy. rapy}, immunotherapy, radiation therapy, surgery, or any combination thereof. That's fine too.

[0381] As used throughout this application, the terms "therapeutic benefit" or "therapeutically effective" refers to anything that promotes or enhances the well-being of a subject with regard to the medical treatment of this condition. This includes, but is not limited to, a reduction in the frequency or severity of signs or symptoms of a disease. For example, cancer treatment may involve, for example, reducing the invasiveness of tumors, slowing the rate of cancer growth, etc. Treatment of cancer may also involve reducing, or preventing metastasis of, a subject with cancer. Treatment of cancer may also refer to reduction in tumor burden. Additional measurements related to cancer treatment, such as time to disease progression, are described herein. It has been done.

[0382] Similarly, an effective response of a patient to a treatment, or a patient's "responsiveness," may depend on the risk of the disease or disorder. This refers to the clinical or therapeutic benefit provided to a patient suffering from or suffering from a disease. Such benefits include cellular or biological responses, complete responses, partial responses, stable disease (progression or For example, an efficient response may include a response that is: It may be a reduction in tumor size or progression-free survival in a patient diagnosed with cancer.

[0383] As used herein, a "broad spectrum" metal chelator is one that is capable of chelating two or more metals. Preferably, it is a compound that chelates arsenic (As), aluminum (Al), and arsenic (As). Sb, barium (Ba), boron (B), cadmium (Cd), cerium (C e), Chromium (Cr), Lead (Pb), Mercury (Hg), Neodymium (Nd), Nickel (Ni ), tin (Sn), titanium (Ti), uranium (U), and vanadium (V). However, in some embodiments, In the cytoplasmic state, these broad spectrum chelators also chelate iron (Fe), copper (Cu), etc. It can be rated.

[0384] As used herein, a "targeted therapy" refers to a therapeutic agent that: i) targets a tumorigenesis or carcinogenesis, such as, for example, an antibody. or ii) antibodies or drugs that target specific classes of molecules involved in sexual signaling. refers to a delivery means that selectively or preferentially delivers therapeutic molecules such as drugs to target cells or tissues. Good too. EXAMPLES

[0385] V. Working Examples The following examples are included to demonstrate preferred embodiments of the invention. The techniques disclosed in the examples have been found by the inventors to function well in the practice of the invention. corresponds to the art discovered and therefore may be considered to constitute a preferred mode for its practice. However, those of skill in the art should understand that, in light of this disclosure, Many variations may be made in the specific embodiments and still depart from the spirit and scope of the invention. It should be understood that the same or similar results would be obtained without the need for any particular method.

[0386] Example 1 - Metal Chelation Therapy for Treating Disease Some metals can induce dose-dependent chromosomal breaks, gaps, and fragments. Lead is present in over 300 metalloenzymes and contributes to the structural stability of various transcription factors and tumor suppressors. They affect gene expression in a variety of ways, including through their functions and functions (VanLandi ngham et al.,2002;Ostrakhovitch and Cher ian, 2005). This study focused on broad-spectrum metal detoxification and the use of minerals, vitamins, and / or the effect of antioxidants on genetic stability was evaluated.

[0387] Methods. Leukemia patients undergoing bone marrow biopsy and blood or other biological sample collection were Approximately 2 milliliters of serum, approximately 2 milliliters of BM aspirate, and Each core BM biopsy was taken at approximately 1–2 mm. Serum samples were stored at approximately 90°C. In a perfluoroalkoxy vessel, it is decomposed and mineralized using HNO3 and H2O2, then The mixture was evaporated in concentrated hydrochloric acid at about 130° C. under a laminar flow hood.

[0388] Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used to determine the stable dry The trace metal content of the dried samples was analyzed. The dried samples were taken up in 1 mL of 10% H3NO2. The solution was then diluted to a volume of 10 mL. 1 μL of this solution was aliquoted using an autosampler. The analytes were then ionized in a hot argon plasma. - A mass spectrometer (quadrupole analyzer) was used to separate the ions and monitor their intensities. Arsenic (As) has a problem with molecular interference (argon chloride dimer), so it requires higher mass resolution. The analysis showed that the bone density was affected by the porosity and Due to the influence of predominant tissue type, e.g. Hg / Ca, Ca and / or P Metal concentrations normalized to Ca content were reported with high relative accuracy. (less than 3% of 1 SD) and with certainty (less than 10% of 1 SD).

[0389] p53 mutation status was assessed using standard of care including next-generation sequencing.

[0390] Subjects. Subject characteristics are shown in Table 1 below.

[0391] [Table 1]

[0392] Results: Metal levels were found to differ significantly between AML cytogenetic risk groups. The cytogenetic risk groups of newly diagnosed AML patients were The study also found that the difference in the levels of α- and β-blockers was significantly associated with the difference in the levels of α- and β-blockers (Table 2). 3 mutation status was significantly associated with differences in copper, zinc, and arsenic levels (Table 3) Therefore, treatment with metal detoxification and administration of antioxidants, minerals, and / or vitamins is recommended. These are expected to normalize the abnormalities and thereby restore genetic stability. These observations also support the notion that cytogenetic and molecular mutations are already being used in prognosis. Similarly, it is shown that metals can be utilized for risk assessment during treatment.

[0393] The amount of toxic substances in the bone marrow and serum of healthy individuals compared with patients with acute myeloid leukemia (AML) Significant differences in the concentrations of metals and essential metals were observed. For example, patients with AML The bone marrow of the rats contained significantly higher levels of cadmium, lead, antimony, and arsenic (Table 4 ) In serum, levels of toxic metals such as antimony, cadmium, mercury, arsenic, and uranium significantly increased and certain essential metal levels, such as iodine and selenium, significantly decreased, The essential elements copper and iron were significantly elevated in AML compared with normal controls. Overall survival rates for patients with rituximab are significantly higher with increasing levels of certain toxic metals (e.g., mercury, antimony, and lead). As shown in Figures 1-6, the levels of certain essential metals (e.g., Low levels of magnesium and zinc reduce survival rates and reduce the essential element copper. Excessive levels decrease survival rates. Metal levels are therefore important during cancer and leukemia treatment. It is useful for risk stratification in cancer patients and for improving outcomes in cancer patients with unfavorable These observations are consistent with the mineral / antioxidant deficiency. of minerals and antioxidants to replenish the feet while eliminating excess levels of certain toxic metals. This provides a rationale for metal detoxification and rebalancing. The results are also shown in Figures 1-6.

[0394] Metal levels were measured in biological samples from patients with AML and in control samples. Ta.

[0395] The results are shown in Tables 2 to 5 below. Statistically significant differences were observed. As shown in Table 3 Thus, p53 mutation status was significantly associated with copper, zinc, and arsenic levels. Values ​​and ranges are shown below.

[0396] [Table 2]

[0397] [Table 3]

[0398] [Table 4]

[0399] [Table 5]

[0400] [Table 6]

[0401] Example 2 - Multi-metal scoring system A total of 67 patients with newly diagnosed AML and 94 healthy volunteers were treated with microgold Serum was collected for gene analysis. The median age of AML patients was 67 years (range 28–87 years). The ages of the subjects were 58 years (range 20-89 years) and 58 years (range 20-89 years) in the control group. The two groups had a similar gender distribution. Most patients with AML have FLT3 internal tandem duplication (ITD) mutations ( 75.6%) lacking NPM1 mutations (68.1%) and intermediate-risk cytogenetic profile The majority of participants were considered to have a pulmonary function (63.1%).

[0402] This case-control study compared control participants without hematological malignancies with those receiving frontline chemotherapy. Blood serum samples were collected from patients newly diagnosed with AML before the start of the study. The diagnosis was confirmed by analysis of bone marrow morphology, and bone marrow aspirates and biopsies were obtained from all AML patients. All AML cases were subclassified using the World Health Organization's 2016 classification criteria for AML. To characterize the immunophenotype of the samples, multicolor flow cytometry was performed as previously described. A 10-fold increase in mitogenicity was observed in 100% erythrocytes from bone marrow aspirates cultured without mitogenic stimulation using standard techniques. Conventional cytogenetic analysis was performed on G-banded metaphases, and internation al System for Human Cytogenetic Nomencla reported using a polymerase chain reaction-based assay for molecular analysis. As mentioned above, the Dual Color Break Apart Probe was used. Fluorescence in situ hybridization analysis was performed on bone marrow cultures using the ELISA kit. Risk stratification was performed according to karyotype, gene mutations, and ELN classification.

[0403] Serum samples were dissolved in HNO3 and HO in a perfluoroalkoxy container at approximately 130 °C. The product was mineralized by digestion with 2 and then evaporated in concentrated hydrochloric acid at approximately 120° C. under a laminar flow hood. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used to determine the stability and dryness of The samples were analyzed for trace metal content.

[0404] Results. The median metal levels obtained from patients and controls are shown in Table 6 below.

[0405] [Table 7]

[0406] Metal Score. A novel metal scoring system was used to stratify patients' risk. The system evaluates whether a patient's values ​​for 10 toxic and essential metals fall within the specified cutoff values. These cutoffs were based on clinical judgment and the serum metal ion concentrations in the control group. The patients were assessed based on a combination of the value distributions. A score was assigned for each metal above or below a given limit. The total score was The rationale for constructing the score is straightforward. Relative deficiencies of magnesium, selenium, zinc, and rubidium have been associated with malignancies. Therefore, patients were given 1 point for values ​​lower than those specified in Table 7. Slight elevations of cadmium, lead, and and arsenic are established carcinogens and therefore are also included in the scoring system. Each exceedance of the limits in the table in Table 6 is given 1 point. For 7 patients, ICPM Calcium levels obtained from a clinical laboratory were not available for scoring, and standard of care calcium levels were obtained from a clinical laboratory. The sodium value was used.

[0407] [Table 8]

[0408] The scores may then be classified into risk groups. Risk groups can be stratified in various ways. For example, patients may be classified into low (1-3), medium (4-6), and high metal scores ( They may be classified according to three groups corresponding to 7–10).

[0409] The above cutoff values ​​are examples; the exact cutoff values ​​for these groups will vary depending on when they were extracted. It should be understood by those skilled in the art that the results will depend on the size and other characteristics of the patient population selected. Similarly, risk group assignment may be done in alternative ways.

[0410] Results: Patients with higher metal scores had significantly higher survival rates than those with lower metal scores. Figure 11 shows the 6-month survival rate of patients with metal scores of 1 to 3 in this study. The estimated mean score was 81%, compared with 60% for scores 4-6 and 36% for scores 7-9. Figure 12 shows that the results of a similar study conducted at a different hospital showed that The estimated 6-month survival rate for patients with a metal score of 1–3 was 91%, compared with 41% for patients with a score of 1–3. The percentage of those with scores of 4 to 6 was 87%, and for those with scores of 7 to 9 it was 60% (p=0.02).

[0411] These two analyses showed that risk varied according to imbalances in the levels of essential and toxic metals. By stratifying patients, it is possible to predict outcomes, such as the likelihood of survival at a particular date. These data also support the rebalancing of essential minerals and toxic metals in patients, i.e. Restratification into intrinsically lower-risk groups improves response to anticancer therapy It also supports the concept.

[0412] Example 3 - Positive responses following treatment with metal detoxification during AML and MDS therapy In addition to metal chelators, antioxidants and minerals are included in the standard treatment for myelodysplastic syndromes and AML. Clinical trials are ongoing to test the use of rivaroxaban in combination with other treatments. The iron chelator dexrazoxane was used, and in another clinical trial, calcium-EDTA (Ca-EDTA) and / or DMSA were used. Metal chelators and antioxidants / minerals When combined with standard AML or MDS therapy, A significantly favorable initial response was observed.

[0413] AML, high-risk MDS, myeloblastic phase of CML, Ph+AML, and myeloblastic phase of MPN Dexrazoxane in This ongoing research includes: 1) Removal of toxic metals in AML, MPN, and CML (myeloblastic stage) ) and treatment for improving clinical outcomes; 2) reducing the rate of transformation from MDS to AML; Standard chemotherapy (Mylotargin, Cladribine, Idarubicin, and / or Cytarabine (araC), (collectively "CLIA-M")) MDS treatment with antioxidants / minerals (zinc, selenium, magnesium, vitamin C) Monitor the effectiveness of the removal of toxic metals during the procedure. If clinically indicated for a mutated mutation, the protocol included standard FDA-approved targeted therapy. Because research is ongoing, in what follows, the past tense or the present tense may be used. This may also occur.

[0414] Study endpoints included: ●Overall survival; ● Overall response; • recurrence-free survival; ● Duration of remission; Complete remission (CR) / complete remission with incomplete blood count recovery (CRi) rates. Other efficacy endpoints included overall response, overall survival, recurrence-free survival, and duration of remission. Contains; 6-month recurrence-free survival rate (6-month recurrence-free survival rate is the rate of death occurring within 6 months after treatment) recurrence, including death, is considered a "recurrent event"; this is a binary endpoint); Quantification of toxic and essential metal concentrations in blood and bone marrow before and during treatment to determine chemical Combined with chemotherapy (Mylotarg, Cladribine, Idarubicin, and Cytarabine) Evaluation of the metal chelating effect of selected dexrazoxa; and Associations between pretreatment patient / disease characteristics (including cytogenetic and molecular abnormalities) and clinical outcomes Description of.

[0415] Patients. Ambulatory, self-care capable adults aged 12 years or older with: ●Diagnosis of AML, high-risk MDS (10% or more blasts or intermediate-2 High-risk myeloproliferative neoplasms (IPSS ≥ 100 or ≥ 100; untreated or previously treated myeloblastic phase) isolated extramedullary CML or (Philadelphia chromosome-positive (Ph+)) AML Patients with myeloid malignancies and eligible active CNS disease; Adequate organ function as defined below: Liver function (bilirubin less than 2 mg / dL, less than 3 × ULN, if related to leukemia) AST and / or ALT <5×ULN) Renal function (cretion less than 1.5 x ULN) except for those due to leukemia / hematological malignancies Atinine) Hyperbilirubinemia is acceptable if it is considered to be due to Gilbert's hyperbilirubinemia. Will be Baseline left ventricular ejection fraction (LVEF) was measured by echocardiography (Echo) or MUGA scan. 50% or more in the

[0416] In this study, patients with active heart disease (unstable coronary syndrome, unstable or severe angina, and and / or myocardial infarction (MI) within 6 months), decompensated heart failure (HF), Clinically significant arrhythmias, severe valvular disease, history of coronary artery disease (CAD), and compliance with study requirements Documented limiting psychiatric illness or any component of the chemotherapy program Hypersensitivity reactions reported and laboratory-based reactions that, as judged by the investigator, expose patients to unacceptable risk Patients with any other medical condition, including the presence of visual abnormalities, as well as those undergoing pregnancy and and / or breastfeeding women, and / or heterosexual intercourse with a negative urine pregnancy test within 7 days Continuous abstinence from sex or the use of at least one highly effective method of contraception Women of childbearing potential were excluded unless they had a confirmed commitment to do so.

[0417] Treatment. Chemotherapy is administered in stages from induction to consolidation and maintenance of remission as follows: It was.

[0418] Induction. Patients were treated with Mylotarg, Cladribine, Idarubicin, and Cytarabine (Dexamethasone). 1 or 2 cycles of induction therapy with razoxane (standard guidelines) Dexrazoxane at a 50:1 ratio of dexrazoxane to dexrazoxane: Idarubicin (e.g., idarubicin dose 10 mg / m 2 500 mg / m 2 )of Administer IV daily, 30 minutes before each dose of idarubicin. Idarubicin (with dexrazoxane) and cytarabine introduction: in the best interest of the patient Mylotarg 3mg if considered necessary (e.g. in refractory / recurrent or proliferative disease) / m 2 (maximum dose 4.5 mg) over 2 hours in up to 2 separate doses on days 1 and 4 IV administration: Cladribine 5 mg / m 2 / day, approximately 1-5 days daily IV over 2 hours; dexrazoxane at a dose of 500 mg / m2 / day, 1 to 3 Administer IV over 15-30 minutes on day 1, 30 minutes before idarubicin; Approximately 1 hour after initiation of cladribine infusion at a dose of 0 mg / m2 / day over 30 minutes on days 1-3 Start IV administration 1 to 2 hours later; cytarabine 1 g / m 2 / day dose, for 1-5 days Inject IV into the eye daily over 2 hours, approximately 3-6 hours after starting the Cladribine infusion ( 2 grams / m for healthy patients aged 60 years or younger 2 / day over 2 hours IV daily on days 1-5 In patients with a PS of 2 or greater or older than 60 years, cladribine and The number of days of administration of cytarabine was randomly selected to be 4 days (cladribine 5 mg / m 2 / day for days 1-4, Cytarabine 1 g / m2 / day administered IV over 2 hours on days 1-4) or for 3 days (clampsia) Drivine 5mg / m 2 / day on days 1-3, cytarabine 1g / m 2 / day on days 1-3 This can be shortened to IV administration over 2 hours per day. The number of days of administration of idarubicin (combined with idarubicin) was reduced to 2 days. 2 / day 1-2 days 3 IV over 10 minutes).

[0419] Patients who do not achieve CR / CRi after one induction course should receive a second induction course if possible. The second introductory course will be the same as the previous one. The doses may be administered in small doses or reduced doses as needed.

[0420] Consolidation of remission. Patients who achieved CR or CRi were treated with up to 6 cycles of consolidation therapy as follows: Mylotarg, Cladribine, Idarubicin, and Cytarabine Intensification: Irotarg 3mg / m 2 (maximum dose 4.5 mg) over 2 hours on day 1 of each cycle IV administration: Cladribine 5 mg / m 2 / day, approximately 1-3 days daily IV over 2 hours; dexrazoxane 400 mg / m 2 / day dose for 1-2 days Administer IV to the eye over 15-30 minutes approximately 30 minutes before idarubicin; 8 mg / m 2 / day over 30 minutes on days 1 and 2, at the time of starting the Ladribine infusion. One to two hours later, IV administration of cytarabine is started at 0.75 grams / m 2 / day dose, IV over 2 hours daily on days 1-3, approximately 3-6 hours after initiation of cladribine infusion (In healthy patients aged 60 years or younger, 1.5 grams / m 2 / days 1-3 (The drug is administered intravenously over 2 hours daily.) In patients with a PS of 2 or greater or age >60 years, For all drugs, the intensification is optionally shortened to 2 days. Cycles are approximately every 3-7 weeks, with several and depending on the resolution of toxicity. One cycle of treatment is considered to be 4 weeks. Cycles may be resumed at the start of the previous cycle depending on recovery of hematopoiesis and resolution of toxicity as determined by the treating physician. Subsequent cycle delays of more than 7 weeks should be reported to the supervisor. This may be permitted following consultation with the researcher and documentation of the consultation.

[0421] Maintenance Therapy. Continue monthly cycles to complete a total of 24 cycles of treatment: Mylotor 3 mg / m2 (maximum dose 4.5 mg) over 2 hours on day 1 of the first maintenance cycle IV, then optionally repeat on day 1 every 2 to 3 months; idarubicin 4 mg / m 2 of IV over 30 minutes on day 1; low-dose cytarabine 10 mg / m 2 on days 1-7 Dexrazoxane 50 mg subcutaneously BID for 7 days (may be self-administered at home): A dexrazoxane:idarubicin ratio of 1 (e.g., idarubicin 4 mg / m 2 2 for 00mg / m 2 ) over 15 minutes on day 1, approximately 30 minutes before each idarubicin dose. Administer V.

[0422] Maintenance cycles are approximately every 3-7 weeks (e.g., 2 Subsequent cycle delays of more than 7 weeks will be discussed with the principal investigator. may be granted after consultation and documentation of the consultation.

[0423] Patients deemed too unwell by their treating physician to continue standard induction / consolidation therapy Patients who were not enrolled or experienced significant toxicity from intensification were considered to progress directly to maintenance therapy for up to 24 cycles. A total of 32 studies were conducted, providing that clinical benefit continues and treatment is well tolerated. Patients suitable for transplant may be offered an allogeneic transplant at the discretion of the treating physician. The dose may be reduced after consultation with the principal investigator if clinically indicated. Cytarabine may be omitted during maintenance cycles of treatment if considered in the patient's best interest .

[0424] Targeted therapy, ruxolitinib, venetoclax, drugs for patients with FLT3 mutations agents (e.g., sorafenib, midostaurin, gilteritinib), Philadelphia stain Drugs for somatic negative diseases (e.g., tyrosine kinase inhibitors), myelofibrosis and other Drugs for myeloproliferative neoplasms (e.g., JAK2 inhibitors), drugs for patients with IDH2 mutations agents for patients with IDH1 mutations (e.g., iboshi denib), agents for patients with RAS mutations (e.g., trametinib), CNS disease Intrathecal prophylaxis with cytarabine for patients at risk for rheumatoid arthritis, including amifostine Supportive care, filgrastim / filgrastim-sndz or pegfilgrastim ( Other therapeutic agents, such as hematopoietic growth factors (eg, GCSF), may optionally be administered.

[0425] Ondansetron 8 to 16 mg IV before chemotherapy (except for subcutaneous cytarabine), induction Methylprednisone 40 mg IV daily prior to each cytarabine dose during the initiation and consolidation phases; Prednisolone acetate ophthalmic solution 1% (2 drops in each eye 4 times a day, instilled simultaneously with cytarabine infusion) (continue for at least 2 days during induction and consolidation after the last dose of cytarabine) Premedication / supportive care for induction, consolidation, and maintenance chemotherapy may be used.

[0426] Antioxidants, Minerals, and Vitamins Metal chelation enhances antioxidant and mineral zinc, cerium, and vitamin B12 levels. It can deplete calcium, vitamin C, and magnesium, so these antioxidants and minerals Neural is supplemented during treatment to achieve metal rebalancing. The following antioxidant vitamins and Daily doses of zinc and minerals are administered: zinc 50 mg (monomethionine or zinc citrate); Vitamin C 1000 mg selenium 20, optionally combined with dihydroquercetin (10 mg) 0 μg, combined with vitamin E (20.1 mg as D-α tocopherol succinate) L-selenomethionine sodium selenite 200μg, and magnesium (magnesium citrate (as magnesium) 160mg.

[0427] Evaluation. The abundance of toxic and essential metals and copper isotopes is important in the treatment of hematological malignancies. During chelation therapy, before treatment (within 28 days), and approximately 1 month ± 1 week, 3 months All patients had bone marrow and peritoneal examinations at up to three follow-up times: 0.05 ± 2 weeks, ... and 6 months ± 2 weeks. Measured in serum Approximately 5 ml of blood is drawn at each time point for serum metal analysis. Approximately 1 mm of bone marrow biopsy and / or approximately 400 μL of bone marrow aspirate will be obtained.

[0428] Metals evaluated include, but are not limited to, lead (Pb), cadmium (Cd), and Cadmium (Cd), Mercury (Hg), Nickel (Ni), Cobalt (Co), Chromium (Cr), Aluminum (Al) Aluminum (Al), Arsenic (As), Calcium (Ca), Selenium (Se), Magnesium These include magnesium (Mg), copper (Cu), and zinc (Zn). Bone marrow (approximately 1 mm biopsy and / or approximately 400 μL aspirate) is stored at -20 to -80°C. The samples were frozen and shipped on dry ice to the Geosciences Lab in Lyon. Aliquots of each sample were diluted with HNO3 and H2O2 at 130°C. The samples were digested and mineralized in a PFA container at 100 °C and evaporated in concentrated HCl at 120 °C in a laminar flow hood. The stable, dried specimen is ready for analysis. The trace metal content is determined using inductively coupled plasma Determined using mass spectrometry (ICP-MS).

[0429] Response criteria (e.g., AML, and myeloblastic phase of MPN) are the same as those used below. etc.

[0430] Results. The results are shown in Table 8 below.

[0431] [Table 9]

[0432] Additionally, dexrazoxane, zinc, selenium, magnesium, vitamin C cladribine; and idarubicin, cytarabine, and Mylotarg (CLIA-M) standard AML therapy. Six patients with frontline, secondary, or relapsed / refractory AML treated in clinical trials Of patients with CR, 4 / 6 patients achieved complete remission (n=2), with incomplete platelet recovery Clearly favorable results, including complete remission (n=1) and morphologically leukemia-free state (n=1) Responses were observed within one cycle of treatment. 2 / 6 patients who did not respond after one cycle One patient had recurrent / refractory metastatic ovarian cancer and developed AML The patient had previously failed treatment for therapy-related MDS. and dexrazoxane, antioxidants / minerals, and standard chemotherapy (CLIA-M) The other patient was resistant to zimene. Before starting the magnesium, vitamin C, and CLIA-M trial, six AML patients had already been diagnosed with The patients were very heavily pretreated refractory AML patients who had failed previous chemotherapy regimens. Treated with Zoxan, zinc, selenium, magnesium, vitamin C, and CLIA-M. The clinical courses of these six cases are described below.

[0433] Positive responses after one cycle of treatment were observed in 4 / 6 patients. , dexrazoxane, zinc, selenium, magnesium, vitamin C, cladribine, ida Treated with standard AML therapy (CLIA-M) of rubricin, cytarabine, and mylotargin It was.

[0434] Patient 1: A woman aged 55-60 years diagnosed with hypocellular myelofibrosis (MF) was undergoing treatment for MF. The patient developed secondary AML during the course of the disease. Cytogenetics showed monosomy 7. Molecular Studies have revealed mutations in ASXL1, CEBPA, ETV6, and RUNX1. Dexrazoxane, zinc, selenium, magnesium, vitamin C, and CLIA-M After one cycle, the patient achieved morphologically leukemia-free status (MLFS) and all mutations were detected. It became impossible.

[0435] Patient 2: Targeted chemotherapy with daunorubicin and cytarabine (also known as "7+3") A patient with primary refractory AML and chromosomal translocation t(3;3) presented after failure of standard chemotherapy. (q21;q26.2) and FISH (fluorescence in situ hybridization), MECOM (E 40-40% of patients have harmful cytogenetics, including harmful gene rearrangements due to VI1) A 5-year-old female. The patient was treated with dexrazoxane, zinc, selenium, magnesium, vitamin C, and The patient was treated with a CLIA-M regimen of dexrazoxane, zinc, selenium, and magnesium. After one cycle of sodium, vitamin C and CLIA-M, the patient had normal neutrophil and platelet counts. The patient achieved CR with partial recovery (CRi). The cytogenetic burden of the t(3;3) abnormality was 6 The involvement of 1 metaphase was reduced to 3 metaphases. Similarly, the follow-up FISH results showed , the burden of MECOM (EVI1) gene rearrangements decreased from 75 / 200 to 15 / 200. The patient subsequently achieved a CR.

[0436] Patient 3: Normal karyotype and multiple molecular mutations (DNMT3A, FLT3-D835, IDH Women aged 55 to 60 years with AML associated with 2, NMP1, and PTPN11 were treated with FLT. 3-D835 (midostaurin) and IDH2 (enasidenib, IDHIFA) mutations Along with standard targeted agents for vascular endothelial cell carcinoma, dexrazoxane, zinc, selenium, magnesium, vitamin After one cycle of treatment, the patient achieved complete response. It became like this.

[0437] Patient 4: A 55-60 year old man with AML had normal karyotype AML and these mutations ( NOTCH1, IDH2, DNMT3A, and BRINP3 mutations). 1 cycle of razoxane, zinc, selenium, magnesium, vitamin C, and CLIA-M The patient subsequently achieved CR.

[0438] Patient 5: Patient with metastatic stage IV ovarian cancer who developed high-risk treatment-related MDS. A woman aged 50-55 years with MDS. The patient had failed MDS therapy and progressed to secondary therapy-related AML. The patient had multiple adverse features, including a complex karyotype and a P53 mutation. After failing baseline AML therapy, the patient was treated with dexrazoxane, zinc, selenium, and magnesium. Within one cycle, the patient was treated with a regimen of 50 mg / kg / day, 50 mg / kg / day, 50 mg / kg / day, and 50 mg / kg / day of 1 ... experienced multiple infectious complications, including disseminated cutaneous fusarium, and ultimately The patient was transferred to ER. The patient's leukemia did not respond to treatment.

[0439] Patient 6: A 70-75 year old male with progressive refractory AML had undergone six prior AML therapies. After failure of previous treatment, dexrazoxane, zinc, selenium, magnesium, and bile Standard treatment enasidenib regimen for TAMIN C, CLIA-M, and IDH2 mutations At the start of the treatment, the patient had peripheral blood blasts of 94%. During one cycle, the patient's peripheral blood The blast cell count had decreased to about 50%. The patient also reported extensive oral leukemic infiltration of the gingiva (also known as "dental leukemia"). The patient also showed a significant improvement in bone marrow hyperplasia (BMHD). No evaluation was received.

[0440] AML, high-risk MDS, myeloblastic phase of CML, Ph+AML, and myeloblastic phase of MPN Ca-EDTA and DMSA in (NCT03630991) Ongoing research is being conducted on both calcium edetate disodium (EDTA) (Ca-ED 1) To improve clinical outcomes using TA and dimercaptosuccinic acid (DMSA) elimination of toxic metals during AML therapy; 2) MDS for reducing the rate of transformation from MDS to AML The effectiveness of the removal of toxic metals during therapy is monitored by a method similar to that described in Additional data from patients treated with -EDTA are presented below. Therefore, in what follows, either the past tense or the present tense may be used.

[0441] Study endpoints included: In AML patients receiving treatment in combination with DMSA and / or Ca-EDTA Complete remission (CR) rate and 1-year overall survival (OS) rate in In MDS patients receiving treatment in combination with DMSA and / or Ca-EDTA CR rate, partial response (PR) rate, and 6-month cytogenetic response in patients with refractory myeloma; - AML and MDS therapy in combination with DMSA and / or Ca-EDTA Overall survival in patients with AML and MDS; -AM receiving AML and MDS therapy in combination with DMSA and Ca-EDTA Duration of remission in L and MDS patients; Toxic and clinically significant effects of DMSA and / or Ca-EDTA in combination with AML and MDS therapy and essential metal levels; Newly diagnosed patients undergoing metal detoxification combined with standard AML / MDS therapy Reduction of bone marrow and blood metals in patients with AML and MDS; - AML and MDS therapy in combination with DMSA and / or Ca-EDTA Safety profile in patients with AML and MDS; Correlation of the degree of metal chelation with the degree of treatment response and minimal residual disease (MRD); and • Progression rate in patients with MDS.

[0442] Patients. Ambulatory, self-care capable subjects aged 18 years or older with: Low-risk cytogenetic, low-risk molecular, or secondary AML (i.e., therapy-related Newly diagnosed (or untreated) (treatment)AML. Newly diagnosed (or untreated) myeloblastic phase of MPN (including myeloblastic phase of CML) ; • Newly diagnosed (or untreated) high-risk, very high-risk or secondary MDS; Newly diagnosed (or untreated) MDS / MPN (related to cytogenetic / molecular status) without); Relapsed and / or refractory AML, MDS, MDS / MPN, myeloblastic stage of MPN (C including the myeloblastic phase of ML), either salvage 1 or salvage 2; If already receiving treatment, it is within the first 3 cycles of frontline therapy and the benefit of treatment Patients receiving chemotherapy or salvage therapy.

[0443] The study included patients with poorly controlled comorbidities and those who were pregnant and / or breastfeeding. Women and / or those with a negative urine pregnancy test within 7 days and continuous abstinence from heterosexual intercourse or commit to using at least one highly effective method of contraception. In addition, women of childbearing potential were excluded.

[0444] Treatment: Broad-spectrum metal detoxification and rebalancing includes Ca-EDTA, DMSA, and Daily oral antioxidants, vitamins, and minerals (vitamin C, vitamin E, vitamin K, Amines, Riboflavin, Niacin, Pantothenic Acid, Vitamin B6, Folate, Vitamin B 12. Biotin, choline, magnesium, zinc, selenium, inositol, and / or rubiol Detoxification / rebalancing should be considered in conjunction with planned chemotherapy or other planned transfusions. The solution is administered four times per cycle. Any solution that facilitates administration four times per cycle is available. This study allows for a schedule in which one cycle is the usual treatment for AML or MDS. The expected duration of one cycle is approximately one month (± 1 week), but is not limited to this. However, it may be longer depending on chemotherapy delays or other circumstances. The combination of a-EDTA and DMSA provides optimal broad-spectrum metal detoxification. It is widely used in.

[0445] Ca-EDTA was administered after six cycles of planned leukemia / MDS therapy or other planned For example, Ca-EDTA is administered for 4 days per cycle in a planned It may be administered starting on day 1 of chemotherapy and continued daily on days 2-4. Missed doses should be A cycle consists of four doses of Ca-EDTA. The target dose of Ca-EDTA is 1 g / m 2 The intended starting dose is -1 dose level. Bell (0.75g / m 2 Ca-EDTA is prepared according to standard techniques and has a concentration of about 2 It is administered IV in 50 cc of saline over approximately 30 minutes. It is not administered concomitantly with chemotherapy; it may be administered before or after (preferably before) chemotherapy.

[0446] DMSA is administered daily for 8 days starting on days 1 ± 3 of MDS or AML. As long as eight doses of DMSA are administered during the cycle of MDS / AML therapy, treatment support is available. Other schedules are permitted during the cycle. The target dose is 500 mg (approximately 350 mg). mg / m 2 The intended starting dose is dose level-1 (maximum 375 mg , approximately 262.5 mg / m 2 DMSA is used prior to oral leukemia therapy / chemotherapy. or administered at least one hour later.

[0447] Dose-limiting toxicities (e.g., hypocalcemia, hypomagnesemia, zinc deficiency, copper deficiency) If no adverse events (e.g., hypercalcaemia, low ferritin) are present, dose escalation may proceed as follows:

[0448] [Table 10]

[0449] A daily multivitamin and mineral to replace anticipated losses during a chelation regimen is administered for 28 consecutive days ± 1 week per cycle. An example of a supplement is shown in Table 10 below.

[0450] [Table 11]

[0451] Evaluation. Toxic and essential metals are therapeutically important during the treatment of hematological malignancies and chelation therapy. Before treatment (within 28 days), and approximately 1 month ± 1 week, 3 months ± 2 weeks, and 6 months Measured in bone marrow and serum of all patients at up to three follow-up time points ±2 weeks. Approximately 5 ml of blood is taken for serum metal analysis. A bone marrow biopsy and / or approximately 400 μL of bone marrow aspirate will be obtained.

[0452] Metals evaluated include, but are not limited to, lead (Pb), cadmium (Cd), and Cadmium (Cd), Mercury (Hg), Nickel (Ni), Cobalt (Co), Chromium (Cr), Aluminum (Al) Aluminum (Al), Arsenic (As), Calcium (Ca), Selenium (Se), Magnesium These include magnesium (Mg), manganese (Mn), copper (Cu), and zinc (Zn). Approximately 1 mL) and bone marrow (approximately 1 mm biopsy and / or approximately 400 μL aspirate). The samples were frozen at -20 to -80 °C and stored on dry ice at Geosciences, Lyon. The samples were sent to the ES Lab in batches. Aliquots of each sample were diluted with HNO3 and H2O2. Therefore, digestion and mineralization were performed in a PFA container at 130 °C, followed by incubation in a laminar flow hood at 120 °C for 1 h. Evaporate in HCl. The stable dry specimen is ready for analysis. The trace metal content is , determined using inductively coupled plasma mass spectrometry (ICP-MS).

[0453] NGS 300 gene panel testing was also performed on BM aspirates from enrolled patients (preferred ) or blood (approximately 3-5 mL for bone marrow or approximately 5-10 mL for blood). will also be implemented.

[0454] Metal reductions from baseline will be compared between responders and non-responders. AML / MD Among responders and non-responders to the S regimen plus the chelators DMSA and Ca-EDTA At each time point when metal levels were measured, a two-sample t-test was performed if the data were normal, and if not, If no significant difference was found, the degree of metal chelation was compared using the Wilcoxon rank-sum test. Correlations between gene mutations, MRD status, and genomic DNA fragment size will be evaluated using t-tests. Logistic regression We applied this method to examine the association between cytokine responses and changes in essential metal levels and other clinical predictors. Additionally, we fit a linear mixed model to examine the relationship between the time course and all the measurements. to assess the difference in metal content between responders and non-responders.

[0455] Response criteria for myeloblastic phase of AML and MPN. Myeloblastic phase of AML and MPN The response criteria are based on the International Working Group for A The results are revised from ML (JCO2003;21:4642-9). Responders were cytogenetic CR, CRi, with or without clinical response, hematological improvement, and morphologic leukemia-free status or patients who achieved partial response.

[0456] Overall survival (AML, MPN, MDS, etc.) is the time from the start of treatment to death or last follow-up. The time to event endpoint, such as overall survival, is defined as the time to event. Distribution was estimated using the Kaplan-Meier method. Comparisons of time endpoints (e.g., differences in time to treatment) were performed using the log-rank test. conduct.

[0457] Complete remission (CR) is defined as: Undetectable disease, including extramedullary leukemia. Clinical and / or radiological evidence of disease progression; neutrophil count ≥ 1.0 × 109 / L; Platelet count ≥ 0.00 × 109 / L and bone marrow differential showing ≤ 5% blasts; no circulating blasts Peripheral blood count: no abnormalities, neutrophil count ≥ 1.0 × 109 / L, platelet count ≥ 100 × 109 / L and bone marrow aspirate and biopsy results showing less than 5% blasts, no Auer rods, and no extramedullary leukemia. Inspection.

[0458] Complete remission with incomplete blood count recovery (CRi) is defined as: residual neutrophils Thrombocytopenia (ANC less than 1.0×109 / L) or thrombocytopenia (ANC less than 100×109 / L) All criteria for CR are met except for either circulating blasts or platelet count. low peripheral blood count, neutrophil count less than 1.0 × 109 / L, platelet count less than 100 × 109 / L; and bone marrow aspirate and biopsy showing less than 5% blasts, no Auer rods, and no extramedullary leukemia. .

[0459] A partial response is a 50% or greater decrease in bone marrow blasts, but not a cure unless the blasts are still greater than 5%. CR criteria were defined as any CR criterion that was abnormal prior to treatment.

[0460] A morphologic leukemia-free state is defined as having a bone marrow with 5% or less myeloblasts.

[0461] Hematological improvement (HI) is expressed as the number of positively affected cell lines: Erythrocyte response (E) (pretreatment Hgb < 11 g / dL): Hgb > 1.5 g / dL Increase in Platelet response (P) (100 x 10 9 / L pretreatment platelets): -20×10 9 30 × 10 for patients starting with platelets > 1 / L 9 / L or more absolute Increase -20×10 9 / L to 20 x 10 9 / L, at least a 100% increase Neutrophil response (N) (pretreatment ANC less than 1.0×109 / L): - At least 100% increase and 0.5×10 9 Absolute increase > 1 / L - Blast response (Bl) - A 50% or greater decrease in the percentage of blasts in the bone marrow and / or total blasts in the peripheral blood A reduction in pitch count of more than 50%.

[0462] Response criteria in MDS. Response criteria are based on the International Working Group (Blood 2006;108:419-425). , with or without cytogenetic response, hematologic improvement, and morphologic leukemia-free status Patients achieved R, CRi, or PR.

[0463] A morphologic complete response (CR) was defined as a peripheral blood count of ≥ 1.0 × 109 / L with no circulating blasts. neutrophil count of 100 × 109 / L or greater; platelet count of 100 × 109 / L or greater; bone marrow perfusion with <5% blasts Sputum and biopsy, defined as no extramedullary leukemia.

[0464] A partial response is defined as a 50% or greater decrease in bone marrow blasts, except if the decrease is still greater than 5%. Patients are defined as having all CR criteria if they were abnormal prior to treatment.

[0465] Bone marrow CR was defined as a 50% decrease in bone marrow blasts (5% or less) compared to pretreatment; If there are I responses, they are defined as having a bone marrow CR plus .

[0466] The other criteria are defined above.

[0467] Results. The results are shown below.

[0468] Ca-EDTA chelation, antioxidants, minerals, standard AML or MDS therapy In both treated patients, positive responses were observed after one cycle of treatment as follows:

[0469] Patient 1: Patient with heavily pretreated metastatic stage IV ovarian cancer with low-risk A woman aged 75-80 years with multiple myelodysplastic syndromes (MDS). The MDS is associated with p53 mutations and monosome 7. The patient had adverse clinical features, including monosomal karyotype (-7). Standard MDS therapy was started. In addition, the patient was given zinc, selenium, magnesium, and vitamin D supplements. Combined with a daily mineral and antioxidant supplement including Tammin C, 0.75 g / m2 After one cycle of treatment, the patient's p53 mutation was undetectable. In addition, the patient's CA-125 level decreased from 832.9 to 803.3. Ta.

[0470] The observation that p53 mutations become undetectable during MDS therapy is a promising path forward for the clinical diagnosis of MDS. This was unexpected in the published literature on decitabine alone in treatment and AML / MDS. For example, the New England Journal of Medicine, lch et al. reported a case of MDS / AML that achieved remission, but p5 None of the 3 mutations demonstrated a reduction to undetectable levels. Complete clinical remission Even in patients who showed a phenotype similar to that of decitabine, the elimination of P53 protein mutations was not observed in those who responded to decitabine. It was by no means complete (Welch et al., 2016).

[0471] Patient 2: Normal karyotype and multiple molecular mutations (FLT3-ITD, IDH1, NRAS, U2 A woman aged 65-70 years with AML associated with AF1, DNMT3A, and BCOR was cured. Patients were treated with decitabine x 10 days, venetoclax, and standard of care FL. FLT3-inhibitors (midostaurin) for T3-ITD mutations Patients received standard AML therapy, including chemotherapy, chemotherapy with zinc, selenium, magnesium, and tetrahydrocannabinol. combined with a daily mineral and antioxidant supplement including vitamin C. 0.75g / m 2 After one cycle of treatment, the patient's bone marrow blasts significantly decreased from 85% to 4%, and the FLT3-ITD ratio decreased from 0.35 to 0.02. The patient demonstrated a complete bone marrow response, but blood count recovery was incomplete.

[0472] Furthermore, the results of the above studies yielded the responses shown in Table 11.

[0473] [Table 12]

[0474] Most (5 / 6) frontline AML patients received over-the-counter decitabine for 10 days + over-the-counter These patients received the same hypomethylating agent-based treatment in the venetoclax protocol. All five patients had either high-risk / unfavorable-risk AML or secondary AML. Considering this, a CR / CRi ratio of 100% is favorable.

[0475] The aforementioned clinical trials of metal detoxification combined with standard therapy for MDS and AML have demonstrated that this combination The combination results in favorable overall responses, as well as cytogenetic and molecular responses. The results suggest that metal detoxification plus antioxidants / minerals may be beneficial in patients with AML and MDS. These trials of cyclophosphamide + standard therapy have shown good clinical responses. For example, as shown in Table 10 , metal chelator dexrazoxane + antioxidants / minerals (NCT03589729 ) + frontline de novo AML (5 / 5) treated with standard chemotherapy or 100% of patients with first salvage relapsed / refractory AML (4 / 4) were fully Remission (CR) or CR with incomplete neutrophil recovery (CRi) was achieved (Table 10).

[0476] Metal detoxification for high-risk and treatment-related MDS. As shown in Table 11, either DMSA or Ca-EDTA and minerals / antioxidants (Table 1 0) according to protocol 2017-0752 (NCT036 30991), who received standard-of-care hypomethylating agent-based therapy in conjunction with metal detoxification / rebalancing. The CR rate for the five patients with high-risk or treatment-related MDS was 4 / 5 (80%). one patient reported that a previously detected TP53 mutation became undetectable after one cycle Along with the unexpected positive findings, the patient had stable disease (blasts decreased from 4% to 2%). Four of these five patients with high-risk or treatment-related MDS received standard of care decitabine. × 3–5 days (n=4); 1 patient received standard of care azacitidine × 7 days + The clinical course of hypomethylating agent-based therapy in higher-risk MDS patients is as follows: In the literature, the overall response rate is 38-49%. Sekeres MA, et al. domized Phase II Study of Azacitidine Al one or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelod ysplastic Syndromes and Chronic Myelomon ocytic Leukemia: North American Intergrou p Study SWOG S1117.

[0477] Improved cytogenetic and molecular profile during treatment. Standard frontline or salvage therapy + metal chelator dexrazoxane + anti-inflammatory In 8 / 10 AML or high-risk MDS patients receiving oxidants / minerals, No detectable genetic or molecular abnormality (e.g., FLT3-ITD, t(3;3 ), RUNX1). Protocol 2017-0752 (NCT03630991) Detoxification (Ca-EDTA or DMSA) + antioxidants / minerals + standard therapy (Table 1B) High-risk MDS / AML, therapy-related MDS / AML, relapsed / refractory MDS / Good responses were also observed in patients with AML. AML (n=1) or secondary AML [n=5, (therapy-related AML, n=2; previous hematology (Progression from chronic obstructive pulmonary disease, n=3) and other frontline AML therapies. All high-risk AML patients achieved CR (n=5) or CR with partial platelet recovery (C In addition, 4 / 5 patients with high-risk MDS / treatment-related MDS achieved either A patient with DS achieved a CR, and one patient with refractory MDS / MPN achieved a CR. High-grade patients who underwent metal detoxification with standard therapy using Ca-EDTA or DMSA + antioxidants / minerals In 4 / 5 evaluable patients with high-risk MDS / AML, cytogenetic or Molecular abnormalities became undetectable.

[0478] Decreased burden of mutated TP53. Either Ca-EDTA or DMSA in combination with standard MDS / AML therapy A decrease in TP53 mutation burden was observed during treatment with Of the five patients with MDS / AML, 100% had reduced TP53 burden. In 3 / 5 patients, next-generation sequencing bone marrow samples collected after cycle 1 In 2 of these cases, however, the TP53 mutation was undetectable; It was redetected at a later date, but only at very low levels (<2% mutant allele frequency). .

[0479] Comparison with standard treatment In comparison, based on the current literature on frontline AML, Only approximately 60%-70% of adults achieve a CR after standard induction therapy alone. Lambert J et al., Haematologica, 2019 Ja See n;104(1):113-119. The complete remission rate is lower, estimated at up to 50%. cat JE et al.,Ann Hematol.2018 Jul;97(7) :1115-1153) and Chevallier P et al., J Clin. See Oncol,2008 Nov 10;26(32):5192-7.

[0480] Furthermore, unpublished data suggest that standard of care / commercially available decitabine 10 mg / kg / day without metal detoxification Compared with patients on the same protocol of 24 days + venetoclax (90%), 2017-0752) (NCT03630991), the standard of care / commercially available decitabine 10 Five patients received venetoclax and metal detoxification / rebalancing in combination (Table 11, below) (indicated by an asterisk in the figure) had a higher CR / CRi ratio (100%) [CR(n=5) / C Ri (n=1)]. Patients receiving either Ca-EDTA or DMSA + antioxidants / minerals Simultaneous enrollment in a clinical trial of metal detoxification and rebalancing supportive care (NCT03630991) (If eligibility criteria are met) Concurrent metal detoxification and rebalancing protocols Of 48 frontline AML patients of all risk types who did not enroll in Patients (90%) achieved CR / CRi. Five separate patients (listed in Table 11) who underwent metal detoxification and rebalancing at the same time as the All 5 / 5 (100%) of patients with high-risk / secondary AML achieved CR / CRi. None of these five patients who received a simultaneous metal detoxification and rebalancing regimen had any preference. This result is noteworthy, given that no significant risk of heart failure was associated with metal detoxification or Many patients receiving standard therapy who did not receive a concomitant rebalancing regimen had a significantly favorable outcome. Of these newly diagnosed patients, 48 ​​patients were at high risk for Eleven had favorable risk and the remainder had intermediate or unfavorable risk AML.

[0481] A paper on the standard treatment, hypomethylating agent therapy + venetoclax, also recommended rebalancing therapy. When added, the CR / CRi ratio was shown to be lower than 100% [CR(n= 5) / CRi(n=1)]. DiNardo CD et al., “Venetocl ax combined with decitabine or azacitidi ne in treatment-naive,elderly patients w ith acute myeloid leukemia,”Blood,2019 J an 3;133(1):7-17, of which 67% achieved CR+CRi. We report on patients aged 65 years or older (N=145) with previously unresectable AML.

[0482] Therefore, for the detoxification and rebalancing of metals in leukemia patients undergoing anticancer pharmacological therapy , in combination with antioxidants, minerals, vitamins, and / or free radical scavengers. Rate therapy may also be used.

[0483] All of the methods disclosed and claimed herein can be made without undue experimentation in light of the present disclosure. The compositions and methods of the present invention have been described in terms of preferred embodiments. However, the invention may be modified in a manner not construed as limiting the present invention, without departing from the concept, spirit and scope of the present invention as described herein. It will be apparent to one skilled in the art that the method and its steps or the order of steps may be varied. More specifically, certain agents that are both chemically and physiologically related may be identical or similar. It will be apparent that the agents described herein may be substituted while still achieving the results. All such similar substitutes and modifications apparent to those skilled in the art are intended to be encompassed within the scope of the appended claims. are deemed to be within the spirit, scope and concept of the invention as defined thereby.

[0484] References The following references provide exemplary procedures or equivalents which supplement those described herein: To the extent that other details are provided, they are specifically incorporated herein by reference. Takenaga et al., J. Control Release, 52(1-2 ):81-87,1998. Remington's Pharmaceutical Sciences” 15t h Ed.,1035-1038 and 1570-1580,1990. Remington's Science and Practice of Phar macy,21st Ed.,Mack Printing Company,2005 . Remington’s Pharmaceutical Sciences, 18t h Ed.Mack Printing Company,1289-1329,199 0. Mathiowitz et al.,Nature,386(6623):410-4 14,1997. Hwang et al.,Crit.Rev.Ther.Drug Carrier Syst.,15(3):243-284,1998. U.S.Pat.Nos.6,7537,514,6,613,308,5,466,4 68,5,543,158;5,641,515;and 5,399,363 VanLandingham et al.,2002;Ostrakhovitch and Cherian,2005 Flora and Pachauri.Int J Environ Res Pub lic Health.2010;7(7):2745-2788. FDA.DIMERCAPROL INJECTION,USP:BAL in Oil Ampules. Lamas et al.Ann Intern Med.2013;159(12): 797-805. Lamas et al.Am Heart J.2014;168(1):37-44 e35. Lamas et al.Jama.2013;309(12):1241-1250. 99207-240-05 NCs,Corp PMP.CALCIUM DISODI UM VERSENATE-edetate calcium disodium in jection:Package Insert 2013; Bradberry et al.QJM.2009;102(10):721-732 . . . . Pharmaceuticals O.CHEMET(Federal)FDA Packag and Insert.2007; Bose-O'Reilly et al.Sci Total Environ.20 03;307(1-3):71-82. List AF.Cancer Control.2010;17 Suppl:2-8 . . . . Cermak et al.Hemoglobin.2011;35(3):217-2 27. Cermak et al.Leuk Res.2013;37(12):1612-1 615. Vachhani et al.Leuk Res Rep.2017;7:36-39 . . . . Schloemer et al.J Pediatr Hematol Oncol. 2017;39(5):e254-e258. Walker et al.Pediatr Blood Cancer.2013;6 0(4):616-620. Woodlock et al.Am J Hematol.1998;59(3):2 46-248. FDA.ZINECARD(drug)(dexrazoxane)for injec tion.2014. Fu et al.Mol Cancer Ther.2012;11(6):1221 -1225. Chan et al.Clin Cancer Res.2016. FDA.Ethyol(drug)(amifostine)for Injectio n, 2018. Welch et al.N Engl J Med.2016;375(21):20 23-2036. Frullano et al.Curr Org Synth.8(4):535-5 65,2011. Koedrith P,im H, Weon JI,et al.,Int J Hy g Environ Health 2013;216:587-598. Garcia-Perez J et al.,Environmental rese arch 2015;140:542-553. Van Laecke S et al.,Leukemia 2014;28:729 -731. Birt DF,Magnesium 1989;8:17-30. Su Yet al.,Clin Chim Acta 2011;412:2305- 2309. Wen CP et al.,Cancer Res 2014;74:6589-65 97. Hong M,He G.016 J Transl Int Med 2017;5: 69-71. Huh YO et al.,American journal of clinic al pathology 2001;116:437-443. Ravandi F et al.,Cancer 2017;123:426-435 . Gonzalez Garcia JR et al.,Blood 2006;108 :3952-3953;uthor reply 3953. Poirel H et al.,Blood 1996;87:2496-2505. Boissel N et al., Blood 2005;106:3618-362 0. Boissel N et al., Leukemia 2002;16:1699-1 704. Preudhomme C et al., Blood 2002;100:2717- 2723. Wolff DJ et al., J Mol Diagn 2007;9:134-1 43. Dohner H et al., Blood 2017;129:424-447. Trinidad AG et al.,Mol Cell.2013;50(6):8 05-817

Claims

1. A therapeutically effective amount (i) one or more metal chelators; (ii) anti-cancer therapy; and (iii) optionally, at least one antioxidant, vitamin, or essential mineral; 23. A method of treating a disease in a mammalian subject comprising administering to the subject a

2. The antioxidant, vitamin or mineral is zinc, selenium, magnesium, rubidium, and vitamin C.

3. At least one of zinc, selenium, magnesium, and vitamin C is administered.

2. The method according to claim 2.

4. At least two of zinc, selenium, magnesium, and vitamin C are administered.

3. The method according to claim 3.

5. 5. The method of claim 4, wherein zinc, selenium, magnesium, and vitamin C are administered.

6. wherein the one or more metal chelators are broad spectrum metal chelators. The method according to claim 5.

7. At least one of the one or more metal chelators is capable of chelating at least two metals. The method of claim 6, wherein the signal is rated.

8. The one or more metal chelators reduce the levels of the at least two metals. The method of claim 7, wherein the method is administered in an amount effective to induce

9. The one or more metal chelators are EDTA, dimercaptosuccinic acid (DMSA), ), 2,3-dimercapto-1-propanesulfonic acid (DMPS), BAL, N-acetyl Lucisteine ​​(NAC), Deferasirox, Deferiprone, Deferoxamine, Pen Calcium trisodium pentetate (Ca-DPTA), zinc trisodium pentetate (Zn -DPTA), trientine, tetrathiomolybdate, and dexrazoxane The method of claim 5 .

10. The metal chelating agent is dimercaptosuccinic acid (DMSA), 2,3-dimercapto -1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropyl)- diethyl phthalate (DMPA), calcium trisodium pentetate (Ca-DTPA), and 6. The method according to claim 5, wherein the active ingredient is selected from dimercaprol (BAL).

11. The method of claim 4 , wherein the metal chelator is a dithiol chelator.

12. The metal chelating agent is dimercaptosuccinic acid (DMSA), 2,3-dimercapto -1-propanesulfonic acid (DMPS), N-(2,3-dimercaptopropyl)- 5. The method of claim 4, wherein the organic solvent is selected from the group consisting of dimethylaminopropyl ester (DMPA).

13. The method of claim 4, wherein the metal chelator is an iron chelator.

14. The metal chelator is deferasirox, deferiprone, or deferoxamine The method according to claim 4, wherein

15. The metal chelator is N-acetylcysteine ​​(NAC); or a bifunctional gadolinium 5. The compound according to claim 4, which is a gadolinium chelator, such as a gadolinium(III) chelator. method.

16. The method of claim 4 , wherein the metal chelator is a copper chelator.

17. 17. The copper chelator of claim 16, wherein the copper chelator is trientine or tetrathiomolybdate. The method described above.

18. 5. The method of claim 4, wherein the metal chelator is dexrazoxane.

19. The method of claim 1 , wherein the disease is a proliferative disease.

20. The disease is cancer, myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), bone marrow 20. The method of claim 19, wherein the inflammatory bowel disease is selected from: bone marrow failure; and cytopenia.

21. 21. The method of claim 20, wherein the disease is cancer.

22. 22. The method of claim 21, wherein the cancer has recurred or is refractory to previous treatment. How to.

23. 22. The method of claim 21, wherein the cancer is a hematological malignancy.

24. 24. The method of claim 23, wherein the cancer is leukemia.

25. The leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CRL), or chronic myeloid leukemia (CHL).

2. The cancer is selected from chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).

5. The method according to claim 4.

26. 26. The method of claim 25, wherein the leukemia is AML.

27. 21. The method of claim 20, wherein the disease is myelodysplastic syndrome (MDS).

28. 21. The method of claim 20, wherein the disease is a myeloproliferative neoplasm (MPN).

29. 21. The method of claim 20, wherein the disease is a bone marrow disease or failure.

30. 21. The method of claim 20, wherein the disease is cytopenia.

31. 31. The method of claim 30, wherein the cytopenia is idiopathic cytopenia.

32. Claims: The method further comprises administering to the subject a therapeutically effective amount of an anti-cancer therapy. The method according to claim 1.

33. The anti-cancer therapy is a chemotherapy, an epigenetic therapy, an immunotherapy, or a targeted cancer therapy.

33. The method of claim 32, wherein the method is selected from the group consisting of

34. 34. The method of claim 33, wherein the anti-cancer therapy is chemotherapy.

35. The chemotherapy is selected from Mylotarg, Cladribine, Idarubicin, and Cytarabine.

35. The method of claim 34, comprising one or more agents selected from the group consisting of

36. The chemotherapy includes cladribine, idarubicin, and cytarabine ("CLIA"). The method of claim 34.

37. The chemotherapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and Cytarabine ("C 35. The method of claim 34, comprising the step of:

38. 35. The method of claim 34, wherein the anti-cancer therapy is an immunotherapy.

39. The immunotherapy is selected from a monoclonal antibody and an immune checkpoint inhibitor.

39. The method of claim 38.

40. The immunotherapy is selected from the group consisting of rituximab, ofatumumab, blinatumumab, inotuzumab , gemtuzumab ozogamicin, ipilumumab, and targeting PD-1 / PD-L1 39. The method of claim 38, wherein the inhibitor is selected from an immune checkpoint inhibitor.

41. The immune checkpoint inhibitor targeting PD-1 / PD-L1 is nivolumab, selected from pembrolizumab, atezolizumab, avelumab, and durvalumab; 40. The method of claim 39.

42. 35. The method of claim 34, wherein the anti-cancer therapy is a targeted therapy.

43. The targeted therapy is an FLT3 inhibitor, a BCR-ABL tyrosine kinase inhibitor, a JAK -2 inhibitors, IDH1 or IDH2 inhibitors, BCL-2 inhibitors, and gemtuzumab ozoga 43. The method of claim 42, wherein the anti-inflammatory agent is selected from the group consisting of cyclosporine and cyclosporine.

44. the disease is leukemia; the anti-cancer therapy is chemotherapy; zinc, selenium, magnesium 2. The method of claim 1, wherein all of the vitamin C and vitamin D are administered to the subject.

45. 45. The method of claim 44, wherein the leukemia is AML.

46. The chemotherapy includes cladribine, idarubicin, and cytarabine ("CLIA"). The method of claim 45.

47. The chemotherapy is selected from the group consisting of Mylotarg, Cladribine, Idarubicin, and Cytarabine ("C 46. ​​The method of claim 45, comprising the step of:

48. The method of claim 1 , wherein the subject is a human.

49. 12. The method of claim 11, wherein the human subject is a) having cancer; b) have elevated levels of one or more metals compared to healthy subjects; 49. The method of claim 48.

50. 49. The method of claim 48, wherein the elevated levels of one or more metals are measured in bone marrow or serum. The method described.

51. 49. The method of claim 48, wherein elevated levels of one or more metals are measured in bone marrow and serum. The method described.

52. 50. The method of claim 49, wherein the human subject has elevated levels of two or more metals. 。

53. The metal is arsenic (As), aluminum (Al), antimony (Sb), barium ( Ba), boron (B), cadmium (Cd), cerium (Ce), chromium (Cr), Lead (Pb), mercury (Hg), neodymium (Nd), nickel (Ni), tin (Sn), titanium 51. The method of claim 50, wherein the metal is selected from titanium (Ti), uranium (U), and vanadium (V). method.

54. The human subject is a person having calcium (Ca), magnesium (Mg), selenium (Se), zinc (Zn), and rubidium (Rb).

50. The method according to claim 50.

55. wherein the elevated and / or decreased levels are relative to the median of a non-diseased population. The method of claim 54.

56. The method further comprises reducing or eliminating one or more mutations or cytogenetic abnormalities in the cancer. The method of any one of claims 1 to 44, wherein the method results in the removal of

57. A therapeutically effective amount (i) one or more metal chelators; and (ii) at least one antioxidant, vitamin, or essential mineral; The method of claim 1, further comprising administering to the subject one or more of the following to the subject: Methods for reducing or eliminating mutations or cytogenetic abnormalities.

58. i) measuring the levels of two or more metals in one or more samples of serum or bone marrow from the subject; and ii) determining the level of each of said two or more metals in said sample from a healthy patient; and comparing the determined median value with each of two or more corresponding median reference values ​​for the same metal. iii) the levels of the two or more metals in the sample are greater than the median reference value; classifying the subject as having a chelation therapy responsive proliferative disorder if A method for diagnosing a subject having a chelation therapy responsive proliferative disease, comprising:

59. i) measuring the levels of two or more metals in one or more samples of serum or bone marrow from the subject; and ii) determining the level of each of said two or more metals in said sample from a healthy patient; and comparing the determined median value with each of two or more corresponding median reference values ​​for the same metal. iii) the levels of the two or more metals in the sample are greater than the median reference value; classifying the subject as having a chelation therapy responsive proliferative disorder if iv) a therapeutically effective amount of (a) one or more metal chelators; and (b) at least one of zinc, selenium, magnesium, rubidium and / or vitamin C; t to said subject; A method for diagnosing and treating a subject having a chelation therapy responsive proliferative disease, comprising:

60. (i) one or more metal chelators; (ii) at least one antioxidant, vitamin, or essential mineral, and (iii) a pharma- ceutically acceptable excipient; 20. A pharmaceutical composition or pharmaceutical combination comprising:

61. 61. The pharmaceutical composition or medicament of claim 60, further comprising at least one anti-cancer pharmacological therapy. Drug combination.

62. (i) one or more metal chelators; (ii) at least one anti-cancer pharmacological therapy; and (iii) a pharma- ceutically acceptable excipient; 20. A pharmaceutical composition or pharmaceutical combination comprising:

63. 63. The method of claim 62, further comprising at least one antioxidant, vitamin, or essential mineral. A pharmaceutical composition or pharmaceutical combination as described above.

64. 1. A metal chelator for use in a method of treating cancer in a mammalian subject, comprising: The method comprises administering to the subject a cancer therapy.

65. 1. An anti-cancer therapy for use in a method of treating cancer in a mammalian subject, said method comprising: An anti-cancer therapy comprising administering to said subject a metal chelator.

66. Methods for treating cancer comprising administering a metal chelator and / or a cancer therapy Select from zinc, selenium, magnesium, rubidium and vitamin C for use in the method , antioxidants and / or minerals, preferably essential minerals.

67. 1. A metal chelator for use in a method of treating cancer in a mammalian subject, comprising:

4. A metal chelator, the metal chelator being for administration in combination with a cancer therapy. Chemical agent.

68. 1. A cancer therapy for use in a method for treating cancer in a mammalian subject, comprising:

23. A cancer treatment method, wherein the method is for administration in combination with a metal chelator.

69. Zinc, selenium, magnesium, rubidium, and and / or an antioxidant selected from vitamin C and / or a mineral, preferably an essential mineral. The antioxidants and / or minerals are combined with metal chelators and / or cancer treatments. Antioxidants and / or minerals for co-administration.

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