Combination cancer therapy with pentaaza macrocyclic ring complexes and platinum-based anticancer agents

Abstract

To provide a method of treating a cancer that improves response to an anticancer agent.SOLUTION: The present invention provides a method of treating a cancer in a mammalian subject afflicted with the cancer, consisting of administering to the subject a therapeutically effective amount of a platinum-based anticancer agent, and administering to the subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after administration of the platinum-based anticancer agent.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure generally relates to combination therapies for the treatment of cancer, including administering a pentaaza macrocyclic ring complex in combination with a platinum-based anti-cancer agent.

Background Art

[0002] Transition metal-containing pentaaza macrocyclic ring complexes having a macrocyclic ring group corresponding to Formula A have been shown to be effective in the treatment of many animal and cell models of human diseases, as well as human patients suffering from the diseases.

Chemical Formula

Chemical Formula

Chemical formula

[0003] Certain of these compounds also have potent anti-inflammatory activity and have been shown to suppress oxidative damage in vivo. For example, GC4403 inhibits inflammation in an inflammatory model rat (Salvemini, et.al., Science, 286, 304 (1999)) and has been reported to prevent joint disease in a model rat of collagen-induced arthritis (Salvemini et al., Arthritis & Rheumatism, 44(12), 2009-2021 (2001)). Still other of these compounds, MdPAM and MnBAM, have shown in vivo activity in the inhibition of colonic tissue injury and neutrophil accumulation in colonic tissue (Weiss et al., The Journal of Biological Chemistry, 271(42), 26149-26156 (1996)). Further, these compounds have an analgesic effect and have been reported to reduce inflammation and edema in a rat paw carrageenan hyperalgesia model (see, for example, U.S. Patent No. 6,180,620).

[0004] Compounds of this class have also been shown to be safe and effective in the prevention and treatment of diseases in human subjects. For example, GC4419 has been shown to reduce oral mucositis in head and neck cancer patients undergoing chemoradiotherapy (Anderson, C., Phase 1 Trial of Superoxide Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiotherapy (CRT)-Induced Mucositis (OM) in patients (pts) with Mouth or Oropharyngeal Carcinoma (OCC), Oral Mucositis Research Workshop, MASCC / ISOO Annual Meeting on Supportive Care in Cancer, Copenhagen, Denmark (June 25, 2015)).

[0005] Furthermore, pentaazamacrocyclic ring complexes containing a transition metal corresponding to this class have shown efficacy in the treatment of various cancers. For example, certain compounds corresponding to this class are provided in combination with agents such as paclitaxel and gemcitabine to enhance cancer treatment, such as the treatment of colorectal cancer and lung cancer (non-small cell lung cancer) (see, e.g., U.S. Patent No. 9,998,893). The above 4403 compound has also been used in the treatment of Meth A spindle cell squamous cell carcinoma and RENCA renal carcinoma in an in vivo model (Samlowski et al., Nature Medicine, 9(6), 750-755 (2003)) and in the treatment of spindle cell squamous cell carcinoma metastasis (Samlowski et al., Madame Curie Bioscience Database (Internet), 230-249 (2006)). The above 4419 compound has also been used in combination with cancer treatment, such as in combination with the treatment related to the administration of cisplatin and radiation to enhance the treatment of an in vivo model (Sishc et al., poster for Radiation Research Society (2015)).

[0006] Platinum-based anticancer agents (e.g., cisplatin and oxaliplatin) act by inducing DNA damage in cancer cells (Cruet-Hennequart et al, DNA Repair, 7(4): 582-596 (2008)) and have been shown to be extremely effective in cancer treatment (Kellan et al, J. Inorg Biochem, 77(1-2); 121-124 (1999); Wang X, Anticancer Agents Med Chem, 10(5): 396-411 (2010); Dilruba et al, Cancer Chemother Pharmacol, 77(6): 1103-1124 (2016)). However, while platinum-based anticancer agents (e.g., cisplatin) are widely used as chemotherapeutic agents, such agents also often have toxicities associated with their administration (e.g., nephrotoxicity, ototoxicity, gastrointestinal toxicity, and myelotoxicity) (Miller et al., Toxins (Basel), 2(11): 2490-2518 (2010)). Thus, the use of such platinum-based anticancer agents can be limited by the need to minimize their associated toxic effects.

[0007] Accordingly, there is a need for improved cancer therapies that provide improved efficacy in killing cancer cells while also providing good selectivity for killing cancer cells compared to normal cells. There is also a need for improved treatment methods that improve the prognosis of patients receiving these treatments. There is also a need for treatment methods that reduce the toxic effects associated with platinum-based anticancer agents (e.g., cisplatin).

[0008] Thus, briefly described, aspects of the present disclosure are methods of treating cancer in a mammalian subject afflicted with cancer, comprising administering to the subject a therapeutically effective amount of a platinum-based anticancer agent, and administering to the subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anticancer agent to enhance the responsiveness of the cancer to the platinum-based anticancer agent. [Chemical formula] (I) [wherein, M is Mn 2+ or Mn 3+ ; and R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), and are moieties selected from the group consisting of, where R 11 and R 12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocyclic ring having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocyclic ring, the hydrogen attached to the nitrogen which is part of both the heterocyclic ring and the macrocyclic ring, and R1 and R attached to the carbon atoms which are part of both the heterocyclic ring and the macrocyclic ring 10 shall be considered non-existent; X and Y each represent any suitable ligand derived from a monodentate or polydentate ligand or ligand system, or the corresponding anion; Z is a counterion; n is an integer from 0 to 3; and the dotted line represents a coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese)]

[0009] Another aspect of the present disclosure is a method for enhancing the sensitivity of a mammalian subject to treatment with a platinum-based anti-cancer agent in a subject in need of enhanced sensitivity, comprising administering to the subject a therapeutically effective amount of a pentaazamacrocyclic complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anti-cancer agent to enhance the therapeutic responsiveness to the platinum-based anti-cancer agent. [Chemical formula] (I) [wherein, M is Mn 2+ or Mn 3+ ; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR11 R 12 、 -SR 11 、 -SOR 11 、 -SO2R 11 、 -SO2NR 11 R 12 、 -N(OR 11 )(R 12 )、 -P(O)(OR 11 )(OR 12 )、 -P(O)(OR 11 )(R 12 )、 and -OP(O)(OR 11 )(OR 12 ) selected from the group consisting of, where R 11 and R 12 are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen bonded to the nitrogen which is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms which are part of both the heterocycle and the macrocyclic ring 10 are considered non-existent; X and Y represent either monodentate or polydentate ligands or suitable ligands derived from a ligand system, or anions corresponding thereto; Z is a counterion; n is an integer from 0 to 3; and the dotted line represents a coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese)]

[0010] Another aspect of the present disclosure is a method for reducing toxic effects in a mammalian subject associated with treatment with a platinum-based anticancer agent in a mammalian subject in need thereof, comprising: administering to said subject a therapeutically effective amount of a platinum-based anti-cancer agent; and The present invention relates to a method for reducing the toxic effects of a platinum-based anticancer drug by administering to the subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to formula (I): [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), wherein R 11 and R 12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen which is part of both the heterocycle and the macrocyclic ring, and R1 and R attached to the carbon atoms which are part of both the heterocycle and the macrocyclic ring 10 is considered to be absent; X and Y each represent a suitable ligand derived from a mono- or multi-dentate ligand or ligand system, or the corresponding anion; Z is a counterion; n is an integer from 0 to 3; and the dotted line represents a coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese)]

[0011] Another aspect of the present disclosure is a method for treating the toxic effects associated with treatment with a platinum-based anti-cancer agent in a mammalian subject in need thereof and / or reducing the risk of said toxic effects, comprising administering to the subject a therapeutically effective amount of a pentaaza macrocyclic complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anti-cancer agent to reduce the toxic effects of the platinum-based anti-cancer agent. [Chemical formula] (I) [wherein, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are each independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), and is a moiety selected from the group consisting of, where R 11 and R 12 are each independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R attached to the carbon atoms that are part of both the heterocycle and the macrocyclic ring 10is considered non-existent; X and Y each represent either a suitable ligand derived from a monodentate or polydentate ligand or ligand system, or the corresponding anion; Z is a counterion; n is an integer from 0 to 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0012] Other objects and features are partly obvious and partly shown below.

Brief Description of the Drawings

[0013]

Figure 1

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Figure 11D

DETAILED DESCRIPTION OF THE INVENTION

[0014] Abbreviations and Definitions The following definitions and methods are provided to clarify the present invention and enable those skilled in the art to practice the present invention. Unless otherwise indicated, terms should be understood by those skilled in the art according to their customary usage.

[0015] "Acyl" means a -COR moiety (wherein R is alkyl, haloalkyl, aryl optionally substituted as defined herein, or heteroaryl optionally substituted as defined herein), for example, acetyl, trifluoroacetyl, benzoyl, etc.

[0016] "Acyloxy" means a -OCOR moiety (wherein R is alkyl, haloalkyl, aryl optionally substituted as defined herein, or heteroaryl optionally substituted as defined herein), for example, acetyl, trifluoroacetyl, benzoyl, etc.

[0017] "Alkoxy" means a -OR moiety (wherein R is alkyl as defined herein), for example, methoxy, ethoxy, propoxy, 2-propoxy, n-, iso-, or tert-butoxy, etc.

[0018] "Alkyl" means a straight-chain saturated monovalent hydrocarbon moiety (e.g., 1 to 6 carbon atoms) or a branched-chain saturated monovalent hydrocarbon moiety (e.g., 3 to 6 carbon atoms), and examples thereof include a C1-C6 alkyl group such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.

[0019] Furthermore, unless otherwise indicated, the term "alkyl" as used herein is intended to include both "unsubstituted alkyl" and "substituted alkyl", and the latter of these means an alkyl moiety having a substituent that replaces hydrogen at one or more carbons of the hydrocarbon backbone. In fact, unless otherwise indicated, all groups described herein are intended to include both substituted and unsubstituted options.

[0020] The term "C x-y ", when used in conjunction with a compound moiety (e.g., alkyl and aralkyl), is intended to include a group containing x to y carbons in said chain. For example, the term "C x-y alkyl" means a substituted or unsubstituted saturated hydrocarbon group, and includes straight-chain alkyl and branched-chain alkyl groups containing x to y carbon atoms in said chain.

[0021] "Alkylene", unless otherwise indicated, means a straight-chain saturated divalent hydrocarbon moiety (e.g., 1 to 6 carbon atoms) or a branched-chain saturated divalent hydrocarbon moiety (e.g., 3 to 6 carbon atoms), and examples thereof include methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0022] "Alkenyl" means a straight-chain unsaturated monovalent hydrocarbon moiety (e.g., 2 to 6 carbon atoms) or a branched-chain saturated monovalent hydrocarbon moiety (e.g., 3 to 6 carbon atoms), and examples thereof include ethenyl (vinyl), propenyl, 2-propenyl, butenyl (including all isomeric forms), pentenyl (including all isomeric forms), and the like.

[0023] "Alkaryl" means a monovalent moiety derived from an aryl moiety by substituting one or more hydrogen atoms with alkyl groups.

[0024] "Alkenylcycloalkenyl" means a monovalent moiety derived from an alkenyl moiety by substituting one or more hydrogen atoms with cycloalkenyl groups.

[0025] "Alkenylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by substituting one or more hydrogen atoms with alkenyl groups.

[0026] "Alkylcycloalkenyl" means a monovalent moiety derived from a cycloalkenyl moiety by substituting one or more hydrogen atoms with alkyl groups.

[0027] "Alkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by substituting one or more hydrogen atoms with alkyl groups.

[0028] "Alkynyl" means a straight-chain unsaturated monovalent hydrocarbon moiety (e.g., having 2 to 6 carbon atoms) or a branched-chain saturated monovalent hydrocarbon moiety (e.g., having 3 to 6 carbon atoms), such as ethynyl, propynyl, butynyl, isobutynyl, hexynyl, etc.

[0029] "Alkoxy" means a monovalent moiety derived from an alkyl moiety by substituting one or more hydrogen atoms with hydroxy groups.

[0030] "Amino" is -NR a R b group (where R a and R b are independently hydrogen, alkyl or aryl).

[0031] "Arylalkyl" means a monovalent moiety derived from an alkyl moiety by substituting one or more hydrogen atoms with an aryl group.

[0032] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon moiety of 6 to 10 ring atoms, for example, phenyl or naphthyl.

[0033] "Ring" means a carbocyclic saturated monovalent hydrocarbon moiety of 3 to 10 carbon atoms.

[0034] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon moiety of 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc.

[0035] "Cycloalkylalkyl" means a monovalent moiety derived from an alkyl moiety by substituting one or more hydrogen atoms with a cycloalkyl group, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl, etc.

[0036] "Cycloalkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by substituting one or more hydrogen atoms with a cycloalkyl group.

[0037] "Cycloalkenyl" means a cyclic monounsaturated monovalent hydrocarbon moiety of 3 to 10 carbon atoms, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, etc.

[0038] "Cycloalkenylalkyl" means a monovalent moiety derived from an alkyl moiety by substituting one or more hydrogen atoms with a cycloalkenyl group, for example, cyclopropenylmethyl, cyclobutenylmethyl, cyclopentylethyl, or cyclohexenylethyl, etc.

[0039] "Ether" means a monovalent moiety derived from an alkyl moiety by substituting one or more hydrogen atoms with alkoxy groups.

[0040] "Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

[0041] "Heterocyclic" or "heterocyclyl" is a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, where 1 or 2 ring atoms are heteroatoms selected from N, O, or S(O) n (n is an integer from 0 to 2), and the remaining ring atoms are C. The heterocyclyl ring may optionally be fused to (one) aryl or heteroaryl ring as defined herein, provided that the aryl and heteroaryl rings are monocyclic. A heterocyclyl ring fused to a monocyclic aryl or heteroaryl ring is also referred to herein as a "bicyclic heterocyclyl" ring. Also, 1 or 2 ring carbon atoms in the heterocyclyl ring may optionally be substituted by a -CO- group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, etc. When the heterocyclyl ring is unsaturated, it may contain 1 or 2 ring double bonds, provided that the ring is not aromatic. When the heterocyclyl group is a saturated ring and not fused to an aryl or heteroaryl ring as described above, it is referred to herein as a saturated monocyclic heterocyclyl.

[0042] "Heteroaryl" means a monocyclic or bicyclic aromatic moiety of 5 to 10 ring atoms, where one or more preferably 1, 2, or 3 ring atoms are heteroatoms selected from N, O, or S and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.

[0043] "Nitro" means -NO2.

[0044] "Organosulfur" means a monovalent moiety -SR group (wherein R is hydrogen, alkyl or aryl).

[0045] "Platinum-based anticancer agent" means a coordination complex of platinum, a class of compounds having anticancer effects that can also be called platin, platinate, and platinum-based antineoplastic agents. Examples of platinum-based anticancer agents used in chemotherapy include cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatine, phenanthriplatin, ProLindac, triplatin tetranitrate, picoplatin, satraplatin and / or pharmaceutically acceptable salts thereof.

[0046] "Substituted alkyl", "substituted ring", "substituted phenyl", "substituted aryl", "substituted heterocycle", and "substituted nitrogen heterocycle" each mean an alkyl, a ring, an aryl, a phenyl, a heterocycle, or a nitrogen-containing heterocycle, which are optionally substituted with one, two, or three substituents independently selected from, for example, alkyl, alkoxy, alkoxyalkyl, halo, hydroxy, hydroxyalkyl, or organic sulfur. Generally, the term "substituted" includes a group substituted with any one or more of C1-4 alkyl, C2-4 alkenyl, halogen, alcohol, and / or amine.

[0047] "Thioether" means a monovalent moiety derived from an alkyl moiety by substituting one or more hydrogen atoms with -SR groups (where R is alkyl).

[0048] As used herein, (i) the compounds described herein and in the drawings as compound 401, 4401, or GC4401 are described as the same compound, (ii) the compounds described herein and in the drawings as compound 403, 4403, or GC4403 are described as the same compound, (iii) the compounds described herein and in the drawings as compound 419, 4419, or GC4419 are described as the same compound, and (iv) the compounds described herein and in the drawings as compound 444, 4444, or GC4444 are described as the same compound.

[0049] Detailed Description In one embodiment, aspects of the present disclosure relate to the treatment of cancer by administering a therapeutically effective amount of a pentaazamacrocyclic ring complex according to formula (I) described below in combination with an anti-cancer agent based on a therapeutically effective amount of platinum to a subject suffering from cancer. The pentaazamacrocyclic ring complex can be administered before, simultaneously with, or after the administration of the platinum-based anti-cancer agent to enhance the responsiveness of the cancer to the platinum-based anti-cancer agent. In particular, unexpectedly, when the pentaazamacrocyclic ring complex according to formula (I) is administered in combination with a platinum-based anti-cancer agent, it exhibits a synergistic effect, resulting in more than an additive effect compared to the administration of either the platinum-based anti-cancer agent or the pentaazamacrocyclic ring complex according to formula (I) alone. Without being limited to any particular theory, the pentaazamacrocyclic ring complex according to formula (I) is thought to act to sensitize cancer cells to treatment with a platinum-based anti-cancer agent, such that the cancer cells can become highly responsive to the anti-cancer effect of the platinum-based anti-cancer agent. Further, without being limited to any particular theory, the platinum-based anti-cancer agent can act, via a previously unknown mechanism of action related to hydrogen peroxide, in combination with the pentaazamacrocyclic ring complex according to formula (I) to kill cancer cells, and it has been found that this mechanism can be synergistically enhanced by the combination. Further explanation of the synergistic effect between the pentaazamacrocyclic ring complex according to formula (I) and the platinum-based anti-cancer agent is provided in the examples described herein.

[0050] Accordingly, in one aspect of the present disclosure, there is provided a method of enhancing the sensitivity of a mammalian subject to treatment with a platinum-based anti-cancer agent in a mammalian subject in need of treatment. The method can be characterized by administering a therapeutically effective amount of a pentaazamacrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anti-cancer agent to enhance the therapeutic responsiveness to the platinum-based anti-cancer agent.

[0051] Yet another aspect of the present disclosure relates to the finding that administration of a pentaaza macrocyclic ring complex corresponding to the following formula (I) can reduce the toxic effects (e.g., nephrotoxicity and myelotoxicity) of platinum-based anti-cancer agents. Thus, in one embodiment, a method for reducing the toxic effects on a mammalian subject associated with treatment with a platinum-based anti-cancer agent in a mammalian subject in need of treatment comprises administering to the subject a therapeutically effective amount of a platinum-based anti-cancer agent, and administering a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anti-cancer agent to reduce the toxic effects of the platinum-based anti-cancer agent. In yet another embodiment, a method for treating and / or reducing the risk of toxic effects associated with treatment with a platinum-based anti-cancer agent in a mammalian subject in need of treatment and / or reduction, which comprises administering to the subject a pentaaza macrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anti-cancer agent to reduce the toxic effects of the platinum-based anti-cancer agent, is provided.

[0052] In one embodiment, the subject may be a subject at risk of toxic effects associated with treatment with a platinum-based anti-cancer agent by receiving the platinum-based anti-cancer agent as part of a treatment plan. For example, the subject may be receiving the platinum-based anti-cancer agent as part of a plan for cancer treatment, thereby undergoing cancer treatment while also being at risk of developing toxic effects associated with the platinum-based anti-cancer agent. In another aspect, the subject may be susceptible to and / or currently suffering from toxic effects (e.g., nephrotoxicity, myelotoxicity, and / or other toxicities) associated with a platinum-based anti-cancer agent. In certain embodiments, it has been found that administration of the pentaazamacrocyclic ring complex corresponding to formula (I) can reduce, alleviate, and / or treat diseases associated with the toxicity of a platinum-based anti-cancer agent, and can potentially reduce the risk of development of such toxicity-related diseases in the subject. Thus, in certain embodiments, the pentaazamacrocyclic ring complex according to formula (I) below can reduce the toxicity of a platinum-based anti-cancer agent without substantially reducing the effectiveness of the platinum-based anti-cancer agent. Further, in certain embodiments, the reduction in toxicity provided by the combination can simultaneously result in an enhanced cancer treatment responsiveness to the platinum-based anti-cancer agent. That is, the combination can potentially reduce the toxic effects of the platinum-based anti-cancer agent on normal cells (non-cancerous cells) while simultaneously and synergistically sensitizing cancer cells to killing by the platinum-based anti-cancer agent.

[0053] Transition metal pentaazamacrocyclic ring complex In one embodiment of 1, the pentaazamacrocyclic ring complex has the formula (I):

Chemical formula

[0054] As described above for the pentaaza macrocyclic complex of formula (I), M is Mn 2+ or Mn 3+ is. In certain embodiments where the pentaaza macrocyclic complex corresponds to formula (I), M is Mn 2+ is. In another particular embodiment where the pentaaza macrocyclic complex corresponds to formula (I), M is Mn 3+ is.

[0055] In embodiments where one or more of R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are hydrocarbyl, for example, suitable hydrocarbyl moieties include, but are not limited to, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and aralkyl. In one embodiment, R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclyl. More preferably, in this embodiment, R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10is independently hydrogen or lower alkyl (e.g., C1-C6 alkyl, more typically C1-C4 alkyl). Thus, for example, R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 may each independently be hydrogen, methyl, ethyl, propyl, or butyl (straight-chain, branched, or cyclic).

[0056] In a preferred embodiment of 1, R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 are each independently hydrogen or methyl. In a preferred embodiment of 1 where the pentaaza macrocyclic ring complex corresponds to formula (I), R1, R2, R’2, R3, R4, R5, R’5, R7, R8, R9, R’9, and R 10 are each hydrogen, one of R6 and R’6 is hydrogen, and the other of R6 and R’6 is methyl. In this embodiment, for example, R1, R2, R’2, R3, R4, R5, R’5, R6, R7, R8, R9, R’9, and R 10 may each be hydrogen, and R’6 is methyl. Alternatively, for example, R1, R2, R’2, R3, R4, R5, R’5, R’6, R7, R8, R9, R’9, and R 10 may each be hydrogen, and R6 is methyl. In another preferred embodiment of 1 where the pentaaza macrocyclic ring complex corresponds to formula (I), R1, R3, R4, R5, R’5, R’6, R7, R8, and R 10 are each hydrogen, one of R2 and R’2 is hydrogen, the other of R2 and R’2 is methyl, and one of R9 and R’9 is hydrogen, and the other of R9 and R’9 is methyl. In this embodiment, for example, R1, R’2, R3, R4, R5, R’5, R7, R8, R9, and R 10 may each be hydrogen, and R2 and R’9 are methyl. Alternatively, for example, R1, R2, R3, R4, R5, R’5, R7, R8, R’9, and R 10may each be hydrogen, and R’2 and R9 are methyl. In another embodiment where the pentaazamacrocyclic ring complex corresponds to formula (I), R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 are each hydrogen.

[0057] In certain embodiments, the U and V moieties are independently substituted or unsubstituted fused cycloalkyl moieties having from 3 to 20 ring carbon atoms, more preferably from 4 to 10 ring carbon atoms. In certain embodiments, the U and V moieties are each a trans-cyclohexanyl fused ring.

[0058] In certain embodiments, the W moiety is a substituted or unsubstituted fused heteroaromatic moiety. In certain embodiments, the W moiety is a substituted or unsubstituted fused pyridino moiety. When W is a substituted fused pyridino moiety, the W moiety is typically substituted at a ring carbon atom that is para to the nitrogen atom of the heterocycle with a hydrocarbyl or substituted hydrocarbyl moiety (e.g., alkyl, substituted alkyl). In one preferred embodiment, the W moiety is an unsubstituted fused pyridino moiety.

[0059] As described above, X and Y each represent any suitable ligand derived from a mono- or multi-dentate ligand or ligand system, or the corresponding anions thereof (e.g., benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). For example, X and Y are, in particular, halo, oxo, aco, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycloarylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitrogen oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitric acid, nitrous acid, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiocarboxylic acid, arylthiocarboxylic acid, alkylthiolthiocarboxylic acid, arylthiolthiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkylthiourea, arylthiourea, alkylarylthiourea, sulfuric acid, sulfurous acid, bisulfuric acid, bisulfurous acid, thiosulfuric acid, thiosulfurous acid, hydrosulfurous acid, alkylphosphine, arylphosphine, alkylphosphine oxide, arylphosphine oxide, alkylarylphosphine oxide, alkylphosphine sulfide, arylphosphine sulfide, alkylarylphosphine sulfide, alkylphosphonic acid, arylphosphonic acid, alkylphosphinic acid, arylphosphinic acid, alkylphosphonous acid, arylphosphonous acid, phosphoric acid, thiophosphoric acid, phosphorous acid, pyrophosphorous acid, triphosphoric acid, hydrogen phosphate, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylarylguanidino, alkylcarbamate, arylcarbamate, alkylarylcarbamate, alkylthiocarbamate, arylthiocarbamate,It may be selected from the group consisting of alkyl aryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkyl aryl dithiocarbamate, bicarbonate, carbonate, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, perbromic acid, bromic acid, bromous acid, hypobromous acid, tetrahalomanganate, tetrafluoroboric acid, hexafluoroantimonic acid, hypophosphorous acid, iodic acid, periodic acid, metaboric acid, tetraarylboric acid, tetraalkylboric acid, tartaric acid, salicylic acid, succinic acid, citric acid, ascorbic acid, saccharic acid, amino acid, hydroxamic acid, thiotosylic acid, and anions of ion exchange resins, or their corresponding anions. In one embodiment, X and Y, if present, may be independently selected from the group consisting of halo, nitrate, and bicarbonate ligands. For example, in this embodiment, X and Y, if present, are halo ligands, such as chloro ligands.,

[0060] Furthermore, in one embodiment, X and Y correspond to -O-C(O)-X1, each X1 is -C(X2)(X3)(X4), and each X1 is independently substituted or unsubstituted phenyl or -C(-X2)(-X3)(-X4); each X2 is independently substituted or unsubstituted phenyl, methyl, ethyl or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, -X5C(=O)R 13 [wherein X5 is NH or O, and R 13 is C1-C 18 alkyl, substituted or unsubstituted aryl, or C1-C 18 aralkyl], or -OR 14 [wherein R 14 is C1-C 18 alkyl, substituted or unsubstituted aryl, or C1-C 18 aralkyl], or together with X4 is (=O); and each X4 is independently hydrogen or together with X3 is (=O).

[0061] In yet another embodiment, X and Y are each independently selected from the group consisting of charge-neutralizing anions derived from mono- or multidentate ligands, and ligand systems and their corresponding anions; or X and Y are each independently bonded to one or more of R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 and are each independently bonded to one or more of R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R

[0062] In the pentaaza macrocyclic ring complex corresponding to formula (I), Z is a counterion (e.g., a charge-neutralizing anion), and n is an integer from 0 to 3. Generally, Z may correspond to the counterion of the moiety described above for X and Y.

[0063] In a combination, a preferred embodiment is a pentaaza macrocyclic ring complex corresponding to formula (I), wherein M is Mn 2+ or Mn 3+ ; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are each independently hydrogen or lower alkyl; U and V are each a trans-cyclohexanyl fused ring; W is a substituted or unsubstituted fused pyridino moiety; X and Y are ligands; and Z, if present, is a charge-neutralizing anion, said complex.

[0064] More preferably, in these embodiments, M is Mn 2+ ; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10is, independently, hydrogen or methyl; U and V are each a trans-cyclohexanyl fused ring; W is an unsubstituted fused pyridino moiety; and X and Y are, independently, halo ligands (e.g., fluoro, chloro, bromo, iodo). Z, if present, may be a halide anion (e.g., fluoride ion, chloride ion, bromide ion, iodide ion).

[0065] In yet another embodiment, the pentaazamacrocyclic ring complex is of the following formula (II):

Chemical formula

[0066] Further, in one embodiment, the pentaaza macrocyclic ring complex is represented by formula (III) or formula (IV): [ka] [In the formula, X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or their corresponding anions; and R A , R B , R C , and R D are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), wherein R 11 and R 12 are independently hydrogen or alkyl. is expressed by

[0067] In yet another embodiment, the pentaaza macrocyclic ring complex has the formula (V)-(XVI): [ka] [ka] It is a compound represented by a formula selected from the group consisting of

[0068] In one embodiment, X and Y in any of the formulas herein are independently selected from the group consisting of fluoro, chloro, bromo and iodo anions. In yet another embodiment, X and Y in any of the formulas herein are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates and arylalkyl carboxylates. In yet another embodiment, X and Y in any of the formulas herein are independently amino acids.

[0069] In one embodiment, the pentaaza macrocyclic ring complex is of the following formula (IA): [Chemical formula] (IA) [wherein, M is Mn 2+ or Mn 3+ ; R 1A , R 1B , R2, R3, R 4A , R 4B , R5, R6, R 7A , R 7B , R8, R9, R 10A , and R 10B are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -C(=O)NR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(=O)(OR 11 )(OR12 ), -P(=O)(OR 11 )(R 12 ), and -OP(=O)(OR 11 )(OR 12 ), which is a moiety selected from the group consisting of, where R 11 and R 12 are, independently, hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen which is part of both the heterocycle and the macrocyclic ring, and R5 and R6 which are part of both the heterocycle and the macrocyclic ring, are considered non-existent; Each X1 is, independently, substituted or unsubstituted phenyl, or -C(-X2)(-X3)(-X4); Each X2 is, independently, substituted or unsubstituted phenyl, or alkyl; Each X3 is, independently, hydrogen, hydroxyl, alkyl, amino, -X5C(=O)R 13 [wherein X5 is NH or O, and R 13 is C1-C 18 alkyl, substituted or unsubstituted aryl, or C1-C 18 aralkyl], or -OR 14 [wherein R 14 is C1-C 18 alkyl, substituted or unsubstituted aryl, or C1-C 18is an aralkyl, or together with X4 is (=O); Each X4 is independently hydrogen or together with X3 is (=O); and the bond between the transition metal M and the nitrogen atom of the macrocyclic ring, and the bond between the transition metal M and the oxygen atom of the axial ligand -OC(=O)X1 are coordination covalent bonds. as shown.

[0070] In one embodiment, within formula (IA) and the groups contained therein, in one group of the compound, X1 is -C(-X2)(-X3)(-X4), and each X2, X3, and X4, in combination, corresponds to any of the combinations identified in the following table: [Table 1]

[0071] Furthermore, within embodiment (IA) and the groups contained therein, in one group of the compound, X1 is C(-X2)(-X3)(-X4), X3 is -X5C(=O)R 13 and the combination of X2, X3 and X4 includes any of the combinations identified in the following table: [Table 2] [wherein, R 13 is C1-C 18 alkyl, substituted or unsubstituted aryl or C1-C 18 aralkyl, or -OR 14 (wherein, R 14 is C1-C 18 alkyl, substituted or unsubstituted aryl, or C1-C 18 aralkyl).

[0072] In one embodiment, the pentaazamacrocyclic ring complex corresponding to formula (IA) is of complex formula (IE), for example, (IE R1 ), (IE S1 ), (IE R2 ), (IES2 ), (IE R3 ), or (IE S3 ): [Chemical formula] [Chemical formula] [Chemical formula] [wherein, M is Mn +2 or Mn +3 ; each X1 is independently a substituted or unsubstituted phenyl or -C(X2)(X3)(X4); each X2 is independently a substituted or unsubstituted phenyl, methyl, ethyl, or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, or together with X4 is =O; each X4 is independently hydrogen or together with X3 is =O; and the bond between manganese and the nitrogen atom of the macrocyclic ring and the bond between manganese and the oxygen atom of the axial ligand -OC(O)X1 are coordinate covalent bonds] is one of them.

[0073] In one embodiment, each X1 is -C(X2)(X3)(X4), and each -C(X2)(X3)(X4) corresponds to any one of Combinations 1 to 9 shown in the table for the above formula (IA).

[0074] In yet another embodiment, X and Y in the pentaaza macrocyclic complex of formula (I) correspond to the ligands in formula (IA) or (IE). For example, X and Y in the said complex of formula (I) may correspond to -O-C(O)-X1, where X1 is as defined for the complexes of the above formulas (IA) and (IE).

[0075] In one embodiment, the pentaaza macrocyclic ring complex corresponding to formula (I) (for example, any subset of formula (I) corresponding to formula (I) or formulas (II)-(XIV), (IA) and (IE)) has the following structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0076] In one embodiment, the pentaaza macrocyclic ring complexes for use in the methods and compositions described herein include formulas (2), (3), (4), (5), (6), and (7):

Chemical formula

[0077] In another aspect, the pentaaza macrocyclic ring complex is of formula (6) or formula (7):

Chemical formula

[0078] The chemical structures of 6 (e.g., the dichloro complex form described in Riley, D.P., Schall, O.F., 2007, Advances in Inorganic Chemistry, 59: 233-263, etc.) and 7 (e.g., the dichloro complex structure of 7) described in this specification are identical except that they have mirror-image chirality (i.e., the enantiomeric structures cannot be superimposed).

[0079] For example, the pentaazamacrocyclic ring complex may correspond to at least one of the following complexes:

Chem.

[0080] In yet another embodiment, the pentaazamacrocyclic ring complex may correspond to at least one of the following complexes:

Chem.

Chem.

[0081] In one embodiment, the enantiomeric purity of the pentaaza macrocyclic ring complex is 95% or higher, more preferably 98% or higher, still more preferably 99% or higher, and most preferably 99.5% or higher. As used herein, the term "enantiomeric purity" means the amount of the indicated compound having the indicated absolute stereochemistry expressed as a percentage of the total amount of the indicated compound and its enantiomer. In one embodiment, the diastereomeric purity of the pentaaza macrocyclic ring complex is 98% or higher, more preferably 99% or higher, and most preferably 99.5% or higher. As used herein, the term "diastereomeric purity" means the amount of the indicated compound having the indicated absolute stereochemistry expressed as a percentage of the total amount of the indicated compound and its diastereomer. Methods for examining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be examined by any analytical method capable of quantitatively distinguishing a compound from its diastereomers, for example, by high performance liquid chromatography (HPLC). Similarly, enantiomeric purity can be examined by any analytical method capable of quantitatively distinguishing a compound from its enantiomers. Examples of suitable analytical methods for examining enantiomeric purity include, but are not limited to, the optical rotation of plane-polarized light using a polarimeter, and HPLC using a chiral column packing material.

[0082] In one embodiment, a therapeutically effective amount of the pentaaza macrocyclic ring complex can be an amount sufficient to provide a peak plasma concentration of at least 0.1 μM when administered to a patient. For example, in one embodiment, the pentaaza macrocyclic ring complex can be an amount sufficient to provide a peak plasma concentration of at least 1 μM when administered to a patient. In yet another embodiment, the pentaaza macrocyclic ring complex can be an amount sufficient to provide a peak plasma concentration of at least 10 μM when administered to a patient. Generally, the pentaaza macrocyclic ring complex is not administered in an amount that would provide a peak plasma concentration of 40 μM or more when administered to a patient. For example, the pentaaza macrocyclic ring complex can be administered in an amount sufficient to provide a peak plasma concentration in the range of 0.1 μM to 40 μM in a patient. As another example, the pentaaza macrocyclic ring complex can be administered in an amount sufficient to provide a peak plasma concentration in the range of 0.5 μM to 20 μM in a patient. As another example, the pentaaza macrocyclic ring complex can be administered in an amount sufficient to provide a peak plasma concentration in the range of 1 μM to 10 μM in a patient.

[0083] In yet another embodiment, the dosage of the pentaaza macrocyclic ring complex administered per kg of the patient's body weight can be at least 0.1 mg / kg, for example, at least 0.2 mg / kg. For example, the dosage of the pentaaza macrocyclic ring complex administered per kg of the patient's body weight can be at least 0.5 mg / kg. As another example, the dosage of the pentaaza macrocyclic ring complex administered per kg of the patient's body weight can be at least 1 mg / kg. In another example, the dosage of the pentaaza macrocyclic compound administered per kg of body weight can be at least 2 mg / kg, for example, at least 3 mg / kg, further at least about 15 mg / kg, for example, at least 24 mg / kg, and further at least 40 mg / kg. Generally, the dosage of the pentaaza macrocyclic ring complex administered per kg of the patient's body weight does not exceed 1000 mg / kg. For example, the dosage of the pentaaza macrocyclic ring complex administered per kg of the patient's body weight can be in the range of 0.1 to 1000 mg / kg, for example, 0.2 mg / kg to 40 mg / kg, for example, 0.2 mg / kg to 24 mg / kg, and further 0.2 mg / kg to 10 mg / kg. As another example, the dosage of the pentaaza macrocyclic ring complex administered per kg of body weight can be in the range of 1 mg / kg to 1000 mg / kg, for example, 3 mg / kg to 1000 mg / kg, further 5 mg / kg to 1000 mg / kg, for example, 10 mg / kg to 1000 mg / kg. As another example, the dosage of the pentaaza macrocyclic ring complex administered per kg of body weight can be in the range of 2 mg / kg to 15 mg / kg. As yet another example, the dosage of the pentaaza macrocyclic ring complex administered per kg of body weight can be in the range of 3 mg / kg to 10 mg / kg. As another example, the dosage of the pentaaza macrocyclic ring complex administered per kg of the patient's body weight can be in the range of 0.5 to 5 mg / kg. As yet a further example, the dosage of the pentaaza macrocyclic ring complex administered per kg of the patient's body weight can be in the range of 1 to 5 mg / kg.

[0084] In one embodiment, the dosages and / or plasma concentrations described above may be particularly suitable for pentaazamacrocyclic ring complexes corresponding to GC4419, but they may also be suitable for other pentaazamacrocyclic ring complexes. Further, one of ordinary skill in the art can understand a method for adjusting the dosage and / or plasma concentration based on factors such as the molecular weight and / or activity of the specific compound used. For example, for a pentaazamacrocyclic ring complex having twice the activity of GC4419, the dosage and / or plasma concentration may be halved, or for a pentaazamacrocyclic ring complex having a higher molecular weight than GC4419, a correspondingly higher dosage may be used.

[0085] The dosing schedule of the pentaazamacrocyclic ring complex can be similarly selected according to the intended treatment. For example, in one embodiment, a suitable dosing schedule may include dosing the patient at least once a week, e.g., at least 2, 3, 4, 5, 6, or 7 days (e.g., daily) per week during the treatment period. As another example, in one embodiment, the dosing may be at least once a day (qd) or at least twice a day (bid). In one embodiment, the treatment period with the pentaazamacrocyclic ring complex may continue for at least the same period as the treatment period with a platinum-based anticancer agent (e.g., cisplatin), or may exceed the period during which the platinum-based anticancer agent is administered. The treatment period with the pentaazamacrocyclic ring complex may also start on the same day as the treatment with the platinum-based anticancer agent, or may start some time after the start of dosing with the platinum-based anticancer agent, as described in more detail below. For example, in one embodiment, for a platinum-based anticancer agent administered for a treatment period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, the pentaazamacrocyclic ring complex may be administered for a treatment period continuing for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months.

[0086] Platinum-based anticancer agent According to one embodiment, a platinum-based anticancer agent is provided as part of the treatment methods described herein in combination with a pentaazamacrocyclic ring compound. Platinum-based anticancer agents include coordination complexes of platinum and compounds classes having an anticancer effect. Platinum-based anticancer agents (e.g., cisplatin and oxaliplatin) are understood to exert an anticancer effect by inducing DNA damage in cancer cells (Cruet-Hennequart et al, DNA Repair, 7(4): 582-596 (2008)) and have been shown to be extremely effective in cancer treatment (Kelland et al, J. Inorg Biochem, 77(1-2); 121-124 (1999); Wang X, Anticancer Agents Med Chem, 10(5): 396-411 (2010); Dilruba et al, Cancer Chemother Pharmacol, 77(6): 1103-1124 (2016); Johnstone et al., Anticancer Res, 34(1): 471-476 (2014)). Platinum-based anticancer compounds may include platinum(II) complexes (e.g., cisplatin, carboplatin and oxaliplatin), and may also include platinum(IV) complexes (e.g., satraplatin and LA-12) (see, for example, Bouchal et al. Proteome Science, 9:68 (2011)). The platinum-based anticancer agent may be provided in various formulations, and may also be provided as part of a delivery vehicle or other targeting moiety for targeting tumors and / or cancer cells with a platinum-based anticancer agent prolinac (ProLindac) (AP5346), which is a DACH (diaminocyclohexane) platinum polymer prodrug that uses a 25 kDa polymer delivery vehicle based on hydroxypropylmethacrylamide (HPMA) to target oxaliplatin to tumors (see, for example, Nowotnik et al., Advanced Drug Delivery Reviews, 61(13): 1214-1219 (2009)).Other targeting mechanisms for targeting and / or enhancing the delivery of platinum-based anticancer agents to tumors and / or cancer cells include, for example, peptides, polymer carriers, micelles, radiation and / or photoactivated prodrugs, functionalized carbon nanotubes and / or nanorods, hollow Prussian Blue, magnetic iron oxide, and / or gold nanoparticles, as well as nanogels (see, for example, Butler et al., Current Opinion in Chemical Biology, 17(2): 175-188 (2013)).

[0087] In one embodiment, suitable platinum-based anticancer agents can be selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, heptaplatin, dicloplatin, lipoplatin, LA-12 ((OC-6-43)-bis(acetato)(1-adamantylamine)ammine dichloroplatinum(IV)), phosphaplatine, phenanthriplatin, ProLindac (AP5346), triplatin tetranitrate, picoplatin, satraplatin, pyriplatin, and / or pharmaceutically acceptable salts thereof.

[0088] The dosage of the platinum-based anticancer agent can be selected depending on the treatment provided and the particular platinum-based anticancer agent used. For example, a suitable dosage of a platinum-based anticancer agent (e.g., cisplatin) can be in the range of 10 mg / m 2 ~200 mg / m 2 , for example, in the range of 20 mg / m 2 ~100 mg / m 2 .

[0089] The dosing schedule of the platinum-based anti-cancer agent can likewise be selected according to the intended treatment and the platinum-based anti-cancer agent provided. For example, in one embodiment, a suitable dosing schedule may include dosing the patient once or twice daily, once or twice every other day, once or twice per week, once or twice every two weeks, once or twice every three weeks, or once or twice per month.

[0090] Administration time In one embodiment, the treatment process with the platinum-based anti-cancer agent and the pentaazamacrocyclic complex can include one or more dosings of the said drug and / or complex, depending on the treatment provided. In one embodiment, the treatment process including one or more dosings can include administering the dose of the pentaazamacrocyclic complex during a predetermined period before the administration of the platinum-based anti-cancer agent. For example, the treatment process can include starting the dosing with the pentaazamacrocyclic complex carried out during a predetermined period before the first dosing of the platinum-based anti-cancer agent, and then administering the first dose of the platinum-based anti-cancer agent, and optionally, one or more subsequent doses. In another embodiment, the treatment process including one or more dosings can include administering the dose of the pentaazamacrocyclic complex after a predetermined period has elapsed since the administration of the dose of the platinum-based anti-cancer agent. That is, the treatment process can include starting the dosing with the pentaazamacrocyclic complex delayed by a predetermined period after the administration of the first dose of the platinum-based anti-cancer agent, and then administering the first dose of the platinum-based anti-cancer agent, and optionally, one or more subsequent doses.

[0091] In one embodiment, at least one administration of the pentaazamacrocyclic ring complex during the treatment process is administered at least 1 week before, at least 5 days before, at least 3 days before, at least 2 days before, at least 1 day before, at least 12 hours before, at least 8 hours before, at least 4 hours before, at least 2 hours before, at least 1 hour before, and / or at least 30 minutes before the administration of the platinum-based anti-cancer agent. In another embodiment, at least one administration of the pentaazamacrocyclic ring complex during the treatment process is administered at least 1 week after, at least 5 days after, at least 3 days after, at least 2 days after, at least 1 day after, at least 12 hours after, at least 8 hours after, at least 4 hours after, at least 2 hours after, at least 1 hour after, and / or at least 30 minutes after the administration of the platinum-based anti-cancer agent. Further, the timing of at least one administration of the pentaazamacrocyclic ring complex may also apply to a plurality of doses provided during the treatment process, for example, at least 25%, at least 50%, at least 75%, at least 90% of the doses, and further substantially all of the doses provided during the treatment process.

[0092] Other cancer treatments In one embodiment, the treatment provided herein may further include treatment by another treatment (e.g., one or more of radiation therapy and / or another chemotherapy treatment) other than the treatments specifically described above. As yet another example, the treatment may include administering another anti-cancer agent, such as a PARP inhibitor (poly ADP ribose polymerase inhibitor), for example, any one or more of olaparib, rucaparib, niraparib, iniparib, talazoparib, and veliparib, before, at the same time as, or after the administration of one or more of the platinum-based anti-cancer compound and the pentaazamacrocyclic complex. Other anti-cancer agents may also be provided. For example, in one embodiment, radiation therapy may be administered to the subject before, at the same time as, or after the administration of one or more of the platinum-based anti-cancer agent and the pentaazamacrocyclic ring complex. Further details of radiation therapy and other chemotherapy treatments suitable for cancer treatment are described below.

[0093] In one embodiment, radiation therapy can be administered concurrently with the administration of one or more of a platinum-based anti-cancer agent and a pentaazamacrocyclic ring complex. For example, one or more of the platinum-based anti-cancer agent and the pentaazamacrocyclic ring complex may be administered during, before, or after the administration of radiation therapy, or on the same day as the administration, such that, for example, the subject is undergoing radiation therapy concurrently with the administration of one or more of the platinum-based anti-cancer agent and the pentaazamacrocyclic ring complex.

[0094] In yet another embodiment, combination therapy of a pentaazamacrocyclic ring complex and a platinum-based anti-cancer agent (e.g., cisplatin) can be administered without any other cancer treatment. Unexpectedly, as further shown in the examples below, the pentaazamacrocyclic ring complex can enhance the responsiveness and / or effectiveness to a platinum-based anti-cancer agent (e.g., cisplatin), even when administered without radiation therapy. Thus, in one embodiment, the cancer treatment provided to a subject may consist essentially of a pentaazamacrocyclic ring complex and a platinum-based anti-cancer agent without the administration of radiation exposure (i.e., without administering a radiation dose or dose fraction). For example, the combination of a pentaazamacrocyclic ring complex and a platinum-based anti-cancer agent may be administered to a subject who has not received radiation therapy. That is, in one embodiment, the treatment includes administering a pentaazamacrocyclic ring complex to a subject who has not received radiation therapy. In yet another embodiment, the treatment includes administering a platinum-based anti-cancer agent and a pentaazamacrocyclic ring complex to a subject who has not received radiation therapy. In yet another embodiment, if the treatment process includes the administration of a pentaazamacrocyclic ring complex and a platinum-based anti-cancer agent, they are administered to a subject who is not undergoing radiation therapy during the period of the treatment process.

[0095] In one embodiment, a subject receiving a combination of a pentaaza macrocyclic ring complex and a platinum-based anti-cancer agent (e.g., cisplatin) has not been exposed to radiation (i.e., the received radiation dose or dose fraction) for at least one day, for example, for at least one week, further for at least one month, and further for at least six months, and / or has not received any such treatment prior to the first treatment with one or more of the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent. In yet another embodiment, the radiation therapy administered to the subject after the combination therapy with the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent is delayed by at least one day, for example, for at least one week, further for at least one month, for example, for at least six months after the last administration of one or more of the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent provided during the combination therapy process. That is, the combination therapy of the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent can be administered to a subject who has never received radiation therapy or has received such treatment only in the distant past. Further, the combination therapy of the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent can be administered to provide a treatment process that does not include any exposure to radiation at all. As yet a further embodiment, the combination therapy of the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent can be provided such that during or after the therapy process, radiation therapy is not substantially performed, or such radiation is performed only after a long period has elapsed after the end of the combination therapy process. In one embodiment, the treatment includes administering to the subject one or more of the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent on days other than the days when the subject is receiving radiation therapy.

[0096] Administration method According to one embodiment, a platinum-based anticancer agent (e.g., cisplatin) is administered as a co-therapy or combination therapy with a pentaazamacrocyclic ring complex. The co-therapy or combination therapy described in the methods herein is intended to encompass the administration of each compound in succession in a manner that provides the beneficial effects of drug combination, either simultaneously or sequentially, e.g., in a single capsule formulation containing these active agents in fixed ratios, or in separate capsule formulations of each agent, or in single or multiple parenteral administrations, or co-administration of these agents in other routes of administration and formulations. Therefore, when administered in combination, the therapeutic agents (i.e., the pentaazamacrocyclic ring complex and / or the platinum-based anticancer agent) can be formulated as separate compositions to be administered simultaneously or sequentially at different times, or the therapeutic agents can be provided as a single composition. Pharmaceutical compositions and formulations are described herein.

[0097] The pentaazamacrocyclic ring complex and the platinum-based anticancer agent need not be administered simultaneously or substantially simultaneously; the agents and compounds may be administered sequentially. The advantages of simultaneous or substantial simultaneous administration, or sequential administration, are within the sound discretion of the skilled clinician. For example, a pharmaceutical composition or formulation containing a platinum-based anticancer agent may be advantageously administered first in combination for a particular treatment prior to the administration of the pentaazamacrocyclic ring complex, while pre-administration of the pentaazamacrocyclic ring complex may be advantageous in another treatment. It is also understood that this combination of the pentaazamacrocyclic ring complex and the platinum-based anticancer agent may be used in combination with other methods of treating cancer (including, but not limited to, radiation therapy and surgery, or other chemotherapy). It is further understood that another active agent (e.g., a cytostatic or antiemetic agent) may in some cases be administered in succession with, or simultaneously with, any or all of the other co-treatments.

[0098] Thus, embodiments of the treatment method include the simultaneous or sequential administration of a pentaazamacrocyclic ring complex and a platinum-based anti-cancer agent. For example, embodiments of the present disclosure include methods for treating cancer in which a pentaazamacrocyclic ring complex and a platinum-based anti-cancer agent are administered simultaneously or sequentially. Other active agents can also be administered simultaneously or sequentially with the pentaazamacrocyclic ring complex and the platinum-based anti-cancer agent.

[0099] As described above, if the pentaazamacrocyclic ring complex and the platinum-based anti-cancer agent are not administered simultaneously or substantially simultaneously, the first order of administration of the components may be changed. Thus, for example, the platinum-based anti-cancer agent may be administered first, followed by the administration of the pentaazamacrocyclic ring complex; or the pentaazamacrocyclic ring complex may be administered first, followed by the administration of the platinum-based anti-cancer agent. This alternative administration may be repeated during a single treatment protocol period. Other sequences of administration for eliciting the effects described herein are included, and other sequences of administration of other active agents can also be provided.

[0100] In one embodiment, the subject is pre-treated with a platinum-based anti-cancer agent and subsequently the pentaazamacrocyclic ring complex is administered, or vice versa. According to such an embodiment, the pentaazamacrocyclic ring complex may be administered at least 1 hour, at least 3 days after the administration of the platinum-based anti-cancer agent, or vice versa. For example, in one embodiment, the pentaazamacrocyclic ring complex may be administered between 1 hour and 3 days after the administration of the platinum-based anti-cancer agent, or vice versa. In another embodiment, for example, the pentaazamacrocyclic ring complex may be administered between 1 hour and 1 day after the administration of the platinum-based anti-cancer agent, or vice versa. For example, the pentaazamacrocyclic ring complex may be administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks or 12 weeks after the administration of the platinum-based anti-cancer agent, or vice versa. In these other embodiments, the platinum-based anti-cancer agent may be administered in multiple doses prior to the administration of the pentaazamacrocyclic ring complex, or vice versa.

[0101] Alternatively, the subject may be pre-treated with the pentaazamacrocyclic ring complex and subsequently the platinum-based anti-cancer agent is administered, or vice versa. According to such an embodiment, the pentaazamacrocyclic ring complex may be administered within at least 1 plasma half-life of the platinum-based anti-cancer agent, for example, within 4 plasma half-lives of the platinum-based anti-cancer agent, or vice versa. For example, the pentaazamacrocyclic ring complex may be administered within 1, 2, or 3 plasma half-lives of another platinum-based anti-cancer agent, or vice versa.

[0102] In another alternative embodiment, the subject is pre-treated with a platinum-based anti-cancer agent, followed by administration of the pentaazamacrocyclic ring complex, and further, one or more additional administrations of the platinum-based anti-cancer agent may be performed, or vice versa. For example, the subject may be pre-treated with a single administration of a platinum-based anti-cancer agent, followed by a single administration of the pentaazamacrocyclic ring complex, and further additional (or partial) doses of the same or a different platinum-based anti-cancer agent may be administered, and further additional doses of the pentaazamacrocyclic ring complex may be administered. Further, the subject may be pre-treated with some or all of the doses of the pentaazamacrocyclic ring complex, followed by administration of a platinum-based anti-cancer agent, and subsequently additional (or partial) doses of the pentaazamacrocyclic complex may be administered.

[0103] As described in more detail below, the combinations of the present disclosure may also be co-administered with other well-known therapeutic agents selected for their particular utility against the condition being treated. Alternatively, if multiple combination formulations are not compatible, the combinations may be used sequentially with known pharmaceutically acceptable agents.

[0104] In one embodiment, the pentaazamacrocyclic ring complex and the platinum-based anti-cancer agent can generally be administered by treatment protocols known for these agents. For example, the administration of the various components can vary depending on the disease being treated and the effects of the pentaazamacrocyclic ring complex and the immunotherapeutic agent on that disease. Also, according to the knowledge of a skilled clinician, the treatment protocol (e.g., dosage and timing of administration) can vary considering the observed effects of the therapeutic agents administered to the patient (i.e., the pentaazamacrocyclic ring complex, the platinum-based anti-cancer agent), as well as the observed responsiveness of the disease to the therapeutic agents administered.

[0105] Also, generally, the pentaaza macrocyclic ring complex and the platinum-based anticancer agent should not be administered in the same pharmaceutical composition and may need to be administered by different routes due to their different physicochemical characteristics. For example, the pentaaza macrocyclic ring complex may be administered orally to produce and maintain its good blood levels, while the platinum-based anticancer agent may be administered intravenously or by transfusion, or vice versa. The mode of administration may include, if possible, the same pharmaceutical composition, or separate pharmaceutical compositions (e.g., 2 or 3 separate compositions). Further, once the initial administration has been made, the dose, mode of administration and timing of administration can be modified based on the observed effects.

[0106] The specific selection of the pentaaza macrocyclic ring complex and the platinum-based anticancer agent, as well as other related treatments (e.g., radiation therapy or other chemotherapy) is by the diagnosis of the attending clinician and their judgment of the patient's condition and the appropriate treatment protocol.

[0107] Thus, in accordance with experience and knowledge, the clinician may modify each protocol for the administration of the components of the treatment (the pentaaza macrocyclic ring complex and the platinum-based anticancer agent) according to the needs of each patient so that the treatment progresses.

[0108] When determining whether the treatment is effective at the dose administered, the attending clinician takes into account the patient's overall health status, as well as more definitive signs, such as the alleviation of symptoms related to the disease, the inhibition of tumor growth, the actual shrinkage of the tumor, or the suppression of metastasis. The size of the tumor can be measured by standard methods such as radiological experiments, e.g., CAT or MRI scans, and continuous measurements can be used to determine whether the growth of the tumor has been slowed or reversed. The alleviation of symptoms related to the disease (e.g., pain) and the improvement of overall symptoms can also be used to assist in determining the effectiveness of the treatment.

[0109] The product composed of the said combination may be administered simultaneously, separately, or at intervals over a certain period of time in order to obtain the maximum effect of the said combination; each administration may be for various periods from a rapid administration of any of the components (in another formulation or a single formulation) to a relatively continuous perfusion. As a result, for the purposes of the present disclosure, the said combination is not limited to that obtained by physical combination of the components, but enables separate administrations, which may be simultaneous or at intervals.

[0110] Thus, the administration of the components described herein can be carried out as a single event of treatment or during the course. For example, the pentaaza macrocyclic ring complex and the platinum-based anticancer agent can be administered (simultaneously or sequentially) every hour (e.g., every 1 hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours, etc.), daily, once a week, once every two weeks, or once a month. For the treatment of acute conditions, the treatment process may be at least several hours or days. Certain conditions may extend the treatment from several days to several weeks. For example, the treatment can be extended for 1 week, 2 weeks, or more than 3 weeks. In more chronic conditions, the treatment can be extended from several weeks to several months, 1 year or more, or for the lifetime of the patient who requires such treatment. Alternatively, the said compounds and agents can be administered hourly, daily, weekly, every two weeks, or monthly for periods of several weeks, several months, several years, or over the lifetime of the patient as a preventive measure.

[0111] The dosage or amount of a pharmaceutical composition comprising a pentaaza macrocyclic ring complex and a platinum-based anti-cancer agent administered to a patient should be an amount effective for the intended purpose, i.e., one or more of the diseases, conditions, and medical states described herein, particularly for the treatment or prevention of cancer. Generally speaking, the effective amount of the composition administered can vary depending on various factors such as, for example, age, weight, gender, diet, route of administration, and the medical condition of the patient in need of treatment. Particularly preferred dosages are more fully described herein. However, it is understood that the total daily regimen will be determined by a physician or veterinarian within the scope of sound medical judgment of the compositions described herein.

[0112] As described above, the combination can be co-administered (either by a formulation in which they are co-formulated or by separate formulations administered substantially simultaneously). The combination can also be administered separately in different unit formulations at different times from each agent. Many approaches for administering platinum-based anti-cancer agents and pentaaza macrocyclic ring complexes can be readily applied for use in the present disclosure. The pharmaceutical composition may be delivered orally, for example, in unit formulations such as tablets or capsules, or parenterally, for example, in injectable unit formulations, or by any other route. For systemic administration, for example, the drug can be administered, for example, by intravenous infusion (continuous or bolus infusion). The composition can be used for a therapeutic or prophylactic treatment in which the patient benefits from treatment with the combination.

[0113] The specific therapeutically effective dosage levels for any particular patient will depend on a variety of factors including the disease being treated and the severity of the disease; the activity of the particular compound used; the age, weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the particular compound used; the duration of the treatment; drugs used in combination with, or concurrently with, the particular compound employed, as well as factors well known in the medical and / or veterinary arts. For example, it is well within the skill in the art to start the administration of the compounds at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dosage may be divided into multiple dosages for administration. Thus, a single dosage composition may contain such amounts or may contain sub - multiple dosages to make up the daily dosage.

[0114] In one embodiment, suitable or preferred dosages of each of the components are those used in the methods described herein or included in the compositions. Preferred dosages of the pentaazamacrocyclic ring complex can be, for example, in the range of 10 - 500 mg per patient per day. However, said dosages can be varied by a dosing schedule that can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective dosages provided herein are not intended to be limiting to the typical dosage ranges disclosed and shown. The most preferred dosages are those specific to each subject, taking into account, among other things, the particular combination used, as well as the age, sex, weight, physical condition, diet, etc. of the patient, and can be understood and determined by one of ordinary skill in the art without undue experimentation.

[0115] The treatment of cancer or cancer therapy described in this specification includes achieving a therapeutic benefit, although the therapy may also be administered to achieve a prophylactic benefit. A therapeutic benefit generally means at least a partial eradication or alleviation of the disease that is the cause of the treatment. For example, in a cancer patient, a therapeutic benefit includes (partial or complete) eradication or alleviation of the underlying cancer. Also, a therapeutic benefit is achieved when at least a partial or complete eradication or alleviation of one or more of the physiological symptoms associated with the disease that is the cause is achieved, and improvement is seen in the patient, regardless of the fact that the patient may still be suffering from the disease that is the cause. For prophylactic benefits, for patients at high risk of developing cancer or patients in whom one or more of the physiological symptoms of such a disease are seen, although the disease has not been diagnosed, the methods of the present disclosure may be performed, or the compositions of the present invention may be administered.

[0116] Furthermore, the treatment of toxic effects associated with the administration of platinum-based anti-cancer agents, and / or the treatment of conditions resulting from the administration of platinum-based anti-cancer agents, includes achieving a therapeutic benefit, although the treatment may also be administered to achieve a prophylactic benefit. A therapeutic benefit generally means the eradication or remission of at least a portion of the underlying disorder being treated. For example, in a patient at risk of, or suffering from, toxic effects associated with the administration of a platinum-based anti-cancer agent, a therapeutic benefit includes the (partial or complete) eradication or remission of the underlying condition and / or symptoms. Also, a therapeutic benefit is achieved by at least partial, or complete, eradication or remission of one or more of the physiological symptoms associated with the underlying disorder such that improvement is seen in the patient regardless of the fact that the patient may already be suffering from the underlying disorder. With respect to a prophylactic benefit, the methods of the present disclosure may be performed on a patient at risk of toxicity associated with a platinum-based anti-cancer agent (e.g., a human who has received or is receiving a platinum-based anti-cancer agent, or a human who is planned to receive a platinum-based anti-cancer agent), or a patient who reports and / or suffers from one or more of the physiological symptoms of such a disorder, or the compositions of the present invention may be administered to such a patient, even in the absence of a diagnosis of such a disorder.

[0117] Method for treating cancer Generally, any subject having or susceptible to cancer or other proliferative diseases can be treated using the compositions and methods of the present disclosure. Subjects being treated according to the methods described herein are mammalian subjects, typically human patients. Other mammals that can be treated according to the present disclosure include companion animals (e.g., dogs and cats), livestock animals (e.g., cows, horses, and pigs), as well as birds and further exotic animals (e.g., animals found in zoos or nature reserves). In certain aspects of the present disclosure, methods of treating cancerous tumors, particularly solid tumors, are provided. Advantageously, the methods described herein can reduce tumorigenesis, reduce tumor burden, or cause tumor regression in a mammalian host. Cancer patients and individuals desiring cancer prevention can be treated with the combinations described herein.

[0118] Cancer and tumors generally refer to or describe a physiological state of a mammal typically characterized by uncontrolled cell proliferation. The pharmaceutical combinations, co-formulations, and combination therapies of the present disclosure can treat various tumors such as tumors of the breast, heart, lung, small intestine, large intestine, spleen, kidney, bladder, head and neck, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testis, neck, and liver.

[0119] In one embodiment, the tumor or cancer is selected from adenoma, angiosarcoma, astrocytoma, epithelial carcinoma, embryonal carcinoma, glioblastoma, glioma, hamartoma, hemangioendothelioma, hemangioma, hematoma, hepatoblastoma, leukemia, lymphoma, medulloblastoma, melanoma, neuroblastoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, sarcoma, and teratoma. The tumor can be selected from acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenoid squamous cell carcinoma, astrocytic tumor, Bartholin gland adenocarcinoma, basal cell carcinoma, bronchial gland tumor, capillary, carcinoid, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondrosarcoma, choroid plexus papilloma / carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, epithelioma, epithelioid, Ewing sarcoma, fibrolamellar type, focal nodular hyperplasia, gastrinoma, germ cell tumor, glioblastoma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasm, intraepithelial squamous neoplasm, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, malignant lentigo-derived melanoma, malignant melanoma, malignant mesothelioma, medulloblastoma, medulloepithelioma, melanoma, meningioma, mesothelioma, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelium, adenocarcinoma, nodular melanoma, oat cell carcinoma, oligodendroglioma, osteosarcoma, pancreas, papillary serous adenocarcinoma, pineal cell, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinoma, somatostatin-secreting cell carcinoma, squamous cell carcinoma, squamous epithelial cell carcinoma, solitary submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, VIP-producing tumor, well-differentiated carcinoma, and Wilms tumor.

[0120] Thus, for example, the present disclosure includes, but is not limited to, the following: cancers including cancers of the bladder (including progressive and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small cell and non-small cell lung cancer, and lung adenocarcinoma), ovary, prostate, testis, urinary tract, lymphatic system, rectum, larynx, pancreas (including pancreatic exocrine tumors), esophagus, stomach, gallbladder, neck, thyroid, and skin (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burkitt lymphoma); hematopoietic tumors of the myeloid system (including acute and chronic myelogenous leukemia, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma); tumors derived from mesenchymal tissue (including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma); and other tumors (including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, follicular thyroid carcinoma, and teratoma).

[0121] For example, specific leukemias that can be treated with the combinations and methods described herein include, but are not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, Gloss leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphoid leukemia, lymphotropic leukemia, lymphoid-like leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacytic leukemia, plasmacytoid leukemia, promyelocytic leukemia, leader cell leukemia, Schilling's leukemia, hepatocytic leukemia, subaleukemic leukemia, and undifferentiated cell leukemia.

[0122] Lymphomas can also be treated with the combinations and methods described herein. Lymphomas generally represent a neoplastic transformation of cells that primarily reside in lymphoid tissues. Lymphomas are tumors of the immune system and generally exist as both T-cell and B-cell related diseases. Among lymphomas, there are two major distinct groups: non-Hodgkin lymphoma (NHL) and Hodgkin disease. In particular, the bone marrow, lymph nodes, spleen, and circulating cells can be involved. Treatment protocols can include removing bone marrow from the patient, washing the tumor cells of the bone marrow, using antibodies against antigens present in the tumor cell type, and subsequently storing it. The patient is administered a toxic dose of radiation or chemotherapeutic agents and the washed bone marrow is re-infused to restore the patient's hematopoietic system.

[0123] Other hematological malignancies that can be treated by the combinations and methods described herein include myelodysplastic syndromes (MDS), myeloproliferative disorders (MPS), and myelomas (e.g., solitary myeloma and multiple myeloma). Multiple myeloma (also called plasmacytic myeloma) is associated with the skeletal system and is characterized by multiple tumors of neoplastic plasma cells scattered throughout this system. It can spread to lymph nodes and other sites (e.g., the skin). Solitary myeloma is associated with solitary lesions that tend to occur in the same location as multiple myeloma.

[0124] In one embodiment, the methods and pharmaceutical compositions described herein are used to treat cancer that is any one of breast cancer, melanoma, oral squamous cell carcinoma, lung cancer (including non-small cell lung cancer), renal cell carcinoma, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, urothelial carcinoma, bladder cancer, colorectal cancer, head and neck cancer (e.g., squamous cell carcinoma), and pancreatic cancer. In yet another embodiment, the methods and pharmaceutical compositions described herein are used to treat cancer that is either head and neck cancer or lung cancer.

[0125] Method for treating toxicity associated with platinum-based anticancer agents Generally, a subject suffering from, or susceptible to, a condition resulting from the toxic effects of administration of a platinum-based anti-cancer agent (e.g., cisplatin) can be treated using the compositions and methods of the present disclosure. A subject being treated by the methods described herein is a mammalian subject, typically a human patient. Other mammals that can be treated in accordance with the present disclosure include companion animals (e.g., dogs and cats), livestock animals (e.g., cows, horses, and pigs), as well as birds and further exotic animals (e.g., animals found in zoos or nature preserves). In one aspect of the present disclosure, there is provided a method of treating a condition associated with the toxicity of a platinum-based anti-cancer agent (such as a condition the subject has after administration of the platinum-based anti-cancer agent to the subject, e.g., as provided during cancer treatment), the method for reducing said condition. In another embodiment, said treatment is provided for reducing and / or inhibiting the toxicity of a platinum-based anti-cancer agent, e.g., where a platinum-based anti-cancer agent is provided during cancer treatment to reduce the risk of a condition associated with the toxicity of the platinum-based anti-cancer agent occurring. Advantageously, the methods described herein enable cancer treatment with a platinum-based anti-cancer agent while simultaneously reducing the toxic effects and / or alleviating the toxic condition, e.g., in a mammalian host, to reduce the occurrence of tumors, reduce the total amount of tumor tissue in the body, or cause tumor regression. Cancer patients and individuals desiring cancer prevention can be treated with the combinations described herein.

[0126] In one embodiment, the toxicities and / or toxic states associated with the administration of platinum-based anti-cancer agents and treatable (and / or the risk of developing such conditions can be reduced) by the methods described herein include at least one of nephrotoxicity, myelotoxicity, ototoxicity, and neurotoxicity, and conditions associated therewith. For example, in one embodiment, administration of the pentaazamacrocyclic ring complex can reduce the neurotoxic effects associated with the administration of platinum-based anti-cancer agents. Nephrotoxicity means toxicity to the kidneys, resulting in a decrease in kidney function, and acute kidney injury, and even renal failure, and is generally associated with the administration of anti-cancer agents (see, for example, Lameire N., Clin Kidney J, 7(1): 11-22 (2014); Zhu et al, Arch Toxicol, 89(12): 2197-2205 (2015)). Blood urea nitrogen (BUN) levels and creatinine levels in whole blood may be measured to provide an indication of the degree of kidney injury, where high levels indicate a decrease in kidney function. Other markers of kidney injury include kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL). As another example, in one embodiment, administration of the pentaazamacrocyclic ring complex can reduce the myelotoxic effects associated with the administration of platinum-based anti-cancer agents. Myelotoxicity, also referred to as myelosuppression and / or bone marrow suppression, means a decrease in the production of cells such as lymphocytes, erythrocytes, and platelets, and can result in conditions such as neutropenia, thrombocytopenia, and anemia, and is generally associated with anti-cancer agents (see, for example, Kurtin S., J Adv Pract Oncol, 3(4): Jul-Aug (2012); Son et al., Hum Exp Toxicol, 30(7): 649-655 (2011)). Neutrophil and white blood cell counts can also be decreased. In yet another embodiment, administration of the pentaazamacrocyclic ring complex can reduce the ototoxic effects (toxicity to the ear such as the cochlea, auditory nerve, and / or vestibular system) associated with the administration of platinum-based anti-cancer agents.Thus, in one embodiment, the treatment method described herein can include treating a subject suffering from and / or at risk of suffering from toxicity resulting from platinum-based anticancer treatment, e.g., a subject suffering from and / or at risk of suffering from one or more of nephrotoxicity and myelotoxicity due to administration of a platinum-based anticancer agent.

[0127] Pharmaceutical formulation Another aspect of the present disclosure relates to a pharmaceutical composition comprising the combinations described herein together with a pharmaceutically acceptable excipient. The pharmaceutical composition may include a pentaazamacrocyclic ring complex (e.g., one corresponding to formula (I)), at least one platinum-based anticancer agent, and combinations thereof, as described above, which are typically formulated as a pharmaceutical formulation and may optionally be formulated in combination with a pharmaceutically acceptable carrier, additive, or excipient. In one embodiment, for example, the pharmaceutical composition includes a pentaazamacrocyclic ring complex, a platinum-based anticancer agent, and a pharmaceutically acceptable excipient. The pharmaceutical composition according to the present disclosure can be used for the treatment of cancer.

[0128] The pharmaceutical composition described herein is a product resulting from mixing or combining one or more active ingredients and includes both fixed and unfixed combinations of the active ingredients. A fixed combination is, for example, one in which a pentaazamacrocyclic ring complex and a platinum-based anticancer agent are administered to a patient simultaneously in the form of a single entity or a single dose. Other active agents may also be administered as part of a single entity or a single dose, or separately. An unfixed combination is one in which the active ingredients, e.g., a pentaazamacrocyclic ring complex and a platinum-based anticancer agent, are administered to a patient as separate substances simultaneously, all at once, or in succession without particular limitation on the interval, such that such administration provides an effective level of the compounds in the patient's body. The latter is also used for multi-drug combination therapy, e.g., the administration of three or more active ingredients.

[0129] The pentaaza macrocyclic ring complex and platinum-based anti-cancer agent described above may be dispersed in a pharmaceutically acceptable carrier before administration to mammals; that is, the components described herein are preferably co-formulated. Carriers known in the art as excipients, vehicles, adjuvants, adjuvants, or diluents are typically substances that are pharmaceutically inert, have a hardness or form suitable for the composition, and do not reduce the effectiveness of the compound. The carrier is generally considered "pharmaceutically or pharmacologically acceptable" as long as it does not cause unacceptable harm, allergic reactions, or other adverse reactions when administered to mammals, particularly humans.

[0130] The choice of pharmaceutically acceptable carrier also depends in part on the route of administration. Generally, the compositions described herein can be formulated for any route of administration as long as the bloodstream is available via this route and via conventional routes of administration. For example, suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intratracheal, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (transnasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, otic, intramammary, buccal, topical, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual, and enteral administration.

[0131] Pharmaceutically acceptable carriers for use in combination with the compositions of the present disclosure are well known to those skilled in the art and are selected based on many factors: the particular compound and agent used, and its / their concentration, stability and desired bioavailability; the subject, its age, weight, general condition; and the route of administration. Suitable non-aqueous pharmaceutically acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol formal, 6-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of aliphatic alcohols, such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(6-hydroxyethyl)-lactamide, N,N-dimethylacetamide amide, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone);Esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetic acid esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or ethyl octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO), esters of glycerin such as mono-, di-, or tri-glyceryl citrate or tartrate, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, sorbitan fatty acid esters, PEG esters derived from fatty acids, glyceryl monostearate, glyceride esters (e.g., mono, di or triglycerides), fatty acid esters (e.g., isopropyl myristate), PEG esters derived from fatty acids (e.g., PEG-hydroxyoleic acid and PEG-hydroxystearic acid), N-methylpyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic acid polyester, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and polysorbate (registered trademark) 20, 40, 60 or 80 (ICI Americas, Wilmington, Delaware), polyvinylpyrrolidone, alkylene oxide-modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyethylenated castor oil (e.g., Cremophor (registered trademark) EL solution or Cremophor (registered trademark) RH40 solution), sucrose fatty acid esters (i.e., condensation products of monosaccharides (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and lyxose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharides (e.g., sucrose, maltose, lactose, and trehalose) or oligosaccharides), or 04~0; 22These mixtures with fatty acids (e.g., saturated fatty acids (e.g., caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid), and unsaturated fatty acids (e.g., palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroid esters); alkyl, aryl, or cyclic ethers having 2 to 30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycol flow (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3 to 30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4 to 30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolane, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylene sulfone, tetramethylene sulfoxide, toluene, dimethyl sulfoxide (DMSO), or tetramethylene sulfoxide); inorganic substances, oils derived from plants, animals, natural or synthetic (e.g., mineral oils, e.g., aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic-based hydrocarbons, and refined mineral oils, vegetable oils, e.g., linseed oil, tung, safflower, soybean, castor, cottonseed, peanut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, almond and peanut oils, and glycerides, e.g., mono-, di- or triglycerides, animal oils, e.g., fish, aquatic animals, semen, cod liver, halibut, squalene, squalane, and shark liver oil, olein oil, and polyoxyethylated castor oil); alkyl or aryl halides having 1 to 30 carbon atoms and optionally having one or more halogen groups; methylene chloride; monoethanolamine; petroleum benzine; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol esters of 12-hydroxystearic acid and polyethylene glycol (Soltol® HS-15 (BASF, Ludwigshafen, Germany); polyoxyethylene glycerol;Sodium laurate; sodium oleate; or sorbitan monooleate may be mentioned.

[0132] In certain embodiments, an oily or non-aqueous solvent may be used in the formulation, for example, due to the presence of a large lipophilic moiety, to dissolve one or more compounds in solution. Alternatively, emulsions, suspensions, or other preparations, such as liposome preparations, may be used. With respect to liposome preparations, any of the known liposome preparation methods may be used, for example. See, for example, Bangham et al., J. Mol. Biol, 23: 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci 75: 4194-4198 (1978), which are incorporated herein by reference. Thus, in one embodiment, one or more compounds are administered in the form of a liposome delivery system, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. Ligands may also be bound to the liposomes, for example, to direct these compositions to specific sites of action.

[0133] Other pharmaceutically acceptable solvents for use in the pharmaceutical compositions described herein are well known to those of ordinary skill in the art and are described in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.) (Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.) (Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), and A.J. Spiegel et al., Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

[0134] Formulations containing pentaazamacrocyclic ring complexes and platinum-based anticancer agents are preferably in unit dosage forms suitable for single administration of accurate dosages, in solid, semi-solid, lyophilized powder, or liquid formulations, such as aerosols, capsules, creams, emulsions, foams, gels / jellies, lotions, ointments, pastes, powders, soaps, solutions, sprays, suppositories, suspensions, sustained-release formulations, tablets, tinctures, transdermal patches, etc. When formulated as a fixed dose, such pharmaceutical compositions or dosage products use the pentaazamacrocyclic ring complex and platinum-based anticancer agents within an acceptable dosage range.

[0135] In one embodiment, a formulation containing a platinum-based anticancer agent as part of a liquid formulation (e.g., a sterile liquid formulation suitable for injection) is provided. For example, it is in liquid form containing the platinum-based anticancer agent in combination with one or more additional components, such as disodium edetate (EDTA). In one embodiment, the liquid form can contain EDTA in an amount suitable to act as a preservative and / or metal chelating agent, e.g., in an amount of about 0.025%. The liquid form can further contain water and may also contain a pH adjuster, such as sodium bicarbonate for pH adjustment in the range of pH 5.5 to 7.0. In one embodiment, the pentaazamacrocyclic ring complex can also be provided as part of a sterile liquid formulation suitable for injection, either in the same liquid formulation as the platinum-based anticancer agent or as a separate formulation.

[0136] Formulations for certain pentaazamacrocyclic ring complexes are also described, for example, in U.S. Pat. Nos. 5,610,293, 5,637,578, 5,874,421, 5,976,498, 6,084,093, 6,180,620, 6,204,259, 6,214,817, 6,245,758, 6,395,725, and 6,525,041, each of which is hereby incorporated by reference in its entirety.

[0137] The co-formulation of pentaazamacrocyclic ring complexes and platinum-based anti-cancer agents can be used by combining the conventional formulation techniques for each of these components, or another formulation route based on the compatibility and effectiveness of the various components.

[0138] The pharmaceutical composition described above containing the pentaazamacrocyclic compound and the platinum-based anti-cancer agent may further contain one or more additional pharmaceutically active ingredients. Suitable pharmaceutically active agents that may be included in the composition according to an aspect of the present invention include, for example, antiemetics, anesthetics, antihypertensives, anxiolytics, anticoagulants, anticonvulsants, hypoglycemic agents, blood stasis removers, antihistamines, antitussives, anti-cancer agents, β-blockers, anti-inflammatory agents, antipsychotics, nootropics, cholesterol-lowering agents, anti-obesity agents, autoimmune disease agents, sexual dysfunction treatment agents, antibacterial and antifungal agents, hypnotics, anti-Parkinson's disease agents, anti-Alzheimer's disease agents, antibiotics, antidepressants, and antiviral agents. Each component of such a combination may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations.

[0139] In yet another embodiment, a kit may be provided that includes both a pentaazamacrocyclic ring complex and a platinum-based anti-cancer agent for the treatment of diseases such as cancer and / or to treat and / or reduce the risk of toxicity associated with the administration of the platinum-based anti-cancer agent. For example, the kit may include a first container or box containing a formulation comprising a pentaazamacrocyclic ring complex (e.g., an oral or injectable formulation of the pentaazamacrocyclic ring complex), and a first container or box containing a formulation comprising a platinum-based anti-cancer agent (e.g., an injectable formulation of the platinum-based anti-cancer agent). The kit may further include instructions or other explanatory materials for the administration of the active agent, the recommended dosage, duration, and dosing schedule, warnings, descriptions of possible drug interactions, and other relevant explanations (e.g., instructions indicating a treatment plan (e.g., dosage, dosing frequency, etc.) corresponding to any of those described herein).

[0140] Combination Therapy with Cancer Treatment In one embodiment, the pentaaza macrocyclic ring complex- and platinum-based anti-cancer agent can be administered in combination with another cancer treatment to provide a therapeutic treatment. For example, the pentaaza macrocyclic ring complex- and platinum-based anti-cancer agent may be administered as part of radiotherapy.

[0141] Generally, the timing of administration of the pentaaza macrocyclic ring complex- and platinum-based anti-cancer agent may depend, for example, on the particular radiotherapy selected, or the type, nature, and / or duration of radiation exposure. Other considerations may include the disease or disorder being treated and the severity of the disease or disorder; the activity of the particular compound used; the particular composition used; the age, weight, general health, gender, and diet of the subject; the timing of administration, route of administration, and excretion rate of the particular compound used; the treatment period; factors such as drugs used in combination with or simultaneously with the particular compound used. For example, the compound may be administered in various embodiments before, during, and / or after radiotherapy (e.g., before, during, or after exposure to a radiotherapy process including multiple exposures and / or dosings, and / or before, during, or after dosing). As another example, the compound may be administered in various embodiments before, during, and / or after radiation exposure.

[0142] If necessary, an effective dose can be divided into multiple dosings for administration; thus, a single dosing composition may contain such an amount or a submultiple thereof to constitute a dosing.

[0143] In one embodiment, for example, the pentaaza macrocyclic ring complex and platinum-based anti-cancer agent are administered to the patient before or simultaneously with radiation exposure. In another embodiment, for example, the constituent components are administered to the patient before, but not after, radiation exposure. In yet another embodiment, one or more of the pentaaza macrocyclic ring complex and platinum-based anti-cancer agent are administered to the patient at least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more before radiation exposure (e.g., the first radiation exposure in the course of radiotherapy), or before another dose or dose fraction of radiation which is one of the doses or dose fractions of radiation in the course of treatment. In still another embodiment, for example, the pentaaza macrocyclic ring complex and platinum-based anti-cancer agent are administered to the patient after radiation exposure; thus, for example, the compound may be administered 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more after radiation exposure (which may be a dose or dose fraction of radiation in a multiple-dose course of radiotherapy, or may be a single or final dose or dose fraction of radiation in radiotherapy).

[0144] In one embodiment, the pentaaza macrocyclic ring complex and platinum-based anti-cancer agent are administered as part of a treatment process that includes radiation therapy. In radiation therapy, a patient receives a dose or fraction of ionizing radiation to suppress or control the growth of cancer cells. The dose or fraction of radiation may be directed to a specific part of the body to reduce the harmful effects on parts of the body not affected by cancer, and the radiation beams may be implemented according to a predetermined treatment plan. A typical course of radiation therapy may include one or more doses or fractions of radiation, which can be administered over the course of days, weeks, and months. The total "dose" of radiation administered during the radiation therapy course typically refers to the radiation dose that the patient receives during the entire radiation therapy course, and these doses may be administered as dose "fractions" corresponding to multiple radiation exposures when administered in multiple fractions over a period of time that totals the overall dose.

[0145] In one embodiment, at least one of the pentaaza macrocyclic ring complex and platinum-based anti-cancer agent is administered within a predetermined period before or after radiation exposure (e.g., before or after a radiation dose or fraction). For example, the pentaaza macrocyclic ring complex and platinum-based anti-cancer agent may be administered within one week, 48 hours, 24 hours, 12 hours, 6 hours, 2 hours, 1 hour, or 30 minutes before or after the patient's radiation exposure, e.g., a dose or fraction (before or after the radiation exposure corresponding to the radiation dose or fraction). Other periods between the radiation exposure that enhances cancer cell death and the administration of the compound may also be appropriate. In one embodiment, one of the pentaaza macrocyclic ring complex and platinum-based anti-cancer agents may be administered before radiation exposure, and the remaining one or more of the pentaaza macrocyclic ring complex and platinum-based anti-cancer agents may be administered after radiation exposure. One or more of the pentaaza macrocyclic ring complex and platinum-based anti-cancer agents may be administered both before and after the administration of radiation exposure.

[0146] In one embodiment, the radiation therapy process includes a plurality of radiation doses or dose fractions administered over a predetermined period, such as several hours, several weeks, several days, or even several months, and the plurality of doses or dose fractions may be of the same magnitude or different. That is, the radiation therapy process may include the administration of a series of multiple radiation doses or dose fractions. In one embodiment, the pentaazamacrocyclic ring complex and platinum-based anti-cancer agent can be administered before a series of one or more radiation doses or dose fractions, for example, before each radiation dose or dose fraction, or before several radiation doses or dose fractions. Further, the administration of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agent during the radiation therapy process can be selected, for example, by sensitizing cancer cells to radiation therapy, to enhance the cancer treatment effect of radiation therapy. In one embodiment, the pentaazamacrocyclic ring complex and platinum-based anti-cancer agent are administered for a predetermined period before or after each dose or dose fraction, for example, within the predetermined period described above. In another embodiment, the pentaazamacrocyclic ring complex and platinum-based anti-cancer agent are administered only within a predetermined period before or after the selected dose or dose fraction. In yet another embodiment, at least one of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents is administered within the predetermined period before the dose, while another pentaazamacrocyclic ring complex and platinum-based anti-cancer agent is administered within the predetermined period after the dose or dose fraction. In a further embodiment, at least one of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents is administered only within a predetermined period before or after the selected dose or dose fraction, while another one of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents is administered only within a predetermined period before or after a dose or dose fraction other than the selected dose or dose fraction.

[0147] The overall dose suitable for use during treatment can be determined by the type of treatment provided, the patient's physiological characteristics, and other factors, and the dose fractions provided can likewise be determined. In certain embodiments, the dose fraction of radiation administered to a patient may be at least 1.8 Gy, for example, at least 2 Gy, further at least 3 Gy, for example, at least 5 Gy, further at least 6 Gy. In yet another embodiment, the dose fraction of radiation administered to a patient may be at least 10 Gy, for example, at least 12 Gy, further at least 15 Gy, for example, at least 18 Gy, further at least 20 Gy, for example, at least 24 Gy. Generally, the dose fraction of radiation administered to a patient does not exceed 54 Gy. Additionally, in one embodiment, the dose fraction delivered to a subject may mean the amount delivered to a specific target region of the subject, such as the target region of a tumor, but it should be noted that other regions of the tumor or surrounding tissue may be exposed to more or less radiation than the amount specified by the nominal dose fraction amount.

[0148] In yet another embodiment, the pentaaza macrocyclic ring complex and platinum-based anti-cancer agent are administered as part of a treatment process that includes the administration of additional chemotherapeutic agents. In chemotherapy, chemotherapeutic agents are administered to a patient to inhibit or control the growth of cancer cells. A typical course of chemotherapy can include one or more administrations of one or more chemotherapeutic agents that can be administered over several days, weeks, or even months. Chemotherapeutic agents can include: alkylating anti-neoplastic agents, such as nitrogen mustards (e.g., cyclophosphamide, chlorambucil), nitrosoureas (e.g., n-nitroso-n-methylurea, carmustine, semustine), tetrazines (e.g., dacarbazine, mitozolimide), aziridines (e.g., thiotepa, mitomycin); antimetabolites, such as folic acid antagonists (e.g., methotrexate and pemetrexed), fluoropyrimidines (e.g., fluorouracil, capecitabine), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin), deoxynucleoside analogs (e.g., cytarabine, gemcitabine, decitabine) and thiopurines (e.g., thioguanine, mercaptopurine); microtubule inhibitors, such as taxanes (e.g., paclitaxel, docetaxel); topoisomerase inhibitors (e.g., etoposide, doxorubicin, mitoxantrone, teniposide); and anti-tumor antibiotics (e.g., bleomycin, mitomycin), and may include at least one of them. For example, the chemotherapeutic agent may be selected from the group consisting of all-trans retinoic acid, arsenic trioxide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epsilon, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, tiguanine, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine.The administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR), e.g., the 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA).

[0149] In one embodiment, the pentaazamacrocyclic ring complex and platinum-based anticancer agent are administered as part of a treatment that includes a further chemotherapeutic agent selected from the group consisting of doxorubicin, bleomycin, and paclitaxel. Further, in one embodiment, the further chemotherapeutic agent may be selected from the group consisting of taxanes, anticancer antibiotics, and anthracyclines. Other chemotherapeutic agents include arsenic trioxide and 5-FU, and these agents can also be used in the methods and compositions described herein (Alexandre et al., Cancer Res. 67: (8), 3512-3517 (2007); Yen et al., J. Clin. Invest. 98 (5), 1253-1260 (1996); Masuda et al., Cancer Chemother. Pharmacol. 47(2), 155-160 (2001)).

[0150] According to yet another embodiment, the further chemotherapeutic agent may include at least one of antimetabolite anticancer agents and mitotic inhibitory anticancer agents, and combinations thereof, and may include any of the agents described above and other agents further described herein. A variety of antimetabolites and mitotic inhibitors can be used in the methods and compositions described herein.

[0151] Metabolic antagonists generally structurally resemble natural metabolites and are involved in the normal metabolic processes of cancer cells, such as the synthesis of nucleic acids and proteins. However, metabolic antagonists are sufficiently different from natural metabolites to interfere with the metabolic processes of cancer cells. In said cells, metabolic antagonists are misrecognized for the metabolites they resemble and are processed by the cells in a manner similar to normal compounds. The presence of "decoy" metabolites prevents the cells from performing functions necessary for life support, and the cells are unable to grow and survive. For example, metabolic antagonists exert cytotoxic activity by replacing these false nucleotides in the cell's DNA, thereby preventing cell division, or inhibiting DNA replication by inhibiting essential intracellular enzymes.

[0152] Thus, in one embodiment, the metabolic antagonist is a nucleotide or nucleotide analog. In certain embodiments, for example, the metabolic antagonist can include purines (e.g., guanine or adenosine) or their analogs, or pyrimidines (cytidine or thymidine) or their analogs (with or without the attached sugar moiety).

[0153] Metabolic antagonists suitable for use in the present disclosure may generally be classified by the metabolic processes they affect and may include, but are not limited to, analogs and derivatives of folic acid, pyrimidine, purine, and cytidine. Thus, in one embodiment, the metabolic antagonist is selected from the group consisting of cytidine analogs, folic acid analogs, purine analogs, pyrimidine analogs, and combinations thereof.

[0154] In certain embodiments, for example, the metabolic antagonist is a cytidine analog. According to this embodiment, for example, the cytidine analog may be selected from the group consisting of cytarabine (cytosine arabinoside), azacitidine (5-azacitidine), and salts, analogs, and derivatives thereof.

[0155] In another embodiment, for example, the antimetabolite is a folic acid analog. Folic acid analogs or folic acid antimetabolites generally function by inhibiting dihydrofolate reductase (DHFR), an enzyme involved in nucleotide formation (when this enzyme is inhibited, nucleotides are not formed, inhibiting DNA replication and cell division). According to one embodiment, for example, the folic acid analog may be selected from the group consisting of denopterin, methotrexate (amethopterin), pemetrexed, pteropterin, raltitrexed, trimetrexate, and their salts, analogs, and derivatives.

[0156] In another embodiment, for example, the antimetabolite is a purine analog. Purine-based antimetabolites function by inhibiting DNA synthesis, for example, by preventing the production of adenine and guanine, purine-containing nucleotides, thereby stopping DNA synthesis and inhibiting cell division. Purine analogs can also be incorporated into the DNA molecule itself during DNA synthesis and can prevent cell division. According to one embodiment, for example, the purine analog may be selected from the group consisting of acyclovir, allopurinol, 2-aminoadenosine, arabinosyladenine (ara-A), azacitidine, azathioprine, 8-aza-adenosine, 8-fluoro-adenosine, 8-methoxy-adenosine, 8-oxo-adenosine, cladribine, deoxycoformycin, fludarabine, ganciclovir, 8-aza-guanosine, 8-fluoro-guanosine, 8-methoxy-guanosine, 8-oxo-guanosine, guanosine diphosphate, guanosine diphosphate-beta-L-2-amino fucose, guanosine diphosphate-D-arabinose, guanosine diphosphate-2-fluorofucose, guanosine diphosphate fucose, mercaptopurine (6-MP), pentostatin, amiprine, thioguanine (6-TG), and their salts, analogs, and derivatives.

[0157] In yet another embodiment, for example, the metabolic antagonist is a pyrimidine analog. Similar to the purine analogs described above, pyrimidine-based metabolic antagonists interfere with the synthesis of pyrimidine-containing nucleotides (cytosine and thymine in DNA; cytosine and uracil in RNA). By acting as a "decoy", the pyrimidine-based compound can interfere with nucleotide production and / or be incorporated into the elongating DNA strand, causing its termination. According to one embodiment, for example, the pyrimidine analog is selected from the group consisting of ancitabine, azacitidine, 6-azauridine, bromouracil (e.g., 5-bromouracil), capecitabine, carmofur, chlorouracil (e.g., 5-chlorouracil), cytarabine (cytosine arabinoside), cytosine, didoxuridine, 3'-azido-3'-deoxythymidine, 3'-dideoxycytidine-2'-ene, 3'-deoxy-3'-deoxythymidine-2'-ene, dihydro-uracil, doxifluridine, enocitabine, floxuridine, 5-fluorocytosine, 2-fluorodeoxycytidine, 3-fluoro-3'-deoxythymidine, fluorouracil (e.g., 5-fluorouracil (also known as 5-FU), gemcitabine, 5-methylcytosine, 5-propynylcytosine, 5-propynylthymine, 5-propynyluracil, thymine, uracil, uridine, and salts, analogs, and derivatives thereof. In one embodiment, the pyrimidine analog is other than 5-fluorouracil. In another embodiment, the pyrimidine analog is gemcitabine or a salt thereof.

[0158] In one embodiment, the antimetabolite is selected from the group consisting of 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In other embodiments, the antimetabolite is selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In certain embodiments, the antimetabolite is other than 5-fluorouracil. In a particularly preferred embodiment, the antimetabolite is gemcitabine or a salt thereof (e.g., gemcitabine HCl (Gemzar®)).

[0159] Other metabolic antagonists may be selected from the group consisting of, but not limited to, acanthophoric acid, aminothiadiazole, brequinar sodium, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugate, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, Wellcome EHNA (Merck&Co), EX-015, fazarabine, fludarabine phosphate, N-(2'-furanyl)-5-fluorouracil, Daiichi Seiyaku FO-152, 5-FU-fibrinogen, isopropylpyrrolidine, Lilly LY-188011; Lilly LY-264618, methobenzaprim, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, pirithioxime, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thiazofurin, Erbamont TIF, tyrosine kinase inhibitor, Taiho UFT, and uricytin, etc.

[0160] In one embodiment, the chemotherapeutic agent includes a mitotic inhibitor that is a microtubule inhibitor or a microtubule stabilizer. Generally, microtubule stabilizers, such as taxanes (any of those also described above) and epothilones, bind to the inner surface of the beta-tubulin chains, promote the nucleation and elongation phases of the polymerization reaction, and enhance microtubule assembly by lowering the critical tubulin subunit concentration required to build microtubules. Unlike microtubule inhibitors (e.g., vinca alkaloids that inhibit microtubule construction), microtubule stabilizers (e.g., taxanes) decrease the lag time and dramatically shift the dynamic equilibrium between tubulin dimers and microtubule polymers towards polymerization. Thus, in one embodiment, the microtubule stabilizer is a taxane or an epothilone. In another embodiment, the microtubule inhibitor is a vinca alkaloid.

[0161] One element of the treatment described herein may include the use of a taxane or a derivative or analog thereof, some of which are described above. In one embodiment, the taxane can be a naturally occurring compound or related form, or a chemically synthesized compound or derivative thereof having anti-cancer properties. Taxanes are one family of terpenoids and include, but are not limited to, paclitaxel (Taxol®) and docetaxel (Taxotere®), originally derived from the Pacific yew (Taxus brevifolia) and are active against certain tumors, particularly breast and ovarian tumors. In one embodiment, the taxane is docetaxel or paclitaxel. Paclitaxel is a preferred taxane and is thought to be a mitotic inhibitor that promotes microtubule assembly from tubulin dimers and stabilizes microtubules by inhibiting depolymerization. This stability inhibits the normal and dynamic reorganization of the microtubule network, which is essential for cell functions during interphase and mitosis required for life support.

[0162] Also included are various known taxane derivatives (including hydrophilic and hydrophobic derivatives). Taxane derivatives include, but are not limited to, the galactose and mannose derivatives described in International Patent Application No. WO99 / 18113; the piperazino and other derivatives described in WO99 / 14209; the taxane derivatives described in WO99 / 09021, WO98 / 22451, and U.S. Patent No. 5,869,; the 6-thio derivatives described in WO98 / 28288; the sulfenamide derivatives described in U.S. Patent No. 5,821,263; deoxygenated paclitaxel compounds, such as those described in U.S. Patent No. 5,440,056; and the taxol derivatives described in U.S. Patent No. 5,415,869. As described above, prodrugs of paclitaxel (including, but not limited to, those described in WO98 / 58927; WO98 / 13059; and U.S. Patent No. 5,824,701) are further included. The taxane may also be a taxane conjugate, such as paclitaxel-PEG, paclitaxel-dextran, paclitaxel-xylose, docetaxel-PEG, docetaxel-dextran, docetaxel-xylose, etc. Other derivatives are mentioned in "Synthesis and Anticancer Activity of Taxol Derivatives," D. G. I. Kingston et al., Studies in Organic Chemistry, vol. 26, entitled "New Trends in Natural Products Chemistry" (1986), Atta-ur-Rabman, P. W. le Quesne, Eds. (Elsevier, Amsterdam 1986), etc. Each of these documents is hereby incorporated by reference in its entirety.

[0163] Various taxanes may be readily prepared using techniques known to those skilled in the art (see also WO94 / 07882, WO94 / 07881, WO94 / 07880, WO94 / 07876, WO93 / 23555, WO93 / 10076; U.S. Patent Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; and EP590,267) (each of which is hereby incorporated by reference in its entirety), or may be obtained from various commercial sources (e.g., including Sigma-Aldrich Co., St. Louis, Missouri).

[0164] Alternatively, the mitotic inhibitor can be a microtubule inhibitor; in one preferred embodiment, the microtubule inhibitor is a vinca alkaloid. Generally, the vinca alkaloids are spindle poisons. The vinca alkaloid agents act during mitosis when the chromosomes begin to move along the spindle tubes toward one of the poles before they divide and the cell divides. Under the action of these spindle poisons, the spindle disintegrates due to the dispersion of the chromosomes during mitosis, affecting cell replication. According to one embodiment, for example, the vinca alkaloid is selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine, and salts, analogs, and derivatives thereof.

[0165] The mitotic inhibitor can also be an epothilone. Generally, the epothilone compound members stabilize the function of microtubules by a mechanism similar to that of taxanes. Epothilones can also arrest the cell cycle at the G2-M transition and can cause cytotoxicity and ultimately apoptosis. Suitable epothilones include epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, and epothilone F, and salts, analogs, and derivatives thereof. One specific epothilone analog is the epothilone B analog, ixabepilone (Ixempra®).

[0166] In certain embodiments, the mitotic inhibitory anti-cancer agent is selected from the group consisting of taxanes, epothilones, vinca alkaloids, and salts and combinations thereof. Thus, for example, in one embodiment, the mitotic inhibitor is a taxane. More preferably, in this embodiment, the mitotic inhibitor is paclitaxel or docetaxel, and even more preferably, paclitaxel. In another embodiment, the mitotic inhibitor is an epothilone (e.g., an epothilone B analog). In another embodiment, the mitotic inhibitor is a vinca alkaloid.

[0167] In one embodiment, at least one of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents is administered within a predetermined period before or after the administration of a further chemotherapeutic agent dose. For example, the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents may be administered within 1 week, 48 hours, 24 hours, 12 hours, 6 hours, 2 hours, 1 hour, or even within 30 minutes of a further chemotherapeutic agent (either before or after dosing of the chemotherapeutic agent) that the patient receives. Other periods between the dosing of the further chemotherapeutic agent that enhances cancer cell killing and the administration of the components may also be appropriate. In one embodiment, one or more of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents may be administered before the dosing of the further chemotherapeutic agent, and the remaining one or more of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents may be administered after the dosing of the further chemotherapeutic agent. One or more of the pentaazamacrocyclic ring complex and platinum-based anti-cancer agents may also be administered both before and after the administration of a dose of the further chemotherapeutic agent.

[0168] In one embodiment of 1, the chemotherapy process includes a single administration of an additional chemotherapeutic agent. In another embodiment, the chemotherapy process includes multiple administrations of an additional chemotherapeutic agent administered over a predetermined period, such as a period of several hours, several weeks, several days, or even several months. The multiple administrations may be the same or different dosages and may include administrations of the same or different chemotherapeutic agents and / or combinations of chemotherapeutic agents. Administration of pentaazamacrocyclic ring complexes and platinum-based anti-cancer agents during the chemotherapy process can be selected to enhance the cancer treatment effect of chemotherapy, for example, by increasing the intracellular hydrogen peroxide level to promote oxidative stress in cancer cells. In one embodiment of 1, the pentaazamacrocyclic ring complexes and platinum-based anti-cancer agents are administered before or after each administration for a predetermined period, such as within the predetermined period described above. In another embodiment, the pentaazamacrocyclic ring complexes and platinum-based anti-cancer agents are administered only within a predetermined period before or after a selected administration. In yet another embodiment, at least one of the pentaazamacrocyclic ring complexes and platinum-based anti-cancer agents is administered within a predetermined period before administration, while another pentaazamacrocyclic ring complex and platinum-based anti-cancer agent is administered within a predetermined period after administration. In a further embodiment, at least one of the pentaazamacrocyclic ring complexes and platinum-based anti-cancer agents is administered only within a predetermined period before or after a selected administration, while another pentaazamacrocyclic ring complex and platinum-based anti-cancer agent is administered only within a predetermined period before or after an administration other than the selected administration.

[0169] In yet another embodiment, at least one of the pentaazamacrocyclic ring complexes and platinum-based anti-cancer agents is administered in combination with both radiation therapy and chemotherapy (relating to the administration of additional chemotherapeutic agents).

[0170] Examples The following non-limiting examples are provided to further illustrate aspects of the present invention. The techniques disclosed in the following examples show that the methods found by the inventors can be fully used in the practice of the present invention, and therefore, it should be evaluated by those skilled in the art that examples of such embodiments can be considered. However, those skilled in the art should recognize that many changes can be made to the specific embodiments disclosed in view of the present disclosure, and similar or comparable results can be obtained without departing from the spirit and scope of the present invention.

[0171] Synergistic effect of anticancer therapy Example 1 Effect of GC4419 and cisplatin on the survival of cancer cells in culture H460 human non-small cell lung cancer (NSCLC) cells in medium were treated with 24 μM GC4419 (+GC) or medium (-GC) and the indicated concentrations of cisplatin. After 120 hours, the survival fraction of the cells was examined. Addition of GC4419 to cisplatin treatment decreased the survival fraction of H460 cells compared to cells treated with cisplatin alone. GC4419 significantly enhanced the sensitivity of H460 lung cancer cells to cisplatin (see Figure 1: Effect of GC4419 and cisplatin on the survival of H460 cells in culture).

[0172] Example 2 Effect of GC4419, cisplatin and catalase overexpression on the survival of cancer cells in culture H1299 human NSCLC cells modified to inductively overexpress catalase (CAT) that removes hydrogen peroxide (H2O2) were treated in cell culture medium with 24 μM GC4419 (+GC) or medium (-GC) and the indicated concentrations of cisplatin. CAT overexpression in this strain (H1299CAT) was induced by administration of doxycycline, turning on the transcription of the inserted catalase gene. After 120 hours of treatment with cisplatin in the presence or absence of GC4419, the survival fraction of H1299CAT cells was examined both in the presence and absence of CAT overexpression. Without CAT overexpression (“wt”), addition of GC4419 to cisplatin treatment decreased the survival fraction of H460 cells compared to cells treated with cisplatin alone, similar to H460 cells treated with both GC4419 and cisplatin. In contrast, CAT overexpression (the “CAT” that removes H2O2 generated from superoxide by GC4419) suppressed the contribution of GC4419 to the cisplatin response, and GC4419 significantly enhanced the sensitivity of H460 lung cancer cells to cisplatin, and this enhanced reactivity was shown to be H2O2-dependent (see Figure 2: Effect of GC4419, cisplatin and catalase overexpression in cultured H1299CAT cells).

[0173] Example 3 Effect of GC4419 and cisplatin on PARP activity in cancer cells H460 NSCLC cells in culture were treated with 24 μM GC4419 and 1 μM cisplatin for 24 hours. At this time, the cells were solubilized and PARP (poly(ADP-ribose) polymerase) activity was measured by Western blot as the ratio of the 89 kd active form to the 116 kd inactive form. PARP is a nuclear enzyme involved in single-strand break DNA repair and is activated by cellular stress (including chemotherapy and radiation). As shown in Figure 3, cisplatin increased PARP activity compared to untreated cells or GC4419 treatment alone. When GC4419 was further added to cisplatin, PARP activity was significantly increased (p < 0.01), indicating that GC4419 enhances cisplatin-induced cancer cell damage (see Figure 3: Effects of GC4419 and cisplatin on PARP activity in H460 cells).

[0174] H1299 (wild-type) NSCLC cells in culture were also treated with 24 μM GC4419 and 10 μM cisplatin for 24 hours. At this time, the cells were solubilized and PARP activity was measured by Western blot as the ratio of the 89 kd active form to the 116 kd inactive form. As shown in Figure 4 and consistent with the effects shown in H460 lung cancer cells, cisplatin increased PARP activity compared to untreated cells or GC4419 treatment alone. When GC4419 was further added to cisplatin, PARP activity was significantly increased (p < 0.01), indicating that GC4419 enhances cisplatin-induced cancer cell damage (see Figure 4: Effects of GC4419 and cisplatin on PARP activity in H1299 cells).

[0175] H460 cells in culture were further exposed to 6 Gy of ionizing radiation (IR), and either 24 μM GC4419, 1 μM cisplatin, or GC4419 and cisplatin for 24 hours. Cells were then lysed and PARP activity was measured by Western blot as the ratio of 89 kD active form to 116 kD inactive form. As shown in Figure 5, IR alone significantly increased PARP activity above background (p<0.05). Addition of GC4419 to IR significantly increased PARP activity above that seen with IR alone. Addition of cisplatin to IR significantly increased PARP activity, and addition of GC4419 to this combination significantly increased it further (p<0.01), demonstrating that GC4419 enhances cancer cell damage induced by radiation and cisplatin (see Figure 5: Effect of GC4419, cisplatin, and radiation on PARP activity in H460 cells).

[0176] H1299 (wild-type) cells in culture were also exposed to 6 Gy of ionizing radiation (IR), and either 24 μM GC4419, 1 μM cisplatin, or GC4419 and cisplatin for 24 hours. Cells were then lysed and PARP activity was measured by Western blot as the ratio of 89 kD active form to 116 kD inactive form. As shown in Figure 6A, and consistent with the effects shown in H460 lung cancer cells, IR alone significantly increased PARP activity above background. Addition of cisplatin to IR significantly increased PARP activity, and addition of GC4419 to this combination significantly increased it further (p<0.05), demonstrating that GC4419 enhances cancer cell damage induced by radiation and cisplatin (see Figure 6A: Effect of GC4419, cisplatin, and radiation on PARP activity in H1299 cells).

[0177] H1299CAT cells were also exposed to 6 Gy of radiation (IR), 24 μM GC4419, and / or 1 μM cisplatin for 24 hours. Treatment with doxycycline caused H1299CAT cells to express human catalase (CAT) at higher levels than the "parent" H1299 (wild-type) cells and to remove all or part of the H2O2 generated from superoxide by GC4419 or other Mn pentaazamacrocyclic dismutase mimics. PARP activation in H1299CAT cells not exposed to doxycycline (data not shown) was responsive to cisplatin, IR, and GC4419 treatment compared to H1299 wild-type cells (see Figure 5). However, induction of CAT expression in H1299CAT by doxycycline treatment significantly decreased PARP activation in response to cisplatin (p<0.01, Figure 6B), IR (p<0.05, Figure 6C), and IR+cisplatin (p<0.001, Figure 6C) (p<0.05). These results strongly suggest that superoxide generated by cisplatin causes cytotoxicity and that removal of this superoxide by GC4419 can reduce cytotoxicity, along with the results described in Example 5 below regarding reduction of cisplatin nephrotoxicity and hematotoxicity. However, since GC4419 enhanced PARP against cisplatin in cancer cells except when H2O2 was removed by CAT overexpression, these results support that H2O2 generated by GC4419 (when not removed by CAT) was associated with more promoting cisplatin cytotoxicity and PARP activation than the superoxide it replaced (Figure 6B: Treatment of H1299CAT cells with cisplatin and GC4419 (along with doxycycline-induced CAT overexpression); and Figure 6C: Treatment of H1299CAT cells with cisplatin, IR, and GC4419 (along with doxycycline-induced CAT overexpression)).

[0178] Example 4 Cisplatin treatment increases the total reactive oxygen species (ROS) levels in cancer cells, while GC4419 selectively reduces superoxide and increases H2O2 levels H460 and H1299 (wild-type) cells were exposed to 6 Gy of ionizing radiation (IR), and either 24 μM GC4419, 1 μM cisplatin, or a combination of GC4419 and cisplatin. After the treatment and incubation, the CellROX fluorescent generation probe for total ROS was added and incubated for 30 minutes, and the CellROX signal was measured using flow cytometry. Figures 7A-7D show that GC4419 had little effect on total ROS when used alone against any cancer cell line, while cisplatin or cisplatin and IR increased total ROS. GC4419 may have shown a synergistic effect on total ROS when added to cisplatin treatment (see total reactive oxygen species in Figures 7A-7D).

[0179] Alternatively, after the treatment and initial incubation, the MitoSOX fluorescent generation probe for mitochondrial superoxide was added and incubation was continued for 10 minutes, and the MitoSOX signal was measured using a flow cytometer. Figures 8A-8D show that GC4419 significantly decreased the baseline levels of mitochondrial superoxide in both cancer cell lines. Furthermore, GC4419 significantly decreased the increase in mitochondrial superoxide caused by cisplatin or cisplatin and IR (see mitochondrial superoxide in Figures 8A-8D)

[0180] Alternatively, after the treatment and initial incubation, the PO-1 probe for H2O2 was added. Figures 9A-9D show that GC4419 significantly increased both baseline levels of H2O2 in both cancer cell lines and further significantly increased the increase in H2O2 caused by cisplatin or cisplatin and IR (see hydrogen peroxide in Figures 9A-9D).

[0181] Reduction of the toxicity of platinum-based anticancer agents Example 5 Effect of GC4419 on Cisplatin-Induced Nephrotoxicity in Mice Four-month-old male C57BL / 6J mice (young) were purchased from Jackson Laboratories, and 18-month-old mice (aged) were obtained as part of a collaborative study with Dr. Amy Kindler (University of Iowa) from the National Institute on Aging. All mice were maintained in accordance with ACURF approval #4121235 at the University of Iowa animal facility. Mice were fed ad libitum a standard diet and water throughout the experimental period. Animals were randomly assigned to experimental groups containing vehicle control, cisplatin only, GC4419, and cisplatin + GC4419.

[0182] The cisplatin-induced acute kidney injury (AKI) model was as follows: Four- or 18-month-old male C57BL / 6J mice were administered a single dose of 10 mg / kg cisplatin or 0.9% saline by intraperitoneal injection. Animals were euthanized 72 hours after cisplatin treatment. Animals in the GC4419 only and cisplatin + GC4419 groups were treated daily with 10 mg / kg GC4419 starting 4 days prior to cisplatin dosing and continuing until the day of euthanasia. Animals in the cisplatin only group were also given a bolus dose of saline daily after cisplatin treatment to prevent dehydration.

[0183] Blood urea nitrogen (BUN) and creatinine levels in whole blood were measured using an i-STAT handheld clinical analyzer purchased from Abbott-Point of Care (Princeton, NJ) with a single-use i-STAT test cartridge (Chem8+) before the start of treatment with GC4419 and 72 hours after cisplatin treatment. Animals were weighed every other day after the start of treatment with GC4419.

[0184] As shown in Figure 10A, cisplatin increased BUN and creatinine levels on day 3 of administration in young mice and, more dramatically, in old mice, indicating significant impairment of renal function. GC4419 completely prevented these increases in BUN and creatinine and suppressed acute kidney injury (see Figure 10A: BUN and creatinine levels in mice treated with cisplatin).

[0185] Two specific biomarkers of kidney injury, kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL), were also evaluated. As seen in Figure 10B, these biomarkers were consistent with BUN and creatinine levels, indicating that cisplatin caused nephrotoxicity and that GC4419 suppressed this injury (see Figure 10B: KIM1 and NGAL biomarkers in mice treated with cisplatin).

[0186] Consistent with these kidney injury and function results, cisplatin caused significant weight loss in both young and old mice (Figure 10C) and decreased survival in the more sensitive old mice (Figure 10D). GC4419 decreased the amount of weight loss in both groups of mice and suppressed the mortality of cisplatin in old mice (see Figure 10C: cisplatin-induced weight loss; and Figure 10D: survival in mice treated with cisplatin).

[0187] Consistent with these kidney injury and function results, cisplatin caused significant weight loss in both young and old mice (Figure 10C) and decreased survival in the more sensitive old mice (Figure 10D). GC4419 decreased the amount of weight loss in both groups of mice and suppressed the mortality of cisplatin in old mice.

[0188] Example 6 Effect of GC4419 on Cisplatin-Induced Hematotoxicity in Mice Seven-week-old female thymus-deficient Nu / Nu (nude) mice were transplanted in the hind limb with SQ20B human head and neck squamous cell carcinoma cells. Tumors formed and became palpable in 4 days, and the mice were either untreated or received cisplatin at 2.7 mg / kg and radiation (IR) at 2 Gy once every 2 or 3 days for 5 times. Additionally, one group receiving cisplatin and IR treatment also received 10 mg / kg GC4419 daily during the treatment period and for 2 days thereafter. Mice were evaluated for blood counts by tail vein blood collection 2 days or 2 weeks after the treatment period.

[0189] As shown in Figure 11A, cisplatin + IR treatment resulted in a decrease in platelets (thrombocytopenia) measured 2 days after the end of treatment, and GC4419 significantly restored platelet levels (Figure 11A: see cisplatin-induced thrombocytopenia).

[0190] As shown in Figure 11B, GC4419 treatment activated the production of lymphocytes (WBC) and relative lymphocyte subsets both 2 days and 2 weeks after the end of treatment in mice treated with the combination of cisplatin and radiation (Figure 11B: see GC4419 and WBC counts).

[0191] As shown in Figure 11C, cisplatin + IR treatment resulted in a decrease in the number and percentage of neutrophils (neutropenia) measured 2 days or 2 weeks after the end of treatment, and GC4419 maintained the neutrophil percentage at clearly normal levels (Figure 11C: see cisplatin-induced neutropenia).

[0192] In contrast, as shown in Figure 11D, cisplatin + IR treatment resulted in an increase in the percentage of eosinophils measured 2 days or 2 weeks after the end of treatment, and GC4419 maintained the eosinophil percentage at clearly normal levels (Figure 11D: see cisplatin-induced eosinophilia).

[0193] The following are typical embodiments of aspects of the present disclosure, but are not intended to be limiting, and the present disclosure may encompass additional aspects.

[0194] Embodiment 1 A method for treating and / or reducing the toxic effects on a mammalian subject associated with treatment with a platinum-based anti-cancer agent in a subject in need of treatment and / or reduction, comprising administering to the subject a therapeutically effective amount of a platinum-based anti-cancer agent; then administering to the subject a therapeutically effective amount of a pentaazamacrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after the administration of the platinum-based anti-cancer agent to reduce the toxic effects of the platinum-based anti-cancer agent.

Chemical formula

[0195] Embodiment 2 The method according to embodiment 1, wherein the subject has cancer.

[0196] Embodiment 3 The method according to embodiment 1 or 2, wherein the subject suffers from and / or is at risk of suffering from toxicity (toxicity selected from the group consisting of nephrotoxicity, myelotoxicity, and ototoxicity) induced by treatment with a platinum-based anticancer agent.

[0197] Embodiment 4 The method according to any one of embodiments 1 to 3, wherein the subject suffers from and / or is at risk of suffering from one or more of nephrotoxicity and myelotoxicity.

[0198] Embodiment 5 The method according to any one of Embodiments 1 to 4, wherein the subject suffers from nephrotoxicity and / or myelotoxicity associated with treatment with a platinum-based anticancer agent.

[0199] Embodiment 6 The method according to any one of Embodiments 1 to 5, comprising administering a therapeutically effective amount of a pentaazamacrocyclic ring complex that enhances the therapeutic responsiveness to the platinum-based anticancer agent and the platinum-based anticancer agent.

[0200] Embodiment 7 The method according to any one of Embodiments 1 to 6, wherein the pentaazamacrocyclic ring complex is administered in a therapeutically effective amount that enhances a cancer response corresponding to any one selected from the group consisting of a decrease in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or degree of metastasis, and a decrease in cancer cell proliferation.

[0201] Embodiment 8 The method according to any one of Embodiments 1 to 7, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatinine and blood urea nitrogen (BUN).

[0202] Embodiment 9 The method according to any one of Embodiments 1 to 8, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for kidney injury selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL).

[0203] Embodiment 10 A method for treating and / or reducing the toxic effects associated with treatment with a platinum-based anticancer agent in a mammalian subject in need of treatment and / or reduction, comprising administering a pentaaza macrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anticancer agent to reduce the toxic effects of the platinum-based anticancer agent.

Chemical formula

[0204] Embodiment 11 The method according to embodiment 10, wherein the subject has cancer.

[0205] Embodiment 12 The method according to embodiment 10 or 11, wherein the subject suffers from and / or has a risk of suffering from toxicity (toxicity selected from the group consisting of nephrotoxicity, myelotoxicity, and ototoxicity) induced by treatment with a platinum-based anticancer agent.

[0206] Embodiment 13 The method according to any one of embodiments 10 to 12, wherein the subject suffers from and / or has a risk of suffering from one of nephrotoxicity and myelotoxicity.

[0207] Embodiment 14 The method according to any one of embodiments 10 to 13, wherein the subject suffers from nephrotoxicity and / or myelotoxicity associated with treatment with a platinum-based anticancer agent.

[0208] Embodiment 15 The method according to any one of embodiments 10 to 14, comprising administering a therapeutically effective amount of a platinum-based anticancer agent and a pentaazamacrocyclic ring complex that enhances the therapeutic responsiveness to the platinum-based anticancer agent.

[0209] Embodiment 16 The method according to any one of embodiments 10 to 15, wherein the pentaazamacrocyclic ring complex is administered in a therapeutically effective amount that enhances a cancer response corresponding to any one selected from the group consisting of a decrease in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or degree of metastasis, and a decrease in cancer cell proliferation.

[0210] Embodiment 17 The method according to any one of embodiments 10 to 16, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatinine and blood urea nitrogen (BUN).

[0211] Embodiment 18 The method according to any one of embodiments 10 to 17, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for kidney damage selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL).

[0212] Embodiment 19 A method for treating cancer in a mammalian subject suffering from cancer, comprising: administering to the subject a therapeutically effective amount of a platinum-based anticancer agent; administering to the subject a therapeutically effective amount of a pentaazamacrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby enhancing the responsiveness of the cancer to the platinum-based anticancer agent. [Chemical formula] (I) [In the formula, M is Mn 2+ or Mn 3+ ; and R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), and are moieties selected from the group consisting of, where R 11 and R 12 are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocyclic ring having 2 to 20 ring carbon atoms, provided that when W is a condensed aromatic heterocyclic ring, the hydrogen bonded to the nitrogen which is part of both the heterocyclic ring and the macrocyclic ring, and R1 and R bonded to the carbon atoms which are part of both the heterocyclic ring and the macrocyclic ring 10 is considered to be absent; X and Y each represent any suitable ligand derived from a monodentate or polydentate ligand or ligand system, or the corresponding anion; Z is a counterion; n is an integer from 0 to 3; and the dotted line represents a coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese)]

[0213] Embodiment 20 The method according to embodiment 19, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and the pentaazamacrocyclic complex that reduces the toxic effects of the platinum-based anticancer agent.

[0214] Embodiment 21 The method according to embodiment 19 or 20, wherein the pentaazamacrocyclic complex is administered in a therapeutically effective amount that enhances a cancer response corresponding to any one selected from the group consisting of a decrease in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or degree of metastasis, and a decrease in cancer cell proliferation, and / or reduces cancer complications.

[0215] Embodiment 22 The method according to any one of embodiments 19 to 21, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces at least one level of creatinine and blood urea nitrogen (BUN).

[0216] Embodiment 23 The method according to any one of embodiments 19 to 22, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for kidney injury selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL).

[0217] Embodiment 24 A method for enhancing the sensitivity of a mammalian subject to treatment with a platinum-based anti-cancer agent in a subject in need of enhanced sensitivity, comprising: administering to the subject a therapeutically effective amount of a pentaazamacrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anti-cancer agent, thereby enhancing the therapeutic response to the platinum-based anti-cancer agent. [Chemical formula] (I) [wherein, M is Mn 2+ or Mn 3+ ; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12a moiety selected from the group consisting of, R 11 and R 12 are each independently hydrogen or alkyl; U, together with the adjacent carbon atoms of said macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of said macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of said macrocyclic ring and the carbon atom of said macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen which is part of both the heterocycle and said macrocyclic ring, and R1 and R attached to the carbon atoms which are part of both the heterocycle and said macrocyclic ring 10 shall be non-existent; X and Y each represent either a monodentate or polydentate ligand or a suitable ligand derived from a ligand system, or the corresponding anion; Z is a counterion; n is an integer from 0 to 3; and the dotted line represents a coordination bond between the nitrogen atom of said macrocyclic ring and a transition metal (manganese)]

[0218] Embodiment 25 The method according to embodiment 24, wherein the subject has cancer.

[0219] Embodiment 26 The method according to embodiment 24 or 25, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and the pentaazamacrocyclic complex that reduces the toxic effects of the platinum-based anticancer agent.

[0220] Embodiment 27 The method according to any one of embodiments 24 to 26, wherein the pentaazamacrocyclic ring complex is administered in a therapeutically effective amount that enhances a cancer response corresponding to any one selected from the group consisting of a decrease in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or degree of metastasis, and a decrease in cancer cell proliferation, and / or can reduce cancer complications.

[0221] Embodiment 28 The method according to any one of embodiments 24 to 27, wherein the pentaazamacrocycle is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

[0222] Embodiment 29 The method according to any one of embodiments 24 to 28, wherein the pentaazamacrocycle is administered in a therapeutically effective amount that reduces the level of a marker for kidney damage selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL).

[0223] Embodiment 30 A method for treating a toxic effect selected from the group consisting of nephrotoxicity and myelotoxicity associated with treatment with a platinum-based anticancer agent in a mammalian subject in need of treatment and / or reduction, and / or reducing the risk of said toxic effect, comprising: administering to the subject a therapeutically effective amount of a platinum-based anticancer agent; and then administering to the subject a therapeutically effective amount of a pentaazamacrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anticancer agent, thereby reducing the toxic effect of the platinum-based anticancer agent. [Chemical formula] (I) [In the formula, M is Mn 2+ or Mn 3+ ; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 are each independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), and is a moiety selected from the group consisting of, where R 11 and R 12 are each independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen which is part of both the heterocycle and the macrocyclic ring, and R1 and R attached to the carbon atoms which are part of both the heterocycle and the macrocyclic ring 10 are taken to be absent; X and Y each represent any suitable ligand derived from a mono- or poly-dentate ligand or ligand system, or the corresponding anion; Z is a counterion; n is an integer from 0 to 3; and The dotted line represents a coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0224] Embodiment 31 The method according to embodiment 30, wherein the subject has cancer.

[0225] Embodiment 32 The method according to embodiment 30 or 31, wherein the subject suffers from nephrotoxicity and / or myelotoxicity associated with treatment with a platinum-based anti-cancer agent.

[0226] Embodiment 33 The method according to any one of embodiments 30 to 32, comprising administering a therapeutically effective amount of a platinum-based anti-cancer agent and a pentaazamacrocyclic complex that enhances the therapeutic responsiveness to the platinum-based anti-cancer agent.

[0227] Embodiment 34 The method according to any one of embodiments 30 to 33, wherein the pentaazamacrocyclic complex is administered in a therapeutically effective amount that enhances a cancer response corresponding to any one selected from the group consisting of a decrease in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or degree of metastasis, and a decrease in cancer cell proliferation, and / or can reduce cancer complications.

[0228] Embodiment 35 The method according to any one of embodiments 30 to 34, wherein the pentaazamacrocycle is administered in a therapeutically effective amount that reduces the level of at least one of creatinine and blood urea nitrogen (BUN).

[0229] Embodiment 36 The method according to any one of embodiments 30 to 35, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for kidney injury selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL).

[0230] Embodiment 37 A method of treating and / or reducing the risk of a toxic effect selected from the group consisting of nephrotoxicity and myelotoxicity associated with treatment with a platinum-based anti-cancer agent in a mammalian subject in need of treatment and / or reduction, comprising: administering to the subject a pentaazamacrocyclic ring complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anti-cancer agent, thereby reducing the toxic effect of the platinum-based anti-cancer agent.

Chemical formula

[0231] Embodiment 38 The method according to embodiment 37, wherein the subject is suffering from cancer.

[0232] Embodiment 39 The method according to embodiment 37 or 38, wherein the subject is suffering from nephrotoxicity and / or myelotoxicity associated with treatment with a platinum-based anti-cancer agent.

[0233] Embodiment 40 The method according to any one of embodiments 37 to 39, comprising administering a therapeutically effective amount of the pentaazamacrocyclic ring complex that enhances the therapeutic responsiveness to the platinum-based anticancer agent and the platinum-based anticancer agent.

[0234] Embodiment 41 The method according to any one of embodiments 37 to 40, wherein the pentaazamacrocyclic ring complex is administered in a therapeutically effective amount that enhances a cancer response corresponding to any one selected from the group consisting of a decrease in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or degree of metastasis, and a decrease in cancer cell proliferation, and / or can reduce cancer complications.

[0235] Embodiment 42 The method according to any one of embodiments 37 to 41, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatinine and blood urea nitrogen (BUN).

[0236] Embodiment 43 The method according to any one of embodiments 37 to 42, wherein the pentaazamacrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for kidney injury selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL).

[0237] Embodiment 44 R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 The method according to any one of the above embodiments, wherein each is hydrogen.

[0238] Embodiment 45 The method according to any one of embodiments 1 to 44, wherein W is an unsubstituted pyridine moiety.

[0239] Embodiment 46 The method according to any one of embodiments 1 to 45, wherein U and V are trans-cyclohexanyl fused rings.

[0240] Embodiment 47 The pentaaza macrocyclic ring complex is of formula (II):

Chem.

[0241] Embodiment 48 The pentaaza macrocyclic ring complex is of formula (III) or formula (IV):

Chem.

[0242] Embodiment 49 The pentaaza macrocyclic ring complex is represented by a formula selected from the group consisting of formulas (V) to (XVI):

Chemical formula

Chemical formula

[0243] Embodiment 50 The method according to any one of Embodiments 1 to 49, wherein X and Y are independently a halide, oxo, aco, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycloarylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitrogen oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitric acid, nitrous acid, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiocarboxylic acid, arylthiocarboxylic acid, alkylthiolthiocarboxylic acid, arylthiolthiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkylthiourea, arylthiourea, alkylarylthiourea, sulfuric acid, sulfurous acid, bisulfuric acid, bisulfurous acid, thiosulfuric acid, thiosulfurous acid, hydrosulfurous acid, alkylphosphine, arylphosphine, alkylphosphine oxide, arylphosphine oxide, alkylarylphosphine oxide, alkylphosphine sulfide, arylphosphine sulfide, alkylarylphosphine sulfide, alkylphosphonic acid, arylphosphonic acid, alkylphosphinic acid, arylphosphinic acid, alkylphosphonous acid, arylphosphonous acid, phosphoric acid, thiophosphoric acid, phosphorous acid, pyrophosphorous acid, triphosphoric acid, hydrogen phosphate, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylarylguanidino, alkylcarbamate, arylcarbamate, alkylarylcarbamate, alkylthiocarbamate, arylthiocarbamate, alkylarylthiocarbamate, alkyldithiocarbamate, aryldithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonate, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, perbromic acid, bromic acid, bromous acid, hypobromous acid, tetrahydroxomanganate,Substituted or unsubstituted moieties from the group consisting of tetrafluoroboric acid, hexafluoroantimonic acid, hypophosphorous acid, iodic acid, periodic acid, metaboric acid, tetraarylboric acid, tetraalkylboric acid, tartaric acid, salicylic acid, succinic acid, citric acid, ascorbic acid, saccharinic acid, amino acids, hydroxamic acids, thiotosyl oxo, and anions of ion exchange resins, or corresponding anions thereof, are independently selected; alternatively, X and Y are those corresponding to -O-C(O)-X1, and each X1 is -C(X2)(X3)(X4), each X1 is independently substituted or unsubstituted phenyl or -C(-X2)(-X3)(-X4); each X2 is independently substituted or unsubstituted phenyl, methyl, ethyl, or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, -X5C(=O)R 13 [wherein X5 is NH or O, and R 13 is C1-C18 alkyl, substituted or unsubstituted aryl, or C1-C18 aralkyl], or -OR 14 [wherein R 14 is C1-C18 alkyl, substituted or unsubstituted aryl, or C1-C18 aralkyl], or X4 together with X3 forms (=O); and each X4 is independently hydrogen or together with X3 forms (=O); alternatively, X and Y are independently selected from the group consisting of charge-neutralizing anions derived from monodentate or polydentate ligands, and ligand systems and corresponding anions thereof; alternatively, X and Y are independently those bonded to one or more of R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 in one or more ways.

[0244] Embodiment 51 The method according to any one of Embodiments 1 to 50, wherein X and Y are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions.

[0245] Embodiment 52 The method according to any one of Embodiments 1 to 51, wherein X and Y are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates, and arylalkyl carboxylates.

[0246] Embodiment 53 The method according to any one of Embodiments 1 to 52, wherein X and Y are independently amino acids.

[0247] Embodiment 54 The pentaaza macrocyclic ring complex has the formula:

Chemical formula

[0248] Embodiment 55 The pentaaza macrocyclic ring complex has the formula:

Chemical formula

[0249] Embodiment 56 The pentaaza macrocyclic ring complex has the formula:

Chemical formula

[0250] Embodiment 57 The pentaaza macrocyclic ring complex has the formula:

Chemical formula

[0251] Embodiment 58 wherein the pentaazamacrocyclic ring complex has the formula:

Chemical formula

[0252] Embodiment 59 wherein the pentaazamacrocyclic ring complex has the formula:

Chemical formula

[0253] Embodiment 60 The method according to any one of Embodiments 1 to 59, wherein the platinum-based anticancer agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatine, phenanthriplatin, prolinadac, triplatin tetranitrate, picoplatin, satraplatin, pyrithyldiamine platinum, and / or pharmaceutically acceptable salts thereof.

[0254] Embodiment 61 The method according to any one of Embodiments 1 to 60, wherein the platinum-based anticancer agent contains cisplatin.

[0255] Embodiment 62 wherein the platinum-based anticancer agent is administered at a dose in the range of 20 mg / m 2 ~200 mg / m 2 The method according to any one of Embodiments 1 to 61.

[0256] Embodiment 63 The method according to any one of Embodiments 1 to 62, wherein the administration of the pentaaza macrocyclic ring complex in the treatment process is administered for a certain period before the administration of the platinum-based anticancer agent.

[0257] Embodiment 64 The method according to any one of Embodiments 1 to 63, wherein the administration of the pentaaza macrocyclic ring complex in the treatment process is administered at least 1 week before, 1 day before, or 1 hour before the administration of the platinum-based anticancer agent.

[0258] Embodiment 65 The method according to any one of Embodiments 1 to 64, wherein the administration of the pentaaza macrocyclic ring complex in the treatment process is administered within 1 hour before and / or simultaneously with the administration of the platinum-based anticancer agent.

[0259] Embodiment 66 The method according to any one of Embodiments 1 to 65, wherein the administration of the pentaaza macrocyclic ring complex in the treatment process is administered within 1 hour, 1 day, or 1 week after the administration of the platinum-based anticancer agent.

[0260] Embodiment 67 The method according to any one of Embodiments 1 to 66, comprising administering the platinum-based anticancer agent to a subject who is undergoing radiotherapy simultaneously.

[0261] Embodiment 68 The method according to any one of Embodiments 1 to 66, comprising administering the platinum-based anticancer agent and the pentaaza macrocyclic ring complex to a subject who has not received radiotherapy.

[0262] Embodiment 69 The method according to any one of Embodiments 1 to 66, wherein the treatment process comprising the administration of the pentaaza macrocyclic ring complex and the platinum-based anticancer agent is administered to a subject who has not received radiotherapy during the treatment process.

[0263] Embodiment 70 Administering one or more of the pentaaza macrocyclic ring complex and the platinum-based anti-cancer agent to the subject on days other than the days when the subject is receiving radiotherapy, the method according to any one of Embodiments 1 to 66.

[0264] Embodiment 71 Administering a treatment process comprising administering the platinum-based anti-cancer agent and the pentaaza macrocyclic ring complex to a subject who has not received radiotherapy for at least one day, the method according to any one of Embodiments 1 to 66.

[0265] Embodiment 72 Administering a treatment process comprising administering the platinum-based anti-cancer agent and the pentaaza macrocyclic ring complex to a subject who has not received radiotherapy for at least one week, the method according to any one of Embodiments 1 to 66.

[0266] Embodiment 73 Administering a treatment process comprising administering the platinum-based anti-cancer agent and the pentaaza macrocyclic ring complex to a subject who has not received radiotherapy for at least one month, the method according to any one of Embodiments 1 to 66.

[0267] Embodiment 74 Administering a treatment process comprising administering the platinum-based anti-cancer agent and the pentaaza macrocyclic ring complex to a subject who has not received radiotherapy for at least six months, the method according to any one of Embodiments 1 to 66.

[0268] Embodiment 75 Administering the platinum-based anti-cancer agent and the pentaaza macrocyclic ring complex to the subject, and then delaying radiotherapy that may be appropriately administered to the subject until at least one day after the final administration of the pentaaza macrocyclic ring complex, the method according to any one of Embodiments 1 to 66.

[0269] Embodiment 76 Administering the platinum-based anticancer agent and the pentaazamacrocyclic ring complex to a subject, and delaying radiotherapy that may be appropriately administered to the subject until at least 1 week after the final administration of the pentaazamacrocyclic ring complex, the method according to any one of embodiments 1 to 66.

[0270] Embodiment 77 Administering the platinum-based anticancer agent and the pentaazamacrocyclic ring complex to a subject, and then delaying radiotherapy that may be appropriately administered to the subject until at least 1 month after the final administration of the pentaazamacrocyclic ring complex, the method according to any one of embodiments 1 to 66.

[0271] Embodiment 78 Administering the platinum-based anticancer agent and the pentaazamacrocyclic ring complex to a subject, and then delaying radiotherapy that may be appropriately administered to the subject until at least 6 months after the final administration of the pentaazamacrocyclic ring complex, the method according to any one of embodiments 1 to 66.

[0272] Embodiment 79 The cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, urothelial carcinoma, bladder cancer, pancreatic cancer, head and neck cancer, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, and oral squamous cell carcinoma, the method according to any one of embodiments 1 to 78.

[0273] Embodiment 80 The cancer is selected from the group consisting of breast cancer, lung cancer, renal cell carcinoma, spindle cell carcinoma, colorectal cancer, oral squamous cell carcinoma, and head and neck cancer, the method according to any one of embodiments 1 to 79.

[0274] Embodiment 81 The cancer is at least one of lung cancer and head and neck cancer, the method according to any one of embodiments 1 to 80.

[0275] Embodiment 82 The method according to any one of embodiments 1 to 81, wherein the pentaazamacrocyclic ring complex is administered to the subject at a dose in the range of 0.2 mg / kg to 40 mg / kg.

[0276] Embodiment 83 The method according to any one of embodiments 1 to 82, wherein the pentaazamacrocyclic ring complex is administered to the subject at a dose in the range of 0.2 mg / kg to 24 mg / kg.

[0277] Embodiment 84 The method according to any one of embodiments 1 to 83, wherein the pentaazamacrocyclic ring complex is administered to the subject at a dose in the range of 0.2 mg / kg to 10 mg / kg.

[0278] Embodiment 85 The method according to any one of embodiments 1 to 84, wherein the pentaazamacrocyclic ring complex is administered by at least one of a parenteral route and an oral route.

[0279] Embodiment 86 The method according to any one of embodiments 1 to 85, wherein the pentaazamacrocyclic ring complex is administered intraperitoneally or intravenously.

[0280] Embodiment 87 The method according to any one of embodiments 1 to 86, wherein the subject is a human.

[0281] Embodiment 88 A kit for treating cancer in a mammalian subject in need of treatment and / or reduction, and / or reducing the toxic effects of a platinum-based anti-cancer agent, comprising: The platinum-based anti-cancer agent; A pentaazamacrocyclic ring complex corresponding to the following formula (I): and Instructions for administering a therapeutically effective amount of the platinum-based anti-cancer agent and a therapeutically effective amount of the pentaazamacrocyclic ring complex for carrying out the method according to any one of the preceding claims, A kit, wherein the pentaazamacrocyclic ring complex according to formula (I) is as follows: [Chemical formula] (I) [wherein, M is Mn 2+ or Mn 3+ ; and R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), a moiety selected from the group consisting of, where R 11 and R 12 are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocyclic ring having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocyclic ring, the hydrogen attached to the nitrogen which is part of both the heterocyclic ring and the macrocyclic ring, and R1 and R attached to the carbon atoms which are part of both the heterocyclic ring and the macrocyclic ring 10 shall be considered non-existent; X and Y each represent any suitable ligand derived from a monodentate or polydentate ligand or ligand system, or the corresponding anion; Z is a counterion; n is an integer from 0 to 3; and the dotted line represents a coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

Claims

**Claim 1** A therapeutic agent for treating and / or reducing a toxic effect selected from the group consisting of nephrotoxicity and myelotoxicity associated with treatment with a platinum-based anticancer agent in a mammalian subject in need thereof, and / or for reducing the risk of said toxic effect, the agent comprising a pentaazamacrocyclic ring complex which is a compound represented by the formula: 【Chemical Formula 1】 wherein: the subject has cancer, in the subject who is to receive administration of a platinum-based anticancer agent, essentially administering said pentaazamacrocyclic ring complex at a dose sufficient to reduce the toxic effect of said platinum-based anticancer agent before, simultaneously with, or after administration of said platinum-based anticancer agent. A therapeutic agent for a treatment consisting of this. **Claim 2** The therapeutic agent according to claim 1, wherein the subject suffers from nephrotoxicity and / or myelotoxicity associated with treatment with the platinum-based anticancer agent. **Claim 3** The therapeutic agent according to claim 1 or 2, wherein the pentaazamacrocyclic ring complex is administered at a dose sufficient to enhance the therapeutic responsiveness to the platinum-based anticancer agent. **Claim 4** The therapeutic agent according to any one of claims 1 to 3, wherein the pentaazamacrocyclic ring complex is administered at a dose sufficient to enhance a cancer response corresponding to any one selected from the group consisting of a decrease in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or degree of metastasis, and a decrease in cancer cell proliferation, and / or to reduce cancer complications. **Claim 5** The therapeutic agent according to any one of claims 1 to 4, wherein the pentaazamacrocyclic ring complex is administered at a dose sufficient to reduce the level of at least one of creatinine and blood urea nitrogen (BUN). **Claim 6** The therapeutic agent according to any one of claims 1 to 5, wherein the pentaazamacrocyclic ring complex is administered at a dose sufficient to reduce the level of a marker for kidney injury selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL). **Claim 7** The therapeutic agent according to any one of claims 1 to 6, wherein the platinum-based anticancer agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatine, phenanthriplatin, prolindac, triplatin tetranitrate, picoplatin, satraplatin, pyriplatin, and / or pharmaceutically acceptable salts thereof.

8. The therapeutic agent according to any one of claims 1 to 7, wherein the platinum-based anticancer agent contains cisplatin.

9. The anti-cancer agent based on platinum is used so as to be administered at a dose in the range of 20 mg / m ２ to 200 mg / m ２ The therapeutic agent according to any one of claims 1 to 8, characterized in that it is used.

10. The therapeutic agent according to any one of claims 1 to 9, wherein the administration of the pentaazamacrocyclic ring complex in the treatment process is used to be administered for a certain period before the administration of the platinum-based anticancer agent.

11. The therapeutic agent according to any one of claims 1 to 10, wherein the administration of the pentaazamacrocyclic ring complex in the treatment process is used to be administered at least one week before, one day before, or one hour before the administration of the platinum-based anticancer agent.

12. The therapeutic agent according to any one of claims 1 to 11, wherein the administration of the pentaazamacrocyclic ring complex in the treatment process is used to be administered within one hour before and / or simultaneously with the administration of the platinum-based anticancer agent.

13. The therapeutic agent according to any one of claims 1 to 12, wherein the administration of the pentaazamacrocyclic ring complex in the treatment process is used to be administered within one hour, one day, or one week after the administration of the platinum-based anticancer agent.

14. The therapeutic agent according to any one of claims 1 to 13, wherein the cancer is at least one of lung cancer and head and neck cancer.

15. The therapeutic agent according to any one of claims 1 to 14, wherein the pentaazamacrocyclic ring complex is used to be administered to the subject at a dose in the range of 0.2 mg / kg to 40 mg / kg.

16. The therapeutic agent according to any one of claims 1 to 15, wherein the pentaazamacrocyclic ring complex is used to be administered to the subject at a dose in the range of 0.2 mg / kg to 24 mg / kg.

17. The therapeutic agent according to any one of claims 1 to 16, wherein the pentaazamacrocyclic ring complex is used to be administered to the subject at a dose in the range of 0.2 mg / kg to 10 mg / kg.

18. The therapeutic agent according to any one of claims 1 to 17, wherein the subject is a human.

19. An anti-cancer agent essentially based on platinum; Formula: [Chemical Formula 2] The therapeutic agent according to any one of claims 1 to 18, comprising a pentaazamacrocyclic ring complex which is a compound represented by: and A kit comprising the anti-cancer agent based on platinum and instructions for administering the pentaazamacrocyclic ring complex.

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