Method for treating cancer by analysis of circulating tumor cells (CTCS)

Abstract

To provide a method for treating cancer that has high safety and improved therapeutic effect on cancer, and can prevent the metastasis and relapse of cancer, and a monitoring method that determines the therapeutic effect of PPAR-γ agonist in a cancer patient.SOLUTION: A method for treating cancer includes a first analysis step for analyzing circulating tumor cells (CTCs) in a mammal subject, a step for administering an effective amount of PPAR-γ agonist to a subject in need of treatment on the basis of the results of the analysis, and a second analysis step for analyzing circulating tumor cells (CTCs) in the subject who has undergone the administration of the PPAR-γ agonist.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for combination treatment of cancer patients determined to have peripheral blood circulating tumor cells with a PPAR-γ agonist.

Background Art

[0002] In advanced cancer and metastatic cancer, it is known that cancer cells enter the blood and circulate in the body. Cancer cells that have invaded blood vessels during such a metastasis process are called CTC: Circulating Tumor Cells (peripheral blood circulating tumor cells). The CTC test is a method for directly detecting cancer cells circulating in the blood (Patent Documents 1 to 5).

[0003] The CTC test as an indicator of cancer metastasis and treatment effect can detect even minute cancers that cannot be seen by imaging tests, and is thus also called molecular pathological examination (liquid biopsy). If the CTC test is positive, it is known that recurrence and metastasis can be predicted 1 to 4 years in advance.

[0004] Cancer originally has the characteristics of epithelial cells. However, in highly malignant cancers, the form as epithelial cells and the cell adhesion function with surrounding cells are lost, and a phenomenon called epithelial-mesenchymal transition (EMT), in which the ability to move and infiltrate into other tissues is acquired, occurs. It is known that this phenomenon is deeply involved in the most important issues in cancer treatment, namely cancer metastasis and recurrence. Therefore, if even one CTC is detected, there is suspicion of cancer onset and the possibility of cancer metastasis (Non-Patent Documents 1 to 3).

[0005] ​Cancer, when it undergoes EMT, has cancer stem cell-like traits, and it is known that even the daughter cells of normal cancer cells will transform into cancer stem cell-like properties when they undergo EMT. And the treatment with common anticancer drugs is guided by the shrinkage of solid tumors, targeting only the differentiated cancer cells that do not have the function of cancer stem cells, which account for the majority of the tumor. It has also been pointed out that some cancer stem cells have acquired drug resistance. Therefore, even if most cancer cells are removed by the treatment with anticancer drugs, if a very small number of cancer stem cells remain, recurrence will occur. That is to say, if cancer stem cells can be removed, it will be possible to prevent the metastasis and recurrence of cancer (Non-Patent Documents 4 to 5). From the above, it can be easily inferred that even if mesenchymal cells that have undergone EMT and acquired cancer stem cell-like traits are detected by CTC examination,

[0006] they are difficult to treat with common anticancer drugs. On the other hand, iodine exerts antitumor effects on various tissues (such as breast, prostate, thyroid, melanoma, pancreatic cancer, neuroblastoma cell lines, etc.), and the latest research suggests that these antitumor effects are involved in direct or indirect mechanisms (Non-Patent Documents 6 to 9).

[0007] In the direct effect of iodine, it has been reported that the mitochondrial membrane potential is disrupted due to the oxidation / antioxidation properties of iodine, possibly causing mitochondrial-mediated apoptosis (Non-Patent Documents 8, 11). In the indirect pathway, the generation of iodo lipid intermediates is involved, and 6-iodolactone (6IL) ~9).

[0008] In the direct effect of iodine, due to the oxidation / antioxidation properties of iodine, it has been reported that the mitochondrial membrane potential is disrupted, possibly causing mitochondrial-mediated apoptosis (Non-Patent Documents 8, 11). In the indirect pathway, the generation of iodo lipid intermediates is involved, and 6-iodolactone (6IL) ) is one of its intermediates. The presence of 6IL has been reported in the normal and tumor mammary glands of rats continuously administered iodine in the diet (Non-Patent Document 12). It has been reported in the normal and tumor mammary glands of rats continuously administered iodine in the diet (Non-Patent Document 12).

[0009] And in MCF-7 cells, which are breast cancer cell lines, 6IL has been reported to strongly stimulate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the expression of PPAR alpha (PPARα) (Non-Patent Document 13). And in MCF-7 cells, which are breast cancer cell lines, 6IL has been reported to strongly stimulate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the expression of PPAR alpha (PPARα) (Non-Patent Document 13). It has been reported to inhibit the expression of PPAR alpha (PPARα) (Non-Patent Document 13).

[0010] While PPARα is associated with cancer promotion (Non-Patent Documents 14 and 15), PPARγ (Non-Patent Documents 16 and 17) has been reported to be an antitumor agent because it inhibits proliferation, induces apoptosis, and promotes differentiation (Non-Patent Documents 18 and 19). Also, the opposing effects of PPARα and PPARγ have been reported in normal and tumor breast tissues and breast cell lines (Non-Patent Documents 20 and 21), and it has been reported that PPARγ is involved in cell division arrest of cancer, inhibition of EMT (epithelial-mesenchymal transition), induction of apoptosis, etc. lines (Non-Patent Documents 20 and 21), and it has been reported that PPARγ is involved in cell division arrest of cancer, inhibition of EMT (epithelial-mesenchymal transition), induction of apoptosis, etc. (Non-Patent Document 22). (Non-Patent Document 22). (Non-Patent Document 22).

[0011] Regarding the treatment of cancer with iodine, there are reports on the treatment of cancer using aqueous solutions of sodium iodide and potassium iodide, but in all cases, the evidence proving the mechanism of action and treatment effect of iodine is insufficient, and the conditions for administering iodine, the timing of administration, the duration of administration, and the dose are unknown (Patent Documents 6 and 7). dose are unknown (Patent Documents 6 and 7). (Patent Documents 6 and 7).

Prior Art Documents

Patent Documents

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Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Non-Patent Document

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Non-Patent Document 1

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Summary of the Invention

Problems to be Solved by the Invention

[0014] In recent years, various methods have been developed for detecting CTCs used in the analysis of circulating tumor cells in peripheral blood. Among them, the CellSearch system approved by the FDA is a method for detecting CTCs that uses EpCAM antibody as a surface marker for cancer cells. However, tumor cells that hardly or do not express EpCAM or cytokeratin (CK) have also been reported. Therefore, in this method that uses affinity depending on the expression level of the antigen, the cancer cells that can be captured ​​​​There was a limit to the cells.

[0015] On the other hand, the microfluidic chip method was developed to compensate for the drawbacks of CellSearch. In the microfluidic chip method, a capture rate of 94% has been obtained, as opposed to the 61% CTC capture rate of the CellSearch method, indicating extremely high sensitivity (Non-Patent Documents 23 and 24). It has been shown to be extremely sensitive. (Non-Patent Documents 23, 24).

[0016] In addition, Abnova's CytoQuest(™) CR is a technology that uses a microfluidic chip capable of capturing and isolating viable CTCs and releasing the CTCs captured by antibodies through a temperature change, and is capable of capturing CTCs with high sensitivity in the same way as the microfluidic chip method. It is possible to capture CTCs with high sensitivity in the same way as the microfluidic chip method. (Non-Patent Document 25). (Non-Patent Document 25).

[0017] Although various CTC testing devices based on other principles have been developed, the CTC analysis technology required in the present invention is the ability to analyze in detail the number, properties, and morphology of the captured cancer cells. That is, it is to be able to analyze in detail the number, properties, and morphology of the captured cancer cells. . For example, the captured cancer cells are simultaneously stained with DAPI (nuclear staining of cells), Cytokeratin (expressed in epithelial cells, epithelial-derived cells, and epithelial-derived malignant tumor cells), CD45 (expressed in all human white blood cells), and Vimentin (expressed in mesenchymal cells that have undergone EMT), and (1) epithelial-type CTCs, (2) CTCs having both epithelial and mesenchymal properties, and (3) mesenchymal-type CTCs are detected. Alternatively, by detecting CD44, the properties of cancer stem cells can be analyzed in detail (Non-Patent Document 26). By analyzing the properties of these cancer cells, it becomes possible to maximize the therapeutic effect of iodine, which is a PPAR-γ agonist. It becomes possible to maximize the therapeutic effect of iodine, which is a PPAR-γ agonist. It becomes possible to maximize the therapeutic effect of iodine, which is a PPAR-γ agonist. it becomes possible to maximize the therapeutic effect of iodine, which is a PPAR-γ agonist. (Non-Patent Document 26). By analyzing the properties of these cancer cells, it becomes possible to maximize the therapeutic effect of iodine, which is a PPAR-γ agonist.

[0018] Regarding its safety in iodine administration, even in the case of facing excessive iodine administration, several mechanisms are reported to be involved in maintaining normal thyroid hormone secretion. Among them, the sodium iodide cotransport system accounts for most of this iodine stability (Non-Patent Document 27). However, for administration in cancer treatment, it is always necessary to examine the nature and number of cancer cells of cancer patients and safely administer aqueous iodine while maintaining a stable concentration. Regarding its safety in iodine administration, even in the case of facing excessive iodine administration, several mechanisms are reported to be involved in maintaining normal thyroid hormone secretion. Among them, the sodium iodide cotransport system accounts for most of this iodine stability (Non-Patent Document 27). However, for administration in cancer treatment, it is always necessary to examine the nature and number of cancer cells of cancer patients and safely administer aqueous iodine while maintaining a stable concentration. Regarding its safety in iodine administration, even in the case of facing excessive iodine administration, several mechanisms are reported to be involved in maintaining normal thyroid hormone secretion. Among them, the sodium iodide cotransport system accounts for most of this iodine stability (Non-Patent Document 27). However, for administration in cancer treatment, it is always necessary to examine the nature and number of cancer cells of cancer patients and safely administer aqueous iodine while maintaining a stable concentration. Regarding its safety in iodine administration, even in the case of facing excessive iodine administration, several mechanisms are reported to be involved in maintaining normal thyroid hormone secretion. Among them, the sodium iodide cotransport system accounts for most of this iodine stability (Non-Patent Document 27). However, for administration in cancer treatment, it is always necessary to examine the nature and number of cancer cells of cancer patients and safely administer aqueous iodine while maintaining a stable concentration. Regarding its safety in iodine administration, even in the case of facing excessive iodine administration, several mechanisms are reported to be involved in maintaining normal thyroid hormone secretion. Among them, the sodium iodide cotransport system accounts for most of this iodine stability (Non-Patent Document 27). However, for administration in cancer treatment, it is always necessary to examine the nature and number of cancer cells of cancer patients and safely administer aqueous iodine while maintaining a stable concentration. Regarding its safety in iodine administration, even in the case of facing excessive iodine administration, several mechanisms are reported to be involved in maintaining normal thyroid hormone secretion. Among them, the sodium iodide cotransport system accounts for most of this iodine stability (Non-Patent Document 27). However, for administration in cancer treatment, it is always necessary to examine the nature and number of cancer cells of cancer patients and safely administer aqueous iodine while maintaining a stable concentration.

[0019] Therefore, before administering iodine, blood is collected from cancer patients, and the CTCs in the blood are analyzed in detail. When CTCs with a mesenchymal phenotype that have undergone EMT are detected, iodine, which is a PPAR-γ agonist that inhibits EMT, is safely and plannedly administered. The CTC test is performed over time as a marker for confirming the therapeutic effect, and it is necessary to carry out combination treatment with iodine while verifying the therapeutic effect of cancer. Therefore, before administering iodine, blood is collected from cancer patients, and the CTCs in the blood are analyzed in detail. When CTCs with a mesenchymal phenotype that have undergone EMT are detected, iodine, which is a PPAR-γ agonist that inhibits EMT, is safely and plannedly administered. The CTC test is performed over time as a marker for confirming the therapeutic effect, and it is necessary to carry out combination treatment with iodine while verifying the therapeutic effect of cancer. Therefore, before administering iodine, blood is collected from cancer patients, and the CTCs in the blood are analyzed in detail. When CTCs with a mesenchymal phenotype that have undergone EMT are detected, iodine, which is a PPAR-γ agonist that inhibits EMT, is safely and plannedly administered. The CTC test is performed over time as a marker for confirming the therapeutic effect, and it is necessary to carry out combination treatment with iodine while verifying the therapeutic effect of cancer. Therefore, before administering iodine, blood is collected from cancer patients, and the CTCs in the blood are analyzed in detail. When CTCs with a mesenchymal phenotype that have undergone EMT are detected, iodine, which is a PPAR-γ agonist that inhibits EMT, is safely and plannedly administered. The CTC test is performed over time as a marker for confirming the therapeutic effect, and it is necessary to carry out combination treatment with iodine while verifying the therapeutic effect of cancer. Therefore, before administering iodine, blood is collected from cancer patients, and the CTCs in the blood are analyzed in detail. When CTCs with a mesenchymal phenotype that have undergone EMT are detected, iodine, which is a PPAR-γ agonist that inhibits EMT, is safely and plannedly administered. The CTC test is performed over time as a marker for confirming the therapeutic effect, and it is necessary to carry out combination treatment with iodine while verifying the therapeutic effect of cancer.

[0020] The present invention aims to provide a cancer treatment method and a monitoring method for determining the therapeutic effect of a PPAR-γ agonist in cancer patients, which are highly safe, can enhance the therapeutic effect of cancer, and can prevent cancer metastasis and recurrence. The present invention aims to provide a cancer treatment method and a monitoring method for determining the therapeutic effect of a PPAR-γ agonist in cancer patients, which are highly safe, can enhance the therapeutic effect of cancer, and can prevent cancer metastasis and recurrence. The present invention aims to provide a cancer treatment method and a monitoring method for determining the therapeutic effect of a PPAR-γ agonist in cancer patients, which are highly safe, can enhance the therapeutic effect of cancer, and can prevent cancer metastasis and recurrence.

Means for Solving the Problems

[0021] To solve the above problems, the cancer treatment method of the present invention includes a first analysis step of analyzing circulating tumor cells (CTCs) in the peripheral blood of a mammalian subject, a step of administering an effective amount of a PPAR-γ agonist to a subject in need of treatment based on the result of the analysis, and the To solve the above problems, the cancer treatment method of the present invention includes a first analysis step of analyzing circulating tumor cells (CTCs) in the peripheral blood of a mammalian subject, a step of administering an effective amount of a PPAR-γ agonist to a subject in need of treatment based on the result of the analysis, and the To solve the above problems, the cancer treatment method of the present invention includes a first analysis step of analyzing circulating tumor cells (CTCs) in the peripheral blood of a mammalian subject, a step of administering an effective amount of a PPAR-γ agonist to a subject in need of treatment based on the result of the analysis, and the A second analysis step of analyzing peripheral blood circulating tumor cells (CTC) of the subject after administration, and It is a cancer treatment method.

[0022] As the mammalian subject, a human, a cat, a dog, or the like is suitable.

[0023] It is preferable that the PPAR-γ agonist has an inhibitory effect on PPAR-α. The PPAR-γ agonist preferably contains an iodine-containing compound. The iodine-containing compound is preferably sodium iodide. In the present invention, an aqueous solution containing an iodine-containing compound is referred to as stable iodine water. The PPAR-γ agonist is preferably an aqueous solution containing 100 ppm to 20,000 ppm of iodine as sodium iodide.

[0024] As a method of administering the PPAR-γ agonist, it is preferably administered by ingestion, inhalation, injection, or infusion. When the PPAR-γ agonist is administered by ingestion, the PPAR-γ agonist is preferably an aqueous solution containing sodium iodide, potassium dihydrogen citrate, and / or sodium metasilicate nonahydrate. When the PPAR-γ agonist is administered by inhalation, injection, or infusion, the PPAR-γ agonist preferably contains sodium iodide and physiological saline.

[0025] The analysis of the peripheral blood circulating tumor cells preferably includes quantifying the number of peripheral blood circulating tumor cells. Also, the analysis of the peripheral blood circulating tumor cells preferably includes analyzing the morphology of the peripheral blood circulating tumor cells. The analysis of the peripheral blood circulating tumor cells is the microenvironment (niche) surrounding the peripheral blood circulating tumor cells. It is preferable to include quantifying the number. As the microenvironment (niche), one or more selected from the group consisting of platelets, macrophages, lymphocytes, and stromal cells are mentioned.

[0026] In the first analysis step, when at least one of the following a) to f) is applicable, it is preferable to administer a PPA R-γ agonist. a) When Type.1 CTC leaked from the primary tumor is detected, b) When CTC of metastable cells, which are a subtype (Metastable Cell) of Type.2, is detected, c) When Type.2 CTC that may have undergone EMT is detected, d) When CTC with an amoeboid cell morphology is detected, e) When CTC in which cancer cells aggregate to form a cluster rather than a single cancer cell is detected, f) When circulating tumor microemboli (CTM) that form aggregates containing blood cells or platelets rather than a single cancer cell is detected.

[0027] In the analysis of the peripheral blood circulating tumor cells, detecting one or more peripheral blood circulating tumor cells per 1 mL of blood can be used as an indicator that a cancer patient has a tumor.

[0028] When a cancer patient has one or more selected from the group consisting of epithelial tumors, mesenchymal tumors, tumors having the properties of epithelial and mesenchymal therapies, and metastatic tumors, the present invention is preferably used.

[0029] When the cancer is breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, skin cancer, brain cancer, liver cancer, ​​​​​​​Bladder cancer, gastric cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer, and skin cancer The present invention is preferably used in one or more cases selected from the group consisting of

[0030] The monitoring method of the present invention is a monitoring method for determining the therapeutic effect of a PPAR-γ agonist in cancer patients which comprises a step of analyzing peripheral blood circulating tumor cells of a mammalian subject, and based on the result of the analysis, a step of analyzing the peripheral blood circulating tumor cells of a subject administered with a PPAR-γ agonist, and when the number of peripheral blood circulating tumor cells of the subject decreases over time it is determined that the cancer patient has a positive response to the treatment with the PPAR-γ agonist. This is the method

[0031] The test method of the present invention is a test method for determining the therapeutic effect of a PPAR-γ agonist which comprises analyzing peripheral blood circulating tumor cells (CTC) before and after administration of the PPAR-γ agonist. This is the method

[0032] The use of the PPAR-γ agonist of the present invention is the use of a PPAR-γ agonist in the manufacture of a medicament for enhancing the therapeutic effect of cancer or treating cancer, wherein the peripheral blood circulating tumor cells (CTC) are analyzed before administration of the PPAR-γ agonist. This is the use

Advantages of the Invention

[0033] According to the present invention, there is a great effect that a cancer treatment method with high safety, which can enhance the therapeutic effect of cancer and prevent cancer metastasis and recurrence, and a monitoring method for determining the therapeutic effect of a PPAR-γ agonist in cancer patients can be provided.

[0034] ​​​​In the treatment with general anticancer agents, T ype.2 subtype (Metastable Cell), a metastable cell which is a CTC, and mesenchymal cells which are Type.2 CT C cannot be expected to have an effect, so there are cases where treatment becomes impossible (Non-Patent Documents 4 to 5). However, iodine, a PPAR-γ agonist used in the present invention, inhibits the conversion of EMT and can be expected to kill cancer cells by apoptosis. Therefore, by analyzing peripheral blood circulating tumor cells, metastable cells which are Type.2 subtype (Metastab le Cell) CTCs, mesenchymal cells which are Type.2 CTCs, and amoeboid cells and aggregated cells (clusters, C TM) are detected. If these cancer stem cell-like CTCs can be removed by iodine treatment, the treatment effect of cancer can be enhanced and cancer metastasis and recurrence can be prevented.

Brief Description of the Drawings

[0035]

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Mode for Carrying Out the Invention

[0036] Hereinafter, embodiments of the present invention will be described based on the accompanying drawings. However, the illustrated examples are shown exemplarily, and it goes without saying that various modifications are possible without departing from the technical idea of the present invention. Of course.

[0037] The cancer treatment method of the present invention includes a first analysis step of analyzing peripheral blood circulating tumor cells (CTC) of a mammalian subject, and based on the results of the analysis, a step of administering an effective amount of a PPAR-γ agonist to a subject in need of treatment, and a second analysis step of analyzing the peripheral blood circulating tumor cells (CTC) of the subject after administration of the PPAR-γ agonist.

[0038] As a method for analyzing peripheral blood circulating tumor cells used in the present invention, known CTC analysis methods can be widely used and are not particularly limited. However, the micro fluidic channel device method (Non-Patent Document 23) and microfluidic chip (Non-Patent Document 25) used in the analysis of peripheral blood circulating tumor cells can capture cancer cells circulating in peripheral blood. By staining these cancer cells, CTCs leaked from the primary tumor can be measured as Type.1 CTCs, and CTCs that may have undergone EMT can be measured as Type. 2 CTCs. It is possible.

[0039] It is known that through EMT, epithelial cells lose their cell polarity and adhesion function with surrounding cells, and change into mesenchymal-like cells by acquiring migratory and invasive abilities (Non-Patent Documents 1 to 3). Therefore, as the malignancy of cancer cells increases, they pass through a metastable cell, a subtype of Type.2, and change into mesenchymal cells, which are Type.2 CTCs. And change.

[0040] According to recent research, even the same CTC changes its cell morphology to amoeboid as the malignancy increases. Furthermore, different from single cancer cells, it is reported that cluster CTCs, in which cancer cells aggregate into clusters, are related to metastasis and prognosis (Non-Patent Document 28). Among cluster CTCs, circulating tumor microemboli (CTM) that form aggregates containing blood cells and platelets, etc. are suggested to show different phenotypes and molecular characteristics compared to single CTCs, have higher metastatic ability, and are reported to show resistance to apoptosis (Non- Patent Document 28). And among cluster CTCs, circulating tumor microemboli (CTM) that form aggregates containing blood cells and platelets, etc. are suggested to show different phenotypes and molecular characteristics compared to single CTCs, have higher metastatic ability, and are reported to show resistance to apoptosis (Non- Patent Document 28). Patent Documents 29, 31), tumor-associated macrophages (tumor-associated macrophages: TAM ) In the case of, although not cancer cells, as macrophages that support cancer cells , together with fibroblasts, vascular endothelial cells, etc., form the cancer microenvironment (niche), and cancer cells It has been reported that it has the effect of promoting proliferation (Non-Patent Document 30).

[0041] In the present invention, based on the analysis results of CTC, an effective amount of PPAR -γ agonist is administered to a subject in need of treatment for a predetermined period, and then, again, the CTC of the subject is analyzed, and in cancer patients It is to determine the therapeutic effect of the PPAR-γ agonist in

[0042] As the PPAR-γ agonist, those having an inhibitory effect on PPAR-α are preferable, In particular, iodine-containing compounds are preferable, and sodium iodide is further preferable from the viewpoints of safety and effectiveness.

[0043] Regarding the safety of iodine in iodine treatment, (1) 30 healthy adult men with normal thyroid function were randomly administered iodine (as iodide) at doses of 500, 1,500, and 4,500 μg / day for 14 days. As a result, when the total iodine intake was 800 μg / day (0. 011 mg / kg body weight / day), no effects on serum thyroid hormone levels and serum TSH levels were observed However, at 1,800 μg / day (0.026 mg / kg body weight / day) and 4,800 μ g / day (0.069 mg / kg body weight / day), a small but significant transient decrease (10%) was observed in the serum total T4 level and free T4 level, and an increase (4 8%) was observed in the serum TSH level. Report (2) 11 healthy adult men with normal thyroid function were given iodine as seaweed In a test where iodine was administered at a dose of 25 mg / day for 14 days, the average value of serum TSH levels significantly increased but remained within the normal range. (3) As a long-term test, four healthy adults were orally administered iodine at a dose of approximately 1,000 mg / day for 11 consecutive days. As a result, a small but statistically significant decrease in the average value of serum T4 levels and an increase in serum TSH levels were observed. However, these two changes returned to their original levels within one week after the administration was stopped. (Non-Patent Document 32) is referred to. Based on the reports, (3) as a long-term test, four healthy adults were orally administered iodine at a dose of approximately 1,000 mg / day for 11 consecutive days. As a result, a small but statistically significant decrease in the average value of serum T4 levels and an increase in serum TSH levels were observed. However, these two changes returned to their original levels within one week after the administration was stopped. In the test where iodine was administered at a dose of 25 mg / day for 14 days, the average value of serum TSH levels significantly increased but remained within the normal range. Based on the reports, (3) as a long-term test, four healthy adults were orally administered iodine at a dose of approximately 1,000 mg / day for 11 consecutive days. As a result, a small but statistically significant decrease in the average value of serum T4 levels and an increase in serum TSH levels were observed. However, these two changes returned to their original levels within one week after the administration was stopped. (Non-Patent Document 32) is referred to.

[0044] In the treatment method of the present invention, the inventors of the present application have found that by prescribing an effective amount considering the above-mentioned iodine safety, iodine can inhibit not only metastable cells such as Type 2 subtypes (Metastable Cell) of CTC and mesenchymal cells (mesenchymal cell) which are Type 2 CTC, but also cluster CTC, cluster CTM, and TAM. In the treatment method of the present invention, the inventors of the present application have found that by prescribing an effective amount considering the above-mentioned iodine safety, iodine can inhibit not only metastable cells such as Type 2 subtypes (Metastable Cell) of CTC and mesenchymal cells (mesenchymal cell) which are Type 2 CTC, but also cluster CTC, cluster CTM, and TAM. In the treatment method of the present invention, the inventors of the present application have found that by prescribing an effective amount considering the above-mentioned iodine safety, iodine can inhibit not only metastable cells such as Type 2 subtypes (Metastable Cell) of CTC and mesenchymal cells (mesenchymal cell) which are Type 2 CTC, but also cluster CTC, cluster CTM, and TAM. In the treatment method of the present invention, the inventors of the present application have found that by prescribing an effective amount considering the above-mentioned iodine safety, iodine can inhibit not only metastable cells such as Type 2 subtypes (Metastable Cell) of CTC and mesenchymal cells (mesenchymal cell) which are Type 2 CTC, but also cluster CTC, cluster CTM, and TAM.

[0045] In addition, apoptotic CTC are dead cancer cells that are damaged and have no function. They are often detected when there is a history of cancer treatment with anticancer drugs or when treatment is ongoing. However, iodine has also been reported to have an effect of inducing apoptosis in cancer cells. Therefore, it is analyzed as one of the means for determining the therapeutic effect of iodine. In addition, apoptotic CTC are dead cancer cells that are damaged and have no function. They are often detected when there is a history of cancer treatment with anticancer drugs or when treatment is ongoing. However, iodine has also been reported to have an effect of inducing apoptosis in cancer cells. Therefore, it is analyzed as one of the means for determining the therapeutic effect of iodine. In addition, apoptotic CTC are dead cancer cells that are damaged and have no function. They are often detected when there is a history of cancer treatment with anticancer drugs or when treatment is ongoing. However, iodine has also been reported to have an effect of inducing apoptosis in cancer cells. Therefore, it is analyzed as one of the means for determining the therapeutic effect of iodine. In addition, apoptotic CTC are dead cancer cells that are damaged and have no function. They are often detected when there is a history of cancer treatment with anticancer drugs or when treatment is ongoing. However, iodine has also been reported to have an effect of inducing apoptosis in cancer cells. Therefore, it is analyzed as one of the means for determining the therapeutic effect of iodine.

[0046] From the above facts, in the combination treatment of the PPAR-γ agonist such as the iodine-containing compound of the present invention and CTC analysis, Type 1 CTC, metastable cells which are Type 2 subtypes (Metastable Cell), mesenchymal cells (mesenchymal cell) which are Type 2 CTC, and amoeboid cells, CTM, TAM, apoptotic CTC From the above facts, in the combination treatment of the PPAR-γ agonist such as the iodine-containing compound of the present invention and CTC analysis, Type 1 CTC, metastable cells which are Type 2 subtypes (Metastable Cell), mesenchymal cells (mesenchymal cell) which are Type 2 CTC, and amoeboid cells, CTM, TAM, apoptotic CTC From the above facts, in the combination treatment of the PPAR-γ agonist such as the iodine-containing compound of the present invention and CTC analysis, Type 1 CTC, metastable cells which are Type 2 subtypes (Metastable Cell), mesenchymal cells (mesenchymal cell) which are Type 2 CTC, and amoeboid cells, CTM, TAM, apoptotic CTC ) are involved. Based on the analysis, the therapeutic effect of the PPAR-γ agonist is determined. If a therapeutic effect is recognized, further treatment guidelines such as the dosage, frequency, and duration of administration of the PPAR-γ agonist will be determined. This is what is done.

[0047] Based on the test results by the microfluidic device method below, the analysis table (Table 1) of peripheral blood circulating tumor cells used in the combination therapy with the PPAR-γ agonist used in the present invention and its judgment criteria are shown. This is shown.

[0048]

Table 1

[0049] <Explanation of the captured cancer cell image> Cancer cells captured by the microfluidic device method are simultaneously stained in different colors with DAPI (nuclear staining of cells: blue), fluorescent antibody against CD 45 (expressed in all human white blood cells) (red), fluorescent antibody against Cytokeratin (expressed in epithelial cells, epithelial derived cells, and epithelial-derived malignant tumor cells) (green), and fluorescent antibody against Vimentin (expressed in mesenchymal cells that have undergone EMT) (yellow). Therefore, what each image staining means is as follows. This is as follows. Image 1: Staining of cell nuclei with DAPI (blue). Image 2: Staining of human white blood cells with CD45 (red). Image 3: Staining of epithelial cells and epithelial-derived cells with Cytokeratin (green). Image 4: Staining of mesenchymal cells with Vimentin (yellow). Image 5: Observation by phase-contrast microscopy.

[0050] (1) Criteria for the determination of tumor-associated macrophages. 1) Large in shape and with a nucleus (DAPI: blue). (2) They may weakly express CD45 and Vimentin, or may not express them at all. (3) As a result of phagocytosing cancer cells, there is Cytokeratin (green), which is a characteristic of epithelial cells.

[0051] Figure 1 shows a photograph of an example image of tumor-associated macrophages. (a) to (e) in Figure 1 are photographs showing the results of Image 1 to Image 5 respectively. As shown in Figure 1, they are large in shape (inside the circle of Image 5), have nuclei inside the cytoplasm (inside the circle of Image 1), and weakly express CD45 (inside the circle of Image 2) and Vimentin (inside the circle of Image 4). Also, as a result of phagocytosing cancer cells, there is Cytokeratin (inside the circle of Image 3), which is a characteristic of epithelial cells.

[0052] (2) Criteria for determining dead cells (apoptotic CTCs). (1) They have no nuclei. (2) There is Cytokeratin (green). (3) Their shapes are amorphous (such as cell condensation, etc.).

[0053] Figure 2 shows a photograph of an example image of dead cells (apoptotic CTCs). (a) to (e) in Figure 2 are photographs showing the results of Image 1 to Image 5 respectively. As shown in Figure 2, the nuclei are not inside the cytoplasm (inside the circle of Image 1).

[0054] (3) Criteria for Type.1 intact cells (intact CTCs). (1) Their shapes are spherical or elliptical and they have nuclei (DAPI: blue). (2) They do not express CD45 (red). (3) They express Cytokeratin (green). (4) Their shapes are intact and have tension.

[0055] Figure 3 shows a photograph of an example image of Type.1 intact cells (intact CTCs). (a) in Figure 3 ~(e) are photographs showing the results of Images 1 to 5. As shown in Fig. 3, the nuclei are in the cytoplasm (inside the circle in Image 1), and Cytokeratin (inside the circle in Image 3), which is a characteristic of epithelial cells, is present. Also, there is no expression of CD45 (Image 2) and Vimentin (Image 4), and the cancer cells are shrunken and not present (inside the red circle in Image 5).

[0056] (4) Criteria for determining Type.1 aggregated cells (cluster CTC). 1) There are a large number of nuclei (DAPI: blue). 2) There is no expression of CD45 (red). 3) There is expression of Cytokeratin (green). 4) A cluster is formed.

[0057] Fig. 4 shows a photograph of an example image of Type.1 aggregated cells (cluster CTC). (a) to (e) in Fig. 4 are photographs showing the results of Images 1 to 5 respectively. As shown in Fig. 4, there are a large number of nuclei (inside the circle in Image 1), and there is expression of Cytokeratin, which is a characteristic of epithelial cells (inside the circle in Image 3). Also, there is no expression of CD45 (Image 2) and Vimentin (Image 4), and the cancer cells form clusters (inside the circles in Images 1, 3, and 5).

[0058] (5) Criteria for determining Type.1 aggregated cells (CTM). 1) There are a large number of nuclei (DAPI: blue). 2) Weakly express CD45 (red). 3) There is expression of Cytokeratin (green). 4) There is no expression of Vimentin (yellow). 5) Form a cluster containing blood cells, platelets, etc.

[0059] Fig. 5 shows a photograph of an example image of Type.1 aggregated cells (CTM). (a) to (e) is a photograph showing the results of Images 1 to 5. As shown in Fig. 5, there are a large number of nuclei (inside the circle in Image 1), and Cytokeratin, which is a characteristic of epithelial cells, is present (inside the circle in Image 3). Also, CD45 (inside the circle in Image 2) is weakly expressed to form aggregates (CTM) including blood cells and platelets, etc., the expression of Vimentin (Image 4) is absent, and cancer cells form clusters (inside the circles in Images 1, 2, 3, and 5).

[0060] (6) Criteria for determining intact cells (intact CTC) of subtype (Metastable Cell) of Type.2 . 1) The shape is spherical or elliptical and has a nucleus (DAPI: blue). 2) There is no expression of CD45 (red). 3) There is expression of Cytokeratin (green) and Vimentin (yellow). 4) The shape is intact and has tension.

[0061] Fig. 6 shows a photographic example of intact cells (intact CTC) of subtype (Metastable Cell) of Type.2 . (a) to (e) in Fig. 6 are photographs showing the results of Images 1 to 5 respectively . As shown in Fig. 6, the nucleus is inside the cytoplasm (inside the circle in Image 1), the expression of CD45 (Image 2) is absent, there is expression of Cytokeratin, which is a characteristic of epithelial cells (inside the circle in Image 3), and Vimentin, which is a characteristic of mesenchymal cells (inside the circle in Image 4), and the cancer cells are not withered (inside the circle in Image 5).

[0062] Criteria for determining amoeboid cells of subtype (Metastable Cell) of Type.2. 1) The shape is spherical or elliptical and has a nucleus (DAPI: blue). 2) There is no expression of CD45 (red). 3) There is expression of Cytokeratin (green) and Vimentin (yellow). 4) Cells with an amoeba-like shape.

[0063] Figure 7 shows an image of amoeboid cells (Metastable Cell, a subtype of Type.2) as an example photo. (a) - (e) in Figure 7 are photos showing the results of Image 1 - Image 5 respectively. As shown in Figure 7, the nucleus is inside the cytoplasm (inside the circle in Image 1), there is no expression of CD45 (Image 2), there is expression of Cytokeratin, which is a characteristic of epithelial cells (inside the circle in Image 3), and Vimentin, which is a characteristic of mesenchymal cells (inside the circle in Image 4), and the cells have an amoeba-like form (inside the circles in Images 3 and 4).

[0064] (8) Criteria for determining aggregated cells (cluster CTC) of the subtype (Metastable Cell) of Type.2 1) There are multiple nuclei (DAPI: blue). 2) There is no expression of CD45 (red). 3) There is expression of Cytokeratin (green) and Vimentin (yellow). 4) Clusters are formed.

[0065] Figure 8 shows a photo of an example image of aggregated cells (cluster CTC) of the subtype (Metastable Cell) of Type.2 as an example photo. (a) - (e) in Figure 8 are photos showing the results of Image 1 - Image 5 respectively. As shown in Figure 8, there are multiple nuclei (inside the circle in Image 1), there is no expression of CD45 (Image 2), there is expression of Cytokeratin, which is a characteristic of epithelial cells (inside the circle in Image 3), and Vimentin, which is a characteristic of mesenchymal cells (inside the circle in Image 4), and cancer cells have formed clusters (inside the circles in Images 1, 3, 4, and 5).

[0066] (9) Criteria for determining aggregated cells (CTM) of subtype (Metastable Cell) of Type.2. 1) Presence of multiple nuclei (DAPI: blue). 2) Weak expression of CD45 (red). 3) Expression of Cytokeratin (green) and Vimentin (yellow). 4) Formation of clusters containing blood cells, platelets, etc.

[0067] Figure 9 shows a photographic example of an image of aggregated cells (CTM) of subtype (Metastable Cell) of Type.2. The photographs in (a) to (e) of Figure 9 are photographs showing the results of Images 1 to 5 respectively. As shown in Figure 9, there are multiple nuclei (inside the circle in Image 1), and the expression of Cytokeratin (inside the circle in Image 3), which is a characteristic of epithelial cells, and Vimentin (inside the circle in Image 4), which is a characteristic of mesenchymal cells, is present. Also, CD45 (inside the circle in Image 2) is weakly expressed to form aggregates (CTM) in a form containing blood cells, platelets, etc., and cancer cells form clusters (inside the circles in Images 1, 3, 4 and 5).

[0068] (10) Criteria for determining mesenchymal cells of Type.2. 1) Spherical or elliptical in shape with a nucleus (DAPI: blue). 2) No expression of CD45 (red). 3) No expression of Cytokeratin (green). 4) Expression of Vimentin (yellow) is present.

[0069] Figure 10 shows a photographic example of an image of mesenchymal cells of Type.2 CTC. The photographs in (a) to (e) of Figure 10 are photographs showing the results of Images 1 to 5 respectively. As shown in Figure 10 there is a nucleus inside the cytoplasm (inside the circle in Image 1), and no CD45 (Image 2) and Cytokeratin ( There is no expression of Image 3), but there is expression of Vimentin (inside the circle of Image 4), which is a characteristic of mesenchymal cells. and the cancer cells are not atrophied (inside the circle of Image 5).

[0070] (11) Criteria for determining amoeboid cells of Type.2 CTCs. 1) There is a nucleus (DAPI: blue). 2) There is no expression of CD45 (red) and Cytokeratin (green). 3) There is expression of Vimentin (yellow). 4) Cells with an amoeba-like shape.

[0071] Figure 11 shows a photograph of an example image of amoeboid cells of Type.2 CTCs. (a) - (e) in Figure 11 are photographs showing the results of Images 1 - 5 respectively. As shown in Figure 11, there is a nucleus inside the cytoplasm (inside the circle of Image 1), and there is no expression of CD45 (Image 2) and Cytokeratin ( Image 3), but there is expression of Vimentin (inside the circle of Image 4), which is a characteristic of mesenchymal cells. and the cells have an amoeba-like morphology (inside the red circles of Images 4 and 5).

[0072] (12) Criteria for determining aggregated cells of Type.2 (cluster CTCs). 1) There are multiple nuclei (DAPI: blue). 2) There is no expression of CD45 (red) and Cytokeratin (green). 3) There is expression of Vimentin (yellow). 4) Form a cluster.

[0073] Figure 12 shows a photograph of an example image of aggregated cells of Type.2 (cluster CTCs). Figure 12's (a) - (e) are photographs showing the results of Images 1 - 5 respectively. As shown in Figure 12 as such, there are multiple nuclei (inside the circle of Image 1), CD45 (Image 2) and Cytokeratin (Image 3 ) expression is absent, and there is expression of Vimentin, which is a characteristic of mesenchymal cells rather than epithelial cells (within the circle in Image 4 ), and cancer cells form clusters (within the red circles in Images 1, 4, and 5).

[0074] (13) Criteria for determining Type.2 aggregated cells (CTM). 1) There are a large number of nuclei (DAPI: blue). 2) Weakly express CD45 (red). 3) Absence of Cytokeratin (green) expression. 4) Presence of Vimentin (yellow) expression. 5) Form clusters containing blood cells, platelets, etc.

[0075] Figure 13 shows a photograph of an example image of Type.2 aggregated cells (CTM). (a ) to (e) in Figure 13 are photographs showing the results of Images 1 to 5 respectively. As shown in Figure 13, there are a large number of nuclei (within the circle in Image 1), no Cytokeratin (within the circle in Image 3), and there is expression of Vimentin, which is a characteristic of mesenchymal cells (within the circle in Image 4). Also, CD45 (within the circle in Image 2) is weakly expressed to form an aggregate (CTM) in a shape containing blood cells, platelets, etc., and cancer cells form clusters (within the red circles in Images 1, 4, and 5).

[0076] In the treatment method of the present invention, the criteria for cancers to which a PPAR-γ agonist is administered are, except for the case where a doctor prescribes a PPAR-γ agonist according to the wishes of a patient who has tested positive in the CTC test for health diagnosis purposes, cancers at Stage 3 and Stage 4 that have become difficult to treat with standard treatments such as surgical treatment, radiotherapy, and chemotherapy with anticancer drugs, etc., which are called the three major cancer treatments, and moreover, in the analysis of peripheral blood circulating tumor cells, Type.2 that may undergo EMT ​​​​​​​​Metastable cells, which are a subtype of CTCs, and Type.2 cells that have undergone EMT This is the case when CTCs are detected and the patient's consent has been obtained.

[0077] Analysis of peripheral blood circulating tumor cells is used to determine the treatment strategy based on the purpose and method of the examination and the examination results After obtaining consent from the cancer patient to consider the treatment strategy based on the purpose and method of the examination and the examination results, for example, 10 mL of blood is collected using a dedicated blood collection tube and analysis of peripheral blood circulating tumor cells is performed using the microfluidic device method or the like.

[0078] In the present invention, when iodine treatment is performed using an iodine-containing compound as a PPAR-γ agonist in principle, in the prescription, after the hospital doctor confirms that the patient's thyroid function is normal the doctor himself manufactures stable iodine water in the same hospital and uses it shall be used.

[0079] The effective amount of iodine treatment used in the present invention is a safe amount that does not cause excessive harmful side effects and is sufficient to bring about a cancer treatment response when used by the method described in the specification of this application and means the amount of iodine. Also, as the upper limit of the safe amount of iodine treatment, the safety report (Non-Patent Document 32) for 11 consecutive days of oral administration at a dose of about 1,000 mg per day is referred to for prescription, but the doctor can adjust the dosage as needed according to the malignancy of the cancer progression state, etc. shall be possible.

[0080] In addition, the basic usage and dosage of sodium iodide used in stable iodine water were set with reference to the following non-patent documents. First, regarding the absorption rate of iodine, the iodine in the administered sodium iodide is mostly 100% absorbed from the digestive tract, reduced to iodide in the intestine, and almost ​​It is completely absorbed in the small intestine. In an exposure test involving 7 adults with normal thyroid function, less than 1% of the tracer amount of iodine 131 administered orally was detected in the feces. From this, it has been reported that the absorption rate of the ingested radioactive iodine is nearly 100%. Also, in another exposure test involving 20 other adults with normal thyroid function, potassium iodide was administered daily for 13 weeks, and the daily urinary excretion amount of iodine was approximately 80 - 90% of the estimated daily intake . Therefore, this also suggests that the absorption rate of iodine is nearly 100% (Non - Patent Document 33). Regarding the body distribution of the ingested iodine, in an exposure test where radiolabeled iodine was orally administered to humans as sodium iodide at tracer concentration, approximately 20 - 30% of the iodine was distributed to the thyroid, and approximately 30 - 60% was excreted in the urine in about 10 hours. When Na

[0081] I was orally administered at tracer concentration, essentially the same results were obtained (Non - Patent Document 34). Regarding the inhalation of iodine from exhaled breath, it has been reported that iodine is easily absorbed from the lungs and digestive tract. However, in a test where radioactive iodine was inhaled by volunteers, almost all of the inhaled iodine disappeared from the airways, and the half - life was approximately 10 minutes (Non - Patent Document 35), 131 and much of the inhaled iodine migrated to the digestive tract by mucociliary clearance. The relatively rapid absorption of inhaled iodine has also been confirmed in tests using mice, rats, dogs, and sheep (Non - Patent Document 36). (Non - Patent Document 34).

[0082] Regarding the inhalation of iodine from exhaled breath, although it has been reported that iodine is easily absorbed from the lungs and digestive tract, in a test where radioactive iodine was inhaled by volunteers, almost all of the inhaled iodine disappeared from the airways, and the half - life was approximately 10 minutes (Non - Patent Document 35), and much of the inhaled iodine migrated to the digestive tract by mucociliary clearance. The relatively rapid absorption of inhaled iodine has also been confirmed in tests using mice, rats, dogs, and sheep (Non - Patent Document 36). Almost all of the inhaled iodine disappeared from the airways, and the half - life was approximately 10 minutes (Non - Patent Document 35), and much of the inhaled iodine migrated to the digestive tract by mucociliary clearance. The relatively rapid absorption of inhaled iodine has also been confirmed in tests using mice, rats, dogs, and sheep (Non - Patent Document 36). The relatively rapid absorption of inhaled iodine has also been confirmed in tests using mice, rats, dogs, and sheep (Non - Patent Document 36). (Non - Patent Document 36).

[0083] ​Regarding the antitumor effect of iodine, the view that iodine has the effect of inhibiting tumor progression and improving inflammatory / proliferative lesions is supported by a large number of data obtained from in vitro experiments (Non-Patent Document 37), in vivo experiments (Non-Patent Documents 6 and 38 to 41), clinical trials (Non-Patent Documents 42 to 45), and epidemiological reports (Non-Patent Documents 46 to 48). And it has been reported that these beneficial effects are at relatively high iodine concentrations (milligrams per day). Considering the above reports, for example, the 8,400 ppm stable iodine water preferably used in the present invention is composed of an aqueous solution containing 1 w / v% sodium iodide, 0.08 w / v% potassium dihydrogen citrate, and 0.1 w / v% sodium metasilicate nonahydrate, and the pH at this time is weakly alkaline at 8.3 to 8.7. The 10,000 ppm stable iodine water is composed of an aqueous solution containing 1.2 w / v% sodium iodide, 0.08 w / v% potassium dihydrogen citrate, and 0.1 w / v% sodium metasilicate nonahydrate, and the pH at this time is weakly alkaline at 8.3 to 8.7. Potassium dihydrogen citrate and sodium metasilicate nonahydrate formulated here are safe additives formulated as pH buffers. In addition, after ultrafiltration of this stable iodine water, nitrogen substitution is performed in consideration of the stability of iodine, and it is heat-treated at 85°C and then stored at room temperature until use. The administration of the stable iodine water used in the present invention is diagnosed by a doctor based on the analysis results of peripheral blood circulating tumor cells. The dosage is limited to 1,000 mg / day. For example, in the case of 8,400 ppm stable iodine water, it is 30 mL three times a day (756 mg as iodine).

[0084]

[0085] ​​​​​​​​​​​​​​​ / day), in the case of 10,000 ppm stable iodine water, 30 mL per time, three times a day (iodine amounting to 900 mg / day) is preferred. However, based on the analysis results of peripheral blood circulating tumor cells during the treatment process, the doctor can change the

[0086] usage and dosage at any time or discontinue the administration as appropriate. The stable iodine water for injection used in the present invention is determined by the doctor based on the analysis results of peripheral blood circulating tumor cells. For example, 10 mL of 10 w / v% sodium iodide filtered and sterilized with a 0.02 μm membrane filter is dissolved in 100 mL of physiological saline for intravenous drip injection, and it is preferred to

[0087] administer 110 mL once a day over 30 minutes by intravenous drip. However, based on the analysis results of peripheral blood circulating tumor cells during the treatment process, the doctor can change the number of intravenous drip times or stop the intravenous drip at any time as appropriate.

[0088] In the present specification, cancer refers to, without particularly limiting, any type of cancer found in mammals, including leukemia, lymphoma, melanoma, carcinoma, and sarcoma, or neoplasm or malignant tumor. Examples of ​cervix), colon, head and neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, gastric, uterine, and medulloblastoma cancers. Other cancers include, for example, Hodgkin's disease, non-Hodg kin lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, essential thrombocythemia, Waldenström's macroglobulinemia, small cell lung tumors, primary brain tumors, gastric cancer , colon cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, pre cancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, hypercalcemia of malignancy, cervical cancer, endometrial cancer, adrenocortical cancer, and prostate cancer.

Examples

[0089] The present invention will be further specifically described with the following examples, but it goes without saying that these examples should not be construed as limiting and are merely illustrative.

[0090] The following treatment cases are all the results of free medical treatment carried out under the guidance of a doctor with the consent of the patients, and this disclosure is also disclosed with the consent of the patients themselves. . In the following examples, the analysis of peripheral blood circulating tumor cells was performed by collecting 10 mL of blood in a dedicated blood collection tube and analyzing the peripheral blood circulating tumor cells by the microfluidic device method. Also, as the PPA R-γ agonist, the aforementioned stable iodine water [stable iodine water at 8,400 ppm: 1 w / v% sodium iodide, 0.08 w / v% potassium dihydrogen citrate, 0.1 w / v% meta sodium silicate nonahydrate aqueous solution (pH 8.3 - 8.7), or stable iodine water at 10,000 ppm : 1.2 w / v% sodium iodide, 0.08 w / v% potassium dihydrogen citrate ​ Lithium, an aqueous solution of 0.1 w / v% sodium metasilicate nonahydrate (pH 8.3 - 8.7 ) was used for iodine treatment.

[0091] (Example 1) The information of Patient A and the progress of iodine treatment are shown in Table 2, and the analysis results of peripheral blood circulating tumor cells are shown in Table 3 respectively.

[0092]

Table 2

[0093]

Table 3

[0094] As shown in Table 3, according to the analysis results of peripheral blood circulating tumor cells on June 19, 2018, 1 intact CTC of Type.1, aggregated cells of Type.1 (cluster CTC), aggregated cells of Type.1 (CTM), and 1 amoeboid cell of metastable cell were detected. Therefore, stable iodine water at 8,400 ppm was administered at a dose of 20 mL × 3 times / day.

[0095] According to the analysis results of peripheral blood circulating tumor cells on December 3, 2018, 3 damaged and dead cells (apoptosis CTC) were detected, and no CTC was detected. Therefore, starting from January 7, 2019, the dose of stable iodine water at 8,400 ppm was reduced to 10 mL × 1 time (before breakfast) and administered, and the administration was stopped starting from January 21, 2019.

[0096] In the case of Example 1, by activating PPAR-γ and suppressing PPAR-α of iodine, ​Amoeboid metastable cells, aggregated Type.1 cells (cluster CTC), and disappeared aggregated Type.1 cells (CTM) are considered. Aggregated Type.1 cells (CTM) that disappeared are considered. Considered.

[0097] (Example 2) Information on Patient B and the course of iodine treatment are shown in Table 4, and the analysis results of peripheral blood circulating tumor cells are shown in Table 5, respectively. Respectively shown.

[0098]

Table 4

[0099]

Table 5

[0100] As shown in Table 5, according to the analysis results of peripheral blood circulating tumor cells on December 17, 2018, 9 intact cells of the subtype (Metastable Cell) of Type.2 were detected, and 1 mesenchymal cell of Type.2 was detected. Therefore, 8,400 ppm stable iodine water was started to be taken at a frequency of 20 mL × 3 times / day. detected, so 8,400 ppm stable iodine water was started to be taken at a frequency of 20 mL × 3 times / day. times / day.

[0101] According to the analysis results of peripheral blood circulating tumor cells on January 21, 2019, although no mesenchymal cells of Type.2 were detected, 2 intact cells with low viability of Type.1 were detected, and 5 intact cells of the subtype (Metastable Cell) of Type.2 were detected. Therefore, 8,400 ppm stable iodine water was continuously taken at a frequency of 20 mL × 3 times / day. detected, so 8,400 ppm stable iodine water was continuously taken at a frequency of 20 mL × 3 times / day. times / day. In addition, intact cells of metastable cells (Metastable Cell) that are considered to be in the middle stage of EMT conversion Regarding the cells not disappearing, as seen in the cases of other examples in the present specification, it is speculated that there is an effect due to anti-cancer agent treatment, but the detailed mechanism of action is unknown. Regarding the cells not disappearing, as seen in the cases of other examples in the present specification, it is speculated that there is an effect due to anti-cancer agent treatment, but the detailed mechanism of action is unknown.

[0102] According to the analysis results of peripheral blood circulating tumor cells on March 6, 2019, 3 intact cells (intact CTC) of Type.1 were detected, but no subtypes of Type.2 (Metastable Cell) or mesenchymal cells of Type.2 were detected. (intact CTC) were detected, but no subtypes of Type.2 (Metastable Cell) or mesenchymal cells of Type.2 were detected. pe.2 mesenchymal cells were not detected.

[0103] In the case of Example 2, due to the activation of PPAR-γ by iodine, EMT conversion was inhibited, and it is speculated that the subtypes of Type.2 (Metastable Cell) and mesenchymal cells of Type.2 disappeared. In the case of Example 2, due to the activation of PPAR-γ by iodine, EMT conversion was inhibited, and it is speculated that the subtypes of Type.2 (Metastable Cell) and mesenchymal cells of Type.2 disappeared. It is speculated that they disappeared.

[0104] (Example 3) The information of Patient C and the course of iodine treatment are shown in Table 6, and the analysis results of peripheral blood circulating tumor cells are shown in Table 7 respectively. are shown respectively.

[0105]

Table 6

[0106]

Table 7

[0107] As shown in Table 7, according to the analysis results of peripheral blood circulating tumor cells on April 9, 2018, 39 intact cells (intact CTC) of the subtype of Type.2 (Metastable Cell), 35 amoeboid cells of the subtype of Type.2 (Metastable Cell), and Type.2 pe.2 subtype (Metastable Cell) intact cells (intact CTC) were 39, Type. 2 subtype (Metastable Cell) amoeboid cells were 35, Type.2 Three aggregated cells (cluster CTC) of the metastable cell subtype and four aggregated cells (CTM) of the metastable cell subtype of Type.2, twelve mesenchymal cells of Type.2, and seven amoeboid cells of Type.2 were detected. Four aggregated cells (CTM) of the metastable cell subtype of Type.2 and twelve mesenchymal cells of Type.2 Seven amoeboid cells of Type.2 were detected. Therefore, starting from April 9, 2018, 15 mL of 8,400 ppm stable iodine water was taken twice a day (after breakfast and dinner). Therefore, starting from April 9, 2018, 15 mL of 8,400 ppm stable iodine water was taken twice a day (after breakfast and dinner). Therefore, starting from April 9, 2018, 15 mL of 8,400 ppm stable iodine water was taken twice a day (after breakfast and dinner).

[0108] According to the analysis results of peripheral blood circulating tumor cells on May 15, 2018, one intact cell (intact CTC) of Type.1, one intact cell (intact CTC) of the metastable cell subtype of Type.2, three amoeboid cells of the metastable cell subtype of Type.2, and two aggregated cells (cluster CTC) of the metastable cell subtype of Type.2 were detected. However, since no mesenchymal cells of Type.2 and amoeboid cells of Type.2 were detected, the dosage of 8,400 ppm stable iodine water was reduced to 20 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on May 15, 2018, one intact cell (intact CTC) of Type.1, one intact cell (intact CTC) of the metastable cell subtype of Type.2, three amoeboid cells of the metastable cell subtype of Type.2, and two aggregated cells (cluster CTC) of the metastable cell subtype of Type.2 were detected. However, since no mesenchymal cells of Type.2 and amoeboid cells of Type.2 were detected, the dosage of 8,400 ppm stable iodine water was reduced to 20 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on May 15, 2018, one intact cell (intact CTC) of Type.1, one intact cell (intact CTC) of the metastable cell subtype of Type.2, three amoeboid cells of the metastable cell subtype of Type.2, and two aggregated cells (cluster CTC) of the metastable cell subtype of Type.2 were detected. However, since no mesenchymal cells of Type.2 and amoeboid cells of Type.2 were detected, the dosage of 8,400 ppm stable iodine water was reduced to 20 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on May 15, 2018, one intact cell (intact CTC) of Type.1, one intact cell (intact CTC) of the metastable cell subtype of Type.2, three amoeboid cells of the metastable cell subtype of Type.2, and two aggregated cells (cluster CTC) of the metastable cell subtype of Type.2 were detected. However, since no mesenchymal cells of Type.2 and amoeboid cells of Type.2 were detected, the dosage of 8,400 ppm stable iodine water was reduced to 20 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on May 15, 2018, one intact cell (intact CTC) of Type.1, one intact cell (intact CTC) of the metastable cell subtype of Type.2, three amoeboid cells of the metastable cell subtype of Type.2, and two aggregated cells (cluster CTC) of the metastable cell subtype of Type.2 were detected. However, since no mesenchymal cells of Type.2 and amoeboid cells of Type.2 were detected, the dosage of 8,400 ppm stable iodine water was reduced to 20 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on May 15, 2018, one intact cell (intact CTC) of Type.1, one intact cell (intact CTC) of the metastable cell subtype of Type.2, three amoeboid cells of the metastable cell subtype of Type.2, and two aggregated cells (cluster CTC) of the metastable cell subtype of Type.2 were detected. However, since no mesenchymal cells of Type.2 and amoeboid cells of Type.2 were detected, the dosage of 8,400 ppm stable iodine water was reduced to 20 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on May 15, 2018, one intact cell (intact CTC) of Type.1, one intact cell (intact CTC) of the metastable cell subtype of Type.2, three amoeboid cells of the metastable cell subtype of Type.2, and two aggregated cells (cluster CTC) of the metastable cell subtype of Type.2 were detected. However, since no mesenchymal cells of Type.2 and amoeboid cells of Type.2 were detected, the dosage of 8,400 ppm stable iodine water was reduced to 20 mL three times a day.

[0109] According to the analysis results of peripheral blood circulating tumor cells on November 19, 2018, one damaged and dead cell (apoptosis CTC) was detected and no CTC was detected. Therefore, the dosage of 8,400 ppm stable iodine water was reduced to 10 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on November 19, 2018, one damaged and dead cell (apoptosis CTC) was detected and no CTC was detected. Therefore, the dosage of 8,400 ppm stable iodine water was reduced to 10 mL three times a day. According to the analysis results of peripheral blood circulating tumor cells on November 19, 2018, one damaged and dead cell (apoptosis CTC) was detected and no CTC was detected. Therefore, the dosage of 8,400 ppm stable iodine water was reduced to 10 mL three times a day.

[0110] In the case of Example 3, the activation of PPAR-γ by iodine inhibits EMT conversion, and Type.2 mesenchymal cells and Type.2 metastable cells In the case of Example 3, the activation of PPAR-γ by iodine inhibits EMT conversion, and Type.2 mesenchymal cells and Type.2 metastable cells It is presumed that all circulating tumor cells disappeared, but the reason for this is that iodine The direct effect of oxidative / antioxidative properties of mitochondrial membrane potential is disrupted, leading to It is speculated that Doria-mediated apoptosis may have been induced (Non-patent Document 8, 11).

[0111] Example 4 Table 8 shows information on patient D and the progress of iodine treatment, and Table 9 shows the analysis results of circulating tumor cells in the peripheral blood. Each is shown below.

[0112] [Table 8]

[0113] [Table 9]

[0114] On June 18, 2018, the results of the analysis of peripheral blood circulating tumor cells showed that tumor-associated macrophages There were three Type.1 intact cells (TAMs), two Type.1 intact CTCs, and one Type.1 One aggregated cell (CTM) of Type.1 and one intact cell of Type.2 subtype (Metastable Cell) and 2 amoeboids of the Type.2 subtype (Metastable Cell). , 1 clustered cell (cluster CTC) of Type.2 subtype (Metastable Cell) Three clumped cells (CTM) of the Type.2 subtype (Metastable Cells) were detected. Therefore, the patient was started on 8,400 ppm stable iodine water at 30 mL three times a day.

[0115] On September 26, 2018, the results of the analysis of peripheral blood circulating tumor cells showed that Type.1 intact cells One intact CTC and one intact metastable cell of type 2. ct CTC) and one aggregated cell of type 2 subtype (Metastable Cell) (CTM). Three tumor-associated macrophages were detected, but the tumor-associated macrophages (CTM) were not detected. As a result, the patient was given 8,400 ppm stable iodine water at a reduced dose of 10 mL three times a day. .

[0116] In the case of Example 4, EMT conversion was inhibited by the activation of PPAR-γ by iodine. The amoeboids of the Type.2 subtype (Metastable Cells) disappeared, but However, the clusters of cells (CTM) of the Type.2 subtype (Metastable Cells) ) was detected, so the patient is taking a reduced amount of stable iodine water. On the other hand, the microenvironment including tumor-associated macrophages (TAM) and blood cells and platelets ( The reason why the mitochondrial niche disappeared is that the direct effect of iodine, its oxidative / antioxidative properties, inhibited the mitochondrial It is possible that the endocannabinoid membrane potential was disturbed, leading to mitochondrial-mediated apoptosis. Non-patent literature 8, 11) and the various antitumor effects of iodine are suggested to be involved. (Non-patent documents 6 to 9). In this example, metastable cells (Meta cells) that are thought to be in the middle of EMT transformation were also Regarding the fact that intact cells (stable cells) were not lost, As seen in the case, the effect of anticancer drug treatment is suspected, but the detailed mechanism of action is unknown. The details are unknown.

[0117] Example 5 Table 10 shows information on patient E and the progress of iodine treatment, and Table 11 shows the analysis results of circulating tumor cells in the peripheral blood. are shown respectively in

[0118]

Table 10

[0119]

Table 11

[0120] As shown in Table 11, according to the analysis results of peripheral blood circulating tumor cells on June 8, 2018, there were 2 intact CTCs of Type.1, 12 intact CTCs of the subtype (Metastable Cell) of Type.2, 11 amoeboid cells of the subtype (Metastable Cell) of Type.2, and 51 clustered cells (cluster CTCs) of the subtype (Metastable Cell) of Type.2 were detected. Therefore, the administration of 8,400 ppm stable iodine water was started at 30 mL × 3 times / day. ype.1 intact CTCs, 12 intact CTCs of the subtype (Metastable Cell) of Type.2, 11 amoeboid cells of the subtype (Metastable Cell) of Type.2, and 51 clustered cells (cluster CTCs) of the subtype (Metastable Cell) of Type.2 were detected. Therefore, the administration of 8,400 ppm stable iodine water was started at 30 mL × 3 times / day. ) intact CTCs, 11 amoeboid cells of the subtype (Metastable Cell) of Type.2, and 51 clustered cells (cluster CTCs) of the subtype (Metastable Cell) of Type.2 were detected. Therefore, the administration of 8,400 ppm stable iodine water was started at 30 mL × 3 times / day. member cells (amoeboid) of the subtype (Metastable Cell) of Type.2, and 51 clustered cells (cluster CTCs) of the subtype (Metastable Cell) of Type.2 were detected. Therefore, the administration of 8,400 ppm stable iodine water was started at 30 mL × 3 times / day. ted cells (cluster CTCs) of the subtype (Metastable Cell) of Type.2 were detected. Therefore, the administration of 8,400 ppm stable iodine water was started at 30 mL × 3 times / day. were detected. Therefore, the administration of 8,400 ppm stable iodine water was started at 30 mL × 3 times / day.

[0121] According to the analysis results of peripheral blood circulating tumor cells on June 18, 2018, there were 3 intact CTCs of the subtype ( Metastable Cell) of Type.2, 2 amoeboid cells of the subtype (Metastab le Cell) of Type.2, and 1 clustered cell (cluster CTCs) of the subtype (Metastable Cell ) of Type.2 were detected. Therefore, the dose of 8,400 ppm stable iodine water was reduced to 20 mL × 3 times / day for administration.

[0122] In the case of Example 5, it was obvious that due to the activation of PPAR-γ by iodine, the EMT conversion was It is presumed that the number of intact cells of subtype (Metastable Cell) of Type.2 and amoeboid cells and cell clusters (clusters, CTM) has decreased due to inhibition. oid) and cell clusters (clusters, CTM) are presumed to have decreased.

[0123] (Example 6) The information of Patient F and the course of iodine treatment are shown in Table 12, and the analysis results of peripheral blood circulating tumor cells are shown in Table 13 respectively.

[0124]

Table 12

[0125]

Table 13

[0126] As shown in Table 13, according to the analysis results of peripheral blood circulating tumor cells on November 19, 2018 , there were 4 intact cells (intact CTC) of Type.1, 1 aggregated cell (C TM) of Type.1, 8 intact cells (intact CTC) of subtype (Metastable Cell) of Type.2, and 1 aggregated cell (cluster CTC) of subtype (Metastable Cell) of Type.2, and 1 aggregated cell (CTM) was detected. Therefore, 8,400 ppm of stable iodine water was started to be taken at 30 mL × 3 times / day.

[0127] According to the analysis results of peripheral blood circulating tumor cells on January 7, 2019, intact cells of Type.1 (intact CTC) and aggregated cells (CTM) of Type.1 were not detected, but T wo mesenchymal cells of Type.2 were detected. Therefore, 8,400 p pm of stable iodine water was continuously taken at 30 mL × 3 times / day.

[0128] Analysis of peripheral blood circulating tumor cells on February 14, 2019 showed that Type.1 intact cells There were three intact cells with high intact CTCs and one metastable cell of type 2. There were four intact CTCs and agglomerated cells of type 2 (Metastable Cells). One type 2 mesenchymal cell and one type 3 blastocyst were detected. The patient continued to take 8,400 ppm stable iodine water at 30 mL three times a day.

[0129] On March 8, 2019, the analysis of peripheral blood circulating tumor cells showed that Type.1 intact cells ( One intact CTC and three Type.2 mesenchymal cells were detected. Therefore, the patient continued to take 8,400 ppm stable iodine water at 30 mL three times a day.

[0130] In this example, metastable cells (Metastable C) were used, which are considered to be in the middle stage of EMT transformation. The intact cells of type 2 mesenchymal cells and EMT-transformed type 2 mesenchymal cells did not disappear. As seen in the cases of other examples in this specification, the fact that anticancer drug treatment was It is speculated that this effect is due to the effects of nicotine, but the detailed mechanism of action is unknown.

[0131] Example 7 Table 14 shows information on patient G and the progress of iodine treatment, and Table 15 shows the analysis results of circulating tumor cells in the peripheral blood. are shown in the figures.

[0132] [Table 14]

[0133] [Table 15]

[0134] As shown in Table 15, according to the analysis results of peripheral blood circulating tumor cells on December 4, 2018, 5 intact CTCs of Type.1, 13 intact CTCs of the subtype (Metastable Cell) of Type.2 ll, 26 amoeboid cells of the subtype (Metastable Cell) of Type.2, and 15 aggregated cells (cluster CTCs) of the subtype (Metastable Cell) of Type.2 were detected. Therefore, the intake of 8,400 ppm stable iodine water was started at 30 mL × 3 times / day.

[0135] In addition, at this time, since the number of intact cells of the subtype (Metastable Cell) of Type.2, amoeboid cells of the subtype (Metastable Cell) of Type.2, and cell masses (clusters, CTM) of the subtype (Metastable Cell) of Type.2 was large, infusions (100 mL of raw food + 10 mL of injectable iodine) were performed 13 times, raising the concentration of stable iodine water from 8400 ppm to 10,000 ppm, and

[0136] According to the analysis results of peripheral blood circulating tumor cells on January 7, 2019, intact CTCs of the subtype (Metastable Cell) of Type.2, amoeboid cells of the subtype (Metastable Cell) of Type.2, and aggregated cells (cluster CTCs) of the subtype (Metastable Cell) of Type.2 were not detected, ​Since 1 intact Type-CTC and 4 aggregated Type-1 cells (CTM) were detected, the concentration of the stable iodine solution was kept at 10,000 ppm, and the dosage was increased to 30 mL × 5 times / day and taken. Since 1 intact Type-CTC and 4 aggregated Type-1 cells (CTM) were detected, the concentration of the stable iodine solution was kept at 10,000 ppm, and the dosage was increased to 30 mL × 5 times / day and taken. Since 1 intact Type-CTC and 4 aggregated Type-1 cells (CTM) were detected, the concentration of the stable iodine solution was kept at 10,000 ppm, and the dosage was increased to 30 mL × 5 times / day and taken.

[0137] In the case of Example 7, it is presumed that the EMT conversion was inhibited by the activation of PPAR-γ by iodine, and the intact cells of the Type-2 subtype (Metastable Cell), the amoeboid cells of the Type-2 subtype (Metastable Cell), and the cell clusters (clusters, CTM) of the Type-2 subtype (Metastable Cell) disappeared. In the case of Example 7, it is presumed that the EMT conversion was inhibited by the activation of PPAR-γ by iodine, and the intact cells of the Type-2 subtype (Metastable Cell), the amoeboid cells of the Type-2 subtype (Metastable Cell), and the cell clusters (clusters, CTM) of the Type-2 subtype (Metastable Cell) disappeared. In the case of Example 7, it is presumed that the EMT conversion was inhibited by the activation of PPAR-γ by iodine, and the intact cells of the Type-2 subtype (Metastable Cell), the amoeboid cells of the Type-2 subtype (Metastable Cell), and the cell clusters (clusters, CTM) of the Type-2 subtype (Metastable Cell) disappeared. In the case of Example 7, it is presumed that the EMT conversion was inhibited by the activation of PPAR-γ by iodine, and the intact cells of the Type-2 subtype (Metastable Cell), the amoeboid cells of the Type-2 subtype (Metastable Cell), and the cell clusters (clusters, CTM) of the Type-2 subtype (Metastable Cell) disappeared.

[0138] (Example 8) The information of Patient H and the progress of iodine treatment are shown in Table 16, and the analysis results of peripheral blood circulating tumor cells are shown in Table 17. The information of Patient H and the progress of iodine treatment are shown in Table 16, and the analysis results of peripheral blood circulating tumor cells are shown in Table 17.

[0139]

Table 16

[0140]

Table 17

[0141] As shown in Table 17, according to the analysis results of peripheral blood circulating tumor cells on September 27, 2018, 3 intact Type-1 cells (intact CTC), 9 intact cells of the Type-2 subtype (Metastable Cell), and 2 mesenchymal cells of the Type-2 were detected. Therefore, the administration of 8,400 ppm stable iodine solution at 30 mL × 3 times / day was started. As shown in Table 17, according to the analysis results of peripheral blood circulating tumor cells on September 27, 2018, 3 intact Type-1 cells (intact CTC), 9 intact cells of the Type-2 subtype (Metastable Cell), and 2 mesenchymal cells of the Type-2 were detected. Therefore, the administration of 8,400 ppm stable iodine solution at 30 mL × 3 times / day was started. As shown in Table 17, according to the analysis results of peripheral blood circulating tumor cells on September 27, 2018, 3 intact Type-1 cells (intact CTC), 9 intact cells of the Type-2 subtype (Metastable Cell), and 2 mesenchymal cells of the Type-2 were detected. Therefore, the administration of 8,400 ppm stable iodine solution at 30 mL × 3 times / day was started. As shown in Table 17, according to the analysis results of peripheral blood circulating tumor cells on September 27, 2018, 3 intact Type-1 cells (intact CTC), 9 intact cells of the Type-2 subtype (Metastable Cell), and 2 mesenchymal cells of the Type-2 were detected. Therefore, the administration of 8,400 ppm stable iodine solution at 30 mL × 3 times / day was started. As shown in Table 17, according to the analysis results of peripheral blood circulating tumor cells on September 27, 2018, 3 intact Type-1 cells (intact CTC), 9 intact cells of the Type-2 subtype (Metastable Cell), and 2 mesenchymal cells of the Type-2 were detected. Therefore, the administration of 8,400 ppm stable iodine solution at 30 mL × 3 times / day was started.

[0142] Based on the analysis results of peripheral blood circulating tumor cells on November 19, 2018, no Type 2 mesenchymal cells were detected, but since 3 intact CTCs of the Type 2 subtype (Metastable Cell) were detected, stable iodine water at 8,400 ppm was continuously taken at 30 mL × 3 times / day.

[0143] Based on the analysis results of peripheral blood circulating tumor cells on December 17, 2018, since the number of intact CTCs of the Type 2 subtype (Metastable Cell) decreased to 1, the dosage of stable iodine water at 8,4 00 ppm was reduced to 20 mL × 3 times / day.

[0144] Based on the analysis results of peripheral blood circulating tumor cells on January 21, 2019, the previously disappeared type 2 mesenchymal cells were detected, and 9 intact CTCs of the decreasing Type 2 subtype (Metastable Cell) were detected. Therefore, the concentration of stable iodine water was increased to 10,000 ppm and taken at 30 mL × 3 times / day.

[0145] In the case of Example 8, since treatment with anticancer drugs was continued in parallel during iodine treatment , it is difficult to accurately evaluate the iodine treatment. However, in view of other examples of the present disclosure, it is speculated that the influence of anticancer drugs is involved in the revival of cancer stem cell-like mesenchymal cells due to EMT conversion.

[0146] (Example 9) The information of Patient I and the course of iodine treatment are shown in Table 18, and the analysis results of peripheral blood circulating tumor cells are shown in Table 19 respectively.

[0147]

Table 18

[0148]

Table 19

[0149] As shown in Table 19, according to the analysis results of peripheral blood circulating tumor cells on November 6, 2018, 1 intact CTC of Yype.1, 1 aggregated cell (cluster CTC) of Yype.1, 4 amoeboid cells of the subtype (Metastable Cell) of Type.2, and 2 mesenchymal cells of Type.2 were detected. Therefore, taking 20 mL of 8,400 ppm stable iodine water 3 times a day was started.

[0150] According to the analysis results of peripheral blood circulating tumor cells on December 18, 2018, 12 intact CTCs of Type.1 were detected, but no aggregated cells (cluster CTCs) of Type.1, amoeboid cells of the subtype (Metastable Cell) of Type.2, or mesenchymal cells of Type.2 were detected. Therefore, the dose was reduced to 20 mL taken 3 times a day.

[0151] In the case of Example 8, it is presumed that the activation of PPAR-γ by iodine inhibits EMT conversion, resulting in the disappearance of amoeboid cells of the subtype (Metastable Cell) of Type.2 and mesenchymal cells of Type.2.

[0152] (Example 10) The information of Patient J and the course of iodine treatment are shown in Table 20, and the analysis results of peripheral blood circulating tumor cells are shown in Table 21 respectively.

[0153]

Table 20

[0154]

Table 21

[0155] As shown in Table 21, according to the analysis results of peripheral blood circulating tumor cells on September 4, 2018, 1 intact CTC of Type.1 and 4 intact CTCs of the subtype of Type.2 (Metastable Cell) were detected. Therefore, the patient started taking stable iodine water at 8,400 ppm at 30 mL × 3 times / day. ype.1 intact CTC, 4 intact CTCs of the subtype of Type.2 (Metastable Cell ) were detected, so the patient started taking 30 mL of stable iodine water at 8,400 ppm three times a day.

[0156] According to the analysis results of peripheral blood circulating tumor cells on October 16, 2018, 1 intact CTC of Type.1 and 34 intact CTCs of the subtype of Type.2 (Metastable Cell) and 2 mesenchymal cells of Type.2 were detected. Therefore, the dose of stable iodine water at 8,400 ppm was increased to 40 mL × 3 times / day for administration. intact CTC, 34 intact CTCs of the subtype of Type.2 (Metastable Cell) and 2 mesenchymal cells of Type.2 were detected. Therefore, the dose of stable iodine water at 8,400 ppm was increased to 40 mL three times a day for administration. tact CTC) and 2 mesenchymal cells of Type.2 were detected, so the dose of stable iodine water at 8,400 ppm was increased to 40 mL three times a day for administration.

[0157] According to the analysis results of peripheral blood circulating tumor cells on December 4, 2018, the mesenchymal cells of Type.2 disappeared and the intact CTCs of the subtype of Type.2 (Metastable Cell) decreased. Therefore, the dose of stable iodine water at 8,400 ppm was reduced to 30 mL × 3 times / day for administration. mesenchymal cells disappeared and the intact CTCs of the subtype of Type.2 (Metastable Cell) decreased. Therefore, the dose of stable iodine water at 8,400 ppm was reduced to 30 mL three times a day for administration. tact CTC) decreased, so the dose of stable iodine water at 8,400 ppm was reduced to 30 mL three times a day for administration.

[0158] ​​​In the case of Example 10, treatment with an anticancer agent was continued during iodine treatment, so it is difficult to accurately evaluate the iodine treatment. However, considering other examples in this specification, the analysis results of peripheral blood circulating tumor cells on October 16, 2018 are easily inferred to be those in which cancer stem cell-like mesenchymal cells were revived by EMT conversion under the influence of the anticancer agent. Therefore, although it is difficult to accurately evaluate the iodine treatment, considering other examples in this specification, the analysis results of peripheral blood circulating tumor cells on October 16, 2018 are easily inferred to be those in which cancer stem cell-like mesenchymal cells were revived by EMT conversion under the influence of the anticancer agent. Therefore, although it is difficult to accurately evaluate the iodine treatment, considering other examples in this specification, the analysis results of peripheral blood circulating tumor cells on October 16, 2018 are easily inferred to be those in which cancer stem cell-like mesenchymal cells were revived by EMT conversion under the influence of the anticancer agent.

[0159] (Example 11) The information of Patient K and the progress of iodine treatment are shown in Table 22, and the analysis results of peripheral blood circulating tumor cells are shown in Table 23. respectively.

[0160] [Table 22]

[0161] [Table 23]

[0162] As shown in Table 23, according to the analysis results of peripheral blood circulating tumor cells on November 19, 2018, 5 intact CTCs of Type.1, 37 intact CTCs of the subtype (Metastable Cell) of Type.2, 68 cluster CTCs of the subtype (Metastable Cell) of Type.2 2 CTMs of the subtype (Metastable Cell) of Type.2, 4 mesenchymal cells of Type.2, 1 cluster CTC of Type.2 were detected. Therefore, since January 27, 2018, stable iodine water at 8,400 ppm has been taken at 30 mL × 5 times / day and by intravenous drip (The text continues here, but the original text seems to be incomplete.) (100 mL / raw food + 10 mL of injectable iodine solution) was performed a total of 7 times.

[0163] According to the analysis results of peripheral blood circulating tumor cells on December 28, 2018, 10 intact cells (intact CTC) of Type.1 were detected, but intact cells (intact CTC) of the subtype (Metastable Cell) of Type.2 , intact cells (intact CTC) of the subtype (Metastable Cell) of Type.2, aggregated cells of the subtype (Metastable Cell) of Type.2 (cluster CTC), aggregated cells (CT M) of the subtype (Metastable Cell) of Type.2, mesenchymal cells of Type.2, cell masses (cluster -, CTM) of Type.2 disappeared. Therefore, 30 mL × 3 times / day of 8,400 ppm stable iodine solution was reduced and taken.

[0164] According to the analysis results of peripheral blood circulating tumor cells on January 8, 2019, 8 intact cells (intact CTC) of Type.1, 4 intact cells (intact CTC) of the subtype (Metastable Cell) of Type.2, and 2 aggregated cells (cluster CTC) of the subtype (Metastable Cell) of Type.2 were detected.

[0165] In the case of Example 11, intact cells (intact CTC) of the subtype (Metastable Cell) of Type.2 and aggregated cells (cluster CTC ) of the subtype (Metastable Cell) of Type.2 that had disappeared due to the intravenous drip of stable iodine solution (100 mL / raw food + 10 mL of injectable iodine ) were detected as revived. As a cause, a reduction in the stable iodine solution is considered, but the progress is being observed continuously with 30 mL × 3 times / day of 8,400 ppm stable iodine solution.

[0166] (Example 12) The information of Patient L and the course of iodine treatment are shown in Table 24, and the analysis results of peripheral blood circulating tumor cells are shown in Table 25 respectively.

[0167] [Table 24]

[0168] [Table 25]

[0169] As shown in Table 25, according to the analysis results of peripheral blood circulating tumor cells on November 20, 2018 , 1 intact cell of Type.1 (intact CTC), 12 intact cells of Type.2 subtype (Metastable Cell), and 7 mesenchymal cells of Type.2 were detected. Therefore, 30 mL of 8,400 ppm stable iodine water was taken 3 times a day and drip infusion (100 mL of raw food + 10 mL of injectable iodine water) was performed 7 times in total. According to the analysis results of peripheral blood circulating tumor cells on December 18, 2018, 8 intact cells of Type.1 (intact CTC) were detected, but no intact cells of Type.2 subtype (Metastable Cell) and mesenchymal cells of Type.2 were detected

[0170] . Therefore, the dose of 8,400 ppm stable iodine water was reduced to 20 mL and taken 3 times a day. In the case of Example 12, the activation of PPAR-γ by iodine inhibits EMT conversion and Type.2 mesenchymal cells and Type.2 subtype (Metastable Cell)

[0171] are inhibited ​​is presumed to have disappeared.

[0172] (Example 13) The information of patient M and the course of iodine treatment are shown in Table 26, and the analysis results of peripheral blood circulating tumor cells are shown in Table 27 respectively.

[0173]

Table 26

[0174]

Table 27

[0175] As shown in Table 27, according to the analysis results of peripheral blood circulating tumor cells on April 17, 2018, 2 intact CTCs of Type.1, 9 intact CTCs of the subtype (Metastable Cell) of Type.2, 1 amoeboid cell of the subtype (Metastable Cell) of Type.2, 4 aggregated cells (CTM) of the subtype (Metastable Cell) of Type.2, and 1 mesenchymal cell of Type.2 were detected. Therefore, administration of 30 mL of 8,400 ppm stable iodine water three times a day was started.

[0176] According to the analysis results of peripheral blood circulating tumor cells on June 6, 2018, 2 intact CTCs of Type.1 were detected, but intact CTCs of the subtype (Metastable Cell) of Type.2, amoeboid cells of the subtype (Metastable Cell) of Type.2, (amoeboid), cell clusters (clusters, CTM) of the subtype (Metastable Cell) of Type.2 , Type.2 mesenchymal cells were not detected, and the chest X-ray also normalized. Therefore, since June 18, 2018, stable iodine water at 8,400 ppm was taken in a reduced dose of 20 mL × 3 times / day.

[0177] According to the analysis results of peripheral blood circulating tumor cells on July 31, 2018, 1 intact CTC of Type.1 and 1 intact CTC of the subtype (Metastable Cell) of Type.2 were detected. Therefore, it was taken at 20 nL × 3 times / day. ​

Claims

1. A first analysis step of analyzing peripheral blood circulating tumor cells (CTCs) of a mammalian subject; Based on the results of the analysis, an effective amount of a PPAR-γ agonist is administered to subjects who are in need of treatment. providing a After administration of the PPAR-γ agonist, the subjects' peripheral blood circulating tumor cells (CTCs) were analyzed. A second analysis step; A method for treating cancer, comprising:

2. The method of claim 1 , wherein the mammalian subject is a human, a cat or a dog.

3. The method according to claim 1 or 2, wherein the PPAR-γ agonist has an inhibitory effect on PPAR-α. Law.

4. The method according to any one of claims 1 to 3, wherein the PPAR-γ agonist comprises an iodine-containing compound. Method of posting.

5. 5. The method of claim 4, wherein the iodine-containing compound is sodium iodide.

6. The PPAR-γ agonist contains 100 ppm to 20,000 ppm of iodine.

6. The method according to claim 5, wherein the aqueous solution contains sodium chloride.

7. The method according to any one of claims 1 to 6, wherein the PPAR-γ agonist is administered by oral administration. method.

8. The PPAR-γ agonist is a combination of sodium iodide and potassium dihydrogen citrate and / or 8. The method of claim 7, wherein the aqueous solution comprises sodium metasilicate nonahydrate.

9. The method according to any one of claims 1 to 6, wherein the PPAR-γ agonist is administered by inhalation, injection or infusion. The method according to any one of claims 1 to 5.

10. 10. The method of claim 9, wherein the PPAR-γ agonist comprises sodium iodide and saline. method.

11. The analysis of the peripheral blood circulating tumor cells includes quantifying the number of peripheral blood circulating tumor cells. The method according to any one of claims 1 to 10.

12. 2. The method of claim 1, wherein the analysis of circulating tumor cells in peripheral blood comprises the analysis of the morphology of circulating tumor cells in peripheral blood. The method according to any one of claims 1 to 11.

13. The analysis of the peripheral blood circulating tumor cells reveals the microenvironment (niche) surrounding the peripheral blood circulating tumor cells. The method of any one of claims 1 to 12, comprising quantifying the number of

14. The microenvironment (niche) consists of platelets, macrophages, lymphocytes and stromal cells The method of claim 13, wherein the compound is one or more selected from the group consisting of:

15. In the first analysis step, if at least one of the following a) to f) is met, PPA The method according to any one of claims 1 to 14, wherein an R-gamma agonist is administered. a) When Type. 1 CTCs leaking from the primary tumor are detected, b) Metastable cell CTCs of type 2 were detected. case, c) When Type. 2 CTCs that may have undergone EMT are detected, d) When CTCs with amoeboid cell morphology were detected, e) The CTCs detected were not single cancer cells, but clusters of cancer cells that had aggregated together. If issued, f) Circulating tumor cells that form aggregates containing blood cells, platelets, etc., rather than single cancer cells If ring tumor microemboli (CTM) are detected.

16. In the analysis of peripheral blood circulating tumor cells, one or more peripheral blood circulating tumor cells per 1 mL of blood are detected.

16. The method of claim 1, wherein detecting the cells is an indication that a cancer patient has a tumor.

2. The method according to claim 1.

17. Cancer patients are diagnosed with epithelial tumors, mesenchymal tumors, tumors with both epithelial and mesenchymal characteristics, and metastatic tumors. The method of claim 16, wherein the tumor comprises one or more selected from the group consisting of tumors.

18. Cancer: breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, skin cancer, brain cancer, liver cancer, Bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer and skin cancer The method according to any one of claims 1 to 17, wherein the compound is one or more selected from the group consisting of:

19. A monitoring method for determining the therapeutic effect of a PPAR-γ agonist in a cancer patient. 、 conducting an analysis of peripheral blood circulating tumor cells of a mammalian subject; Based on the results of the above analysis, the peripheral blood circulating tumor cells of subjects who were administered PPAR-γ agonists were performing an analysis; Including, If the number of circulating tumor cells in the peripheral blood of the subject decreases over time, the cancer patient is determining that the patient has had a positive response to agonist treatment.

20. A test method for determining the therapeutic effect of a PPAR-γ agonist, comprising: A method in which peripheral blood circulating tumor cells (CTCs) are analyzed before and after drug administration.

21. In the manufacture of a medicament for enhancing the therapeutic effect of cancer or for treating cancer, - the use of gamma agonists, Before administration of the PPAR-γ agonist, peripheral blood circulating tumor cells (CTCs) are analyzed. For.

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