Anti-cancer activity augmentation compounds and formulations and methods of use thereof

Abstract

The field of the present invention comprises pharmaceuticals and pharmaceutical treatments, including, for example, (i) compounds and formulations which cause the augmentation of anti-cancer activity (i.e., by enhancement of the lethal cytotoxic action in stimulatory [inducing oxidative stress] and/or depletive [decreasing anti-oxidative capacity] manner) of chemotherapeutic agents, in a selective manner; (ii) methods of administering said anti-cancer augmentation compounds and formulations; (iii) delivery devices containing said anti-cancer augmentation compounds and formulations; and (iv) methods of using said anti-cancer augmentation compounds, formulations, and devices to treat subjects in need thereof.

Description

Claims

1. A method of augmenting the anti-cancer cytotoxic activity of chemotherapeutic agents by acting in an additive or synergistic cytotoxic manner with said chemotherapeutic agent or agents to increase intracellular oxidative stress within cancer cells, wherein said method comprises administering to a subject who has received one or more chemotherapeutic agents an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention at a rate of about 0.1 g/min. to about 2.0 g/min.

2. The method of claim 1, wherein said dithio-containing compound of the present invention is administered at a rate of about 0.2 g/min. to about 1.0 g/min.

3. The method of claim 1, wherein said dithio-containing compound of the present invention is administered at a rate of about 0.7 g/min.

4. The method of any one of claims 1, 2 or 3, wherein said dithio-containing compound is administered over a period of about 45 minutes.

5. The method of any one of claims 1, 2 or 3, wherein said dithio-containing compound of the present invention is administered at a concentration of about 100 mg/mL.

6. The method of any one of claims 1, 2 or 3, wherein said dithio-containing compound of the present invention is administered over a period of about 45 minutes, at a concentration of about 100 mg/mL.

7. The method of any one of claims 1, 2 or 3, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every five weeks.

8. The method of claim 1, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every three weeks.

9. The method of claim 1, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every two weeks.

10. The method of claim 1, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every week.

11. The method of claim 1, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: about once every day, about once every two days, about once every three days, about once every four days, once about every five days, or about once every six days.

12. The method of any one of claims 1, 2, or 3, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: at least once in an approximately 24 hour period; at least once in an approximately 48 hour period; at least about once every three days; at least about once every four days; at least about once every five days; at least about once every six days; at least about once a week; at least about once every 1.5 weeks or less; at least about once every 2 weeks or less; at least about once every 2.5 weeks or less; at least about once every 3 weeks or less; at least about once every 3.5 weeks or less; at least about once every 4 weeks or less; at least about once every 5 weeks or less; at least once at any time interval between one day and five weeks; or at least once at a time interval of more than every five weeks.

13. The method of claim 1, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention is caused by a prevention and/or reduction in the normal increase or responsiveness in the concentration and metabolism of glutathione, cysteine, and other physiological cellular thiols.

14. The method of claim 1, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention is caused by thioredoxin inactivation, thereby increasing apoptotic sensitivity and decreasing mitogenic/cellular replication signaling.

15. The method of claim 1, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention is caused by a key metabolite of said dithio-containing compound, such as 2-mercapto ethane sulfonate, which possesses intrinsic cytotoxic activity and causes apoptosis in tumors.

16. The method of claim 1, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention is caused by reducing the oxidative potential or by compromising the anti-oxidative response of tumor cells and enhancing the oxidative biological state and oxidative damage in tumor cells exposed to chemotherapeutic agents, thereby enhancing the cytotoxic and apoptotic function of said chemotherapeutic agents.

17. The method of claim 1, wherein said chemotherapeutic agent or agents are selected from a group consisting of: fluropyrimidine; a pyrimidine nucleoside; a purine nucleoside; an antifolate, a platinum analog; an anthracycline/anthracenedione; an epipodophyllotoxin; a camptothecin; a hormone; a hormonal analog; an antihormonal; an enzyme, protein, peptide, or polyclonal or monoclonal antibody; a vinca alkaloid; a taxane; an epothilone; an antimicrotubule agent; an alkylating agent; an antimetabolite; a topoisomerase inhibitor; an aziridine-containing compound; an antiviral; or another cytotoxic and/or cytostatic agent.

18. The method of claim 1, wherein the chemotherapeutic agent is a taxane analog.

19. The method of claim 1, wherein the chemotherapeutic agent is docetaxel.

20. The method of claim 1, wherein the chemotherapeutic agent is paclitaxel.

21. The method of claim 1, wherein the chemotherapeutic agent is a platinum analog.

22. The method of claim 1, wherein the chemotherapeutic agent is cisplatin.

23. The method of claim 1, wherein the chemotherapeutic agent is carboplatin.

24. The method of claim 1, wherein the chemotherapeutic agent is oxaliplatin.

25. The method of claim 1, wherein said method is utilized for the treatment of a subject with cancer.

26. The method of claim 25, wherein said subject is human.

27. The method of claim 25 or claim 26, wherein said method is utilized for treating any one or more cancers selected from the group consisting of: ovary, breast, lung, esophagus, bladder, stomach, pancreas, liver (e.g., bile ducts, gall bladder, and Ampulla of Vater), testes, germ cell, bone, cartilage, head, neck, oral mucosa, colorectal area, anus, kidney, uroepithelium, central nervous system, prostate, endometrium, cervix, uterus, fallopian tube, peripheral nervous system, and various other cancers including melanoma, mesothelioma, myeloma, lymphoma, leukemia, and Kaposi's sarcoma.

28. The method of claim 1, wherein said method further comprises the prevention, reduction or mitigation of one or more toxicities associated with administration of said chemotherapeutic agent or agents.

29. The method of claim 1, wherein the augmentation of the anti-cancer activity of the chemotherapeutic agent allows said chemotherapeutic agent to be administered at a lower dose, while still achieving the same degree of clinical efficacy as would be obtained with the administration of a higher dose.

30. The method of claim 1, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

31. The method of claim 1, wherein said dithio-containing compound of the present invention is a pharmaceutically-acceptable salt.

32. The method of claim 31, wherein said salt is a disodium salt.

33. The method of claim 31, wherein said salt is selected from the group consisting of: a monosodium salt, a sodium potassium salt, a dipotassium salt, a calcium salt, a magnesium salt, a manganese salt, a monopotassium salt, or an ammonium salt.

34. The method claim 1, further comprising administering a pre-therapy treatment at least one day prior to chemotherapy, prior to each chemotherapy treatment, immediately prior to each chemotherapy treatment, concomitantly with or simultaneously during chemotherapy treatment, immediately subsequent to chemotherapy, or subsequent to chemotherapy.

35. The method of claim 1, further comprising a hydration step.

36. The method of any one of claims 1, 2, or 3, wherein said dithio-containing compound of the present invention is in a form suitable for administration by a method selected from the group consisting of: oral, injection, intra-cavitary, per rectum, and topical administration routes.

37. A method of augmenting the anti-cancer cytotoxic activity of chemotherapeutic agents by acting in an additive or synergistic cytotoxic manner with said chemotherapeutic agent or agents to increase intracellular oxidative stress within cancer cells, wherein said method comprises administering to a subject who has received one or more chemotherapeutic agents an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention at a rate of about 1 mg/mL/min. to about 50 mg/mL/min.

38. The method of claim 37, wherein said dithio-containing compound of the present invention is administered at a rate of about 1 mg/mL/min. to about 20 mg/mL/min.

39. The method of claim 37, wherein said dithio-containing compound of the present invention is administered at a rate of about 7 mg/mL/min.

40. The method of any one of claims 37, 38, or 39, wherein said dithio-containing compound of the present invention is administered over a period of about 45 minutes.

41. The method of any one of claims 37, 38, or 39, wherein said dithio-containing compound of the present invention is administered at a concentration of about 100 mg/mL.

42. The method of any one of claims 37, 38, or 39, wherein said dithio-containing compound of the present invention is administered over a period of about 45 minutes, at a concentration of about 100 mg/mL.

43. The method of any one of claims 37, 38, or 39, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every five weeks.

44. The method of claim 37, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every three weeks.

45. The method of claim 37, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every two weeks.

46. The method of claim 37, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every week.

47. The method of claim 37, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: about once every day, about once every two days, about once every three days, about once every four days, once about every five days, or about once every six days.

48. The method of any one of claim 37, 38, or 39, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: at least once in an approximately 24 hour period; at least once in an approximately 48 hour period; at least about once every three days; at least about once every four days; at least about once every five days; at least about once every six days; at least about once a week; at least about once every 1.5 weeks or less; at least about once every 2 weeks or less; at least about once every 2.5 weeks or less; at least about once every 3 weeks or less; at least about once every 3.5 weeks or less; at least about once every 4 weeks or less; at least about once every 5 weeks or less; at least once at any time interval between one day and five weeks; or at least once at a time interval of more than every five weeks.

49. The method of claim 37, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention is caused by a prevention and/or reduction in the normal increase or responsiveness in the concentration and metabolism of glutathione, cysteine, and other physiological cellular thiols.

50. The method of claim 37, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention is caused by thioredoxin inactivation, thereby increasing apoptotic sensitivity and decreasing mitogenic/cellular replication signaling.

51. The method of claim 37, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention, e.g., 2,2′-dithio-bis-ethane sulfonate is caused by a key metabolite of 2,2′-dithio-bis-ethane sulfonate, 2-mercapto ethane sulfonate, which possesses intrinsic cytotoxic activity and causes apoptosis in tumors.

52. The method of claim 37, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of a dithio-containing compound of the present invention is caused by reducing the oxidative potential or by compromising the anti-oxidative response of tumor cells and enhancing the oxidative biological state and oxidative damage in tumor cells exposed to chemotherapeutic agents, thereby enhancing the cytotoxic and apoptotic function of said chemotherapeutic agents.

53. The method of claim 37, wherein said chemotherapeutic agent or agents are selected from a group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

54. The method of claim 37, wherein the chemotherapeutic agent is a taxane analog.

55. The method of claim 37, wherein the chemotherapeutic agent is docetaxel.

56. The method of claim 37, wherein the chemotherapeutic agent is paclitaxel.

57. The method of claim 37, wherein the chemotherapeutic agent is a platinum analog.

58. The method of claim 37, wherein the chemotherapeutic agent is cisplatin.

59. The method of claim 37, wherein the chemotherapeutic agent is carboplatin.

60. The method of claim 37, wherein the chemotherapeutic agent is oxaliplatin.

61. The method of claim 37, wherein said method is utilized for the treatment of a subject with cancer.

62. The method of claim 61, wherein said subject is human.

63. The method of claim 61 or claim 62, wherein said method is utilized for treating any one or more cancers selected from the group consisting of: ovary, breast, lung, esophagus, bladder, stomach, pancreas, liver (e.g., bile ducts, gall bladder, and Ampulla of Vater), testes, germ cell, bone, cartilage, head, neck, oral mucosa, colorectal area, anus, kidney, uroepithelium, central nervous system, prostate, endometrium, cervix, uterus, fallopian tube, peripheral nervous system, and various other cancers including melanoma, mesothelioma, myeloma, lymphoma, leukemia, and Kaposi's sarcoma.

64. The method of any one of claim 37, 38, or 39, wherein said method further comprises the prevention, reduction or mitigation of one or more toxicities associated with administration of said chemotherapeutic agent or agents.

65. The method of any one of claim 37, 38, or 39, wherein the augmentation of the anti-cancer activity of the chemotherapeutic agent allows said chemotherapeutic agent to be administered at a lower dose, while still achieving the same degree of clinical efficacy as would be obtained with the administration of a higher dose.

66. The method of any one of claim 37, 38, or 39, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

67. The method of claim 37, wherein said dithio-containing compound of the present invention is a pharmaceutically-acceptable salt.

68. The method of claim 67, wherein said salt is a disodium salt.

69. The method of claim 67, wherein said salt is selected from the group consisting of: a monosodium salt, a sodium potassium salt, a dipotassium salt, a calcium salt, a magnesium salt, a manganese salt, a monopotassium salt, or an ammonium salt.

70. The method of claim 37, further comprising administering a pre-therapy treatment at least one day prior to chemotherapy, prior to each chemotherapy treatment, immediately prior to each chemotherapy treatment, concomitantly with or simultaneously during chemotherapy treatment, immediately subsequent to chemotherapy, or subsequent to chemotherapy.

71. The method of claim 37, further comprising a hydration step.

72. The method of any one of claims 37, 38, or 39, wherein said dithio-containing compound of the present invention is in a form suitable for administration by a method selected from the group consisting of: oral, injection, intra-cavitary, per rectum, and topical administration routes.

73. A method of augmenting the anti-cancer cytotoxic activity of chemotherapeutic agents by acting in an additive or synergistic cytotoxic manner with said chemotherapeutic agent or agents to increase intracellular oxidative stress within cancer cells, wherein said method comprises administering to a subject who has received one or more chemotherapeutic agents an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention, wherein said composition has an osmolarity of about 0.1- to about 5-times the osmolarity of the osmolarity of the normal plasma of said subject.

74. The method of claim 73, wherein said composition has an osmolarity of about 2- to about 4-times the osmolarity of the normal plasma of said subject.

75. The method of claim 73, wherein said composition has an osmolarity of about 3-times the osmolarity of the osmolarity of the normal plasma of said subject.

76. The method of any one of claims 73, 74, or 75, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every five weeks.

77. The method of claim 73, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every three weeks.

78. The method of claim 73, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every two weeks.

79. The method of claim 73, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every week.

80. The method of claim 73, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: about once every day, about once every two days, about once every three days, about once every four days, once about every five days, or about once every six days.

81. The method of any one of claims 73, 74, or 75, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: at least once in an approximately 24 hour period; at least once in an approximately 48 hour period; at least about once every three days; at least about once every four days; at least about once every five days; at least about once every six days; at least about once a week; at least about once every 1.5 weeks or less; at least about once every 2 weeks or less; at least about once every 2.5 weeks or less; at least about once every 3 weeks or less; at least about once every 3.5 weeks or less; at least about once every 4 weeks or less; at least about once every 5 weeks or less; at least once at any time interval between one day and five weeks; or at least once at a time interval of more than every five weeks.

82. The method of claim 73, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention is caused by a prevention and/or reduction in the normal increase or responsiveness in the concentration and metabolism of glutathione, cysteine, and other physiological cellular thiols.

83. The method of claim 73, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention is caused by thioredoxin inactivation, thereby increasing apoptotic sensitivity and decreasing mitogenic/cellular replication signaling.

84. The method of claim 73, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention, e.g., 2,2′-dithio-bis-ethane sulfonate is caused by a key metabolite of 2,2′-dithio-bis-ethane sulfonate, 2-mercapto ethane sulfonate, which possesses intrinsic cytotoxic activity and causes apoptosis in tumors.

85. The method of claim 73, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention is caused by reducing the oxidative potential or by compromising the anti-oxidative response of tumor cells and enhancing the oxidative biological state and oxidative damage in tumor cells exposed to chemotherapeutic agents, thereby enhancing the cytotoxic and apoptotic function of said chemotherapeutic agents.

86. The method of claim 73, wherein said one or more chemotherapeutic agents are selected from a group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

87. The method of claim 73, wherein the chemotherapeutic agent is a taxane analog.

88. The method of claim 73, wherein the chemotherapeutic agent is docetaxel.

89. The method of claim 73, wherein the chemotherapeutic agent is paclitaxel.

90. The method of claim 73, wherein the chemotherapeutic agent is a platinum analog.

91. The method of claim 73, wherein the chemotherapeutic agent is cisplatin.

92. The method of claim 73, wherein the chemotherapeutic agent is carboplatin.

93. The method of claim 73, wherein the chemotherapeutic agent is oxaliplatin.

94. The method of claim 73, wherein said method is utilized for the treatment of a subject with cancer.

95. The method of claim 94, wherein said subject is human.

96. The method of claim 94 or claim 95, wherein said method is utilized for treating any one or more cancers selected from the group consisting of: ovary, breast, lung, esophagus, bladder, stomach, pancreas, liver (e.g., bile ducts, gall bladder, and Ampulla of Vater), testes, germ cell, bone, cartilage, head, neck, oral mucosa, colorectal area, anus, kidney, uroepithelium, central nervous system, prostate, endometrium, cervix, uterus, fallopian tube, peripheral nervous system, and various other cancers including melanoma, mesothelioma, myeloma, lymphoma, leukemia, and Kaposi's sarcoma.

97. The method of any one of claims 73, 74, or 75, wherein said method further comprises the prevention, reduction or mitigation of one or more toxicities associated with administration of said chemotherapeutic agent or agents.

98. The method of any one of claims 73, 74, or 75, wherein the augmentation of the anti-cancer activity of the chemotherapeutic agent allows said chemotherapeutic agent to be administered at a lower dose, while still achieving the same degree of clinical efficacy as would be obtained with the administration of a higher dose.

99. The method of any one of claims 73, 74, or 75, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

100. The method of claim 73, wherein said dithio-containing compound of the present invention is a pharmaceutically-acceptable salt.

101. The method of claim 100, wherein said salt is a disodium salt.

102. The method of claim 100, wherein said salt is selected from the group consisting of: a monosodium salt, a sodium potassium salt, a dipotassium salt, a calcium salt, a magnesium salt, a manganese salt, a monopotassium salt, or an ammonium salt.

103. The method of claim 73, further comprising administering a pre-therapy treatment at least one day prior to chemotherapy, prior to each chemotherapy treatment, immediately prior to each chemotherapy treatment, concomitantly with or simultaneously during chemotherapy treatment, immediately subsequent to chemotherapy, or subsequent to chemotherapy.

104. The method of claim 73, further comprising a hydration step.

105. The method of any one of claims 73, 74, or 75, wherein said dithio-containing compound of the present invention is in a form suitable for administration by a method selected from the group consisting of: oral, injection, intra-cavitary, per rectum, and topical administration routes.

106. A method of augmenting the anti-cancer cytotoxic activity of chemotherapeutic agents by acting in an additive or synergistic cytotoxic manner with said chemotherapeutic agent or agents to increase intracellular oxidative stress within cancer cells, wherein said method comprises administering to a subject who has received one or more chemotherapeutic agents an effective amount of a pharmaceutically-acceptable form of said dithio-containing compound of the present invention at a rate of about 0.1 g/min to about 4.6 g/min, at a total dose of about 4 g/m2 to about 41 g/m2.

107. The method of claim 106, wherein said dithio-containing compound of the present invention is administered at a rate of about 0.2 g/min. to about 2.0 g/min.

108. The method of claim 106, wherein said dithio-containing compound of the present invention is administered at a rate of about 0.7 g/min.

109. The method of any one of claims 106, 107, or 108, wherein said dithio-containing compound of the present invention is administered over a period of about 45 minutes.

110. The method of any one of claims 106, 107, or 108, wherein said dithio-containing compound of the present invention is administered at a concentration of about 100 mg/mL.

111. The method of any one of claims 106, 107, or 108, wherein said dithio-containing compound of the present invention is administered over a period of about 45 minutes, at a concentration of about 100 mg/mL.

112. The method of any one of claims 106, 107, or 108, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every five weeks.

113. The method of claim 106, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every three weeks.

114. The method of claim 106, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every two weeks.

115. The method of claim 106, wherein said dithio-containing compound of the present invention is administered from about once a day to about once every week.

116. The method of claim 106, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: about once every day, about once every two days, about once every three days, about once every four days, once about every five days, or about once every six days.

117. The method of any one of claims 106, 107, or 108, wherein said dithio-containing compound of the present invention is administered in a time period which is selected from the group consisting of: at least once in an approximately 24 hour period; at least once in an approximately 48 hour period; at least about once every three days; at least about once every four days; at least about once every five days; at least about once every six days; at least about once a week; at least about once every 1.5 weeks or less; at least about once every 2 weeks or less; at least about once every 2.5 weeks or less; at least about once every 3 weeks or less; at least about once every 3.5 weeks or less; at least about once every 4 weeks or less; at least about once every 5 weeks or less; at least once at any time interval between one day and five weeks; or at least once at a time interval of more than every five weeks.

118. The method of claim 106, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention is caused by a prevention and/or reduction in the normal increase or responsiveness in the concentration and metabolism of glutathione, cysteine, and other physiological cellular thiols.

119. The method of claim 106, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention is caused by thioredoxin inactivation, thereby increasing apoptotic sensitivity and decreasing mitogenic/cellular replication signaling.

120. The method of claim 106, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention, e.g., 2,2′-dithio-bis-ethane sulfonate is caused by a key metabolite of 2,2′-dithio-bis-ethane sulfonate, 2-mercapto ethane sulfonate, which possesses intrinsic cytotoxic activity and causes apoptosis in tumors.

121. The method of claim 106, wherein the augmentation of the anti-cancer activity of said chemotherapeutic agent or agents in said subject who has received one or more chemotherapeutic agents, and an effective amount of said dithio-containing compound of the present invention is caused by reducing the oxidative potential or by compromising the anti-oxidative response of tumor cells and enhancing the oxidative biological state and oxidative damage in tumor cells exposed to chemotherapeutic agents, thereby enhancing the cytotoxic and apoptotic function of said chemotherapeutic agents.

122. The method of claim 106, wherein said one or more chemotherapeutic agents are selected from a group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

123. The method of claim 106, wherein the chemotherapeutic agent is a taxane analog.

124. The method of claim 106, wherein the chemotherapeutic agent is docetaxel.

125. The method of claim 106, wherein the chemotherapeutic agent is paclitaxel.

126. The method of claim 106, wherein the chemotherapeutic agent is a platinum analog.

127. The method of claim 106, wherein the chemotherapeutic agent is cisplatin.

128. The method of claim 106, wherein the chemotherapeutic agent is carboplatin.

129. The method of claim 106, wherein the chemotherapeutic agent is oxaliplatin.

130. The method of claim 106, wherein said method is utilized for the treatment of a subject with cancer.

131. The method of claim 130, wherein said subject is human.

132. The method of claim 130 or claim 131, wherein said method is utilized for treating any one or more cancers selected from the group consisting of: ovary, breast, lung, esophagus, bladder, stomach, pancreas, liver (e.g., bile ducts, gall bladder, and Ampulla of Vater), testes, germ cell, bone, cartilage, head, neck, oral mucosa, colorectal area, anus, kidney, uroepithelium, central nervous system, prostate, endometrium, cervix, uterus, fallopian tube, peripheral nervous system, and various other cancers including melanoma, mesothelioma, myeloma, lymphoma, leukemia, and Kaposi's sarcoma.

133. The method of any one of claims 106, 107, or 108, wherein said method further comprises the prevention, reduction or mitigation of one or more toxicities associated with administration of said chemotherapeutic agent or agents.

134. The method of any one of claims 106, 107, or 108, wherein the augmentation of the anti-cancer activity of the chemotherapeutic agent allows said chemotherapeutic agent to be administered at a lower dose, while still achieving the same degree of clinical efficacy as would be obtained with the administration of a higher dose.

135. The method of any one of claims 106, 107, or 108, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

136. The method of claim 106, wherein said dithio-containing compound of the present invention is a pharmaceutically-acceptable salt.

137. The method of claim 136, wherein said salt is a disodium salt.

138. The method of claim 136, wherein said salt is selected from the group consisting of: a monosodium salt, a sodium potassium salt, a dipotassium salt, a calcium salt, a magnesium salt, a manganese salt, a monopotassium salt, or an ammonium salt.

139. The method of claim 106, further comprising administering a pre-therapy treatment at least one day prior to chemotherapy, prior to each chemotherapy treatment, immediately prior to each chemotherapy treatment, concomitantly with or simultaneously during chemotherapy treatment, immediately subsequent to chemotherapy, or subsequent to chemotherapy.

140. The method of claim 106, further comprising a hydration step.

141. The method of any one of claims 106, 107, or 108, wherein said dithio-containing compound of the present invention is in a form suitable for administration by a method selected from the group consisting of: oral, injection, intra-cavitary, per rectum, and topical administration routes.

142. A method of augmenting the anti-cancer activity of chemotherapeutic agents by acting in an additive or synergistic manner with said chemotherapeutic agent or agents to alter the intracellular oxidative/reduction potential within cancer cells, wherein said method comprises administering to a subject with cancer an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention.

143. A method of selectively altering the intracellular oxidative/reduction potential within cancer cells versus normal, non-cancerous cells in order to have a therapeutic effect on a subject with cancer, wherein said method comprises administering to said subject an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention.

144. A method of selectively altering the intracellular oxidative/reduction potential within cancer cells versus normal, non-cancerous cells in order to selectively sensitize the cancer cells of a subject with cancer in order to have a therapeutic effect on said subject, wherein said method comprises administering to said subject with cancer an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention.

145. A method of augmenting the anti-cancer activity of chemotherapeutic agents by acting in an additive or synergistic manner with said chemotherapeutic agent or agents to alter the intracellular oxidative/reduction potential within cancer cells in a subject with cancer, wherein said method comprises administering to a subject who has received, is receiving, or will subsequently receive one or more chemotherapeutic agents, an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention.

146. A method of selectively altering the intracellular oxidative/reduction potential within cancer cells versus normal, non-cancerous cells in order to have a therapeutic effect on a subject with cancer, wherein said method comprises administering to said subject with cancer who has received, is receiving, or will subsequently receive one or more chemotherapeutic agents, an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention.

147. A method of selectively altering the intracellular oxidative/reduction potential within cancer cells versus normal, non-cancerous cells in order selectively sensitize the cancer cells of a subject with cancer in order to have a therapeutic effect on said subject, wherein said method comprises administering to said subject with cancer who has received, is receiving, or will subsequently receive one or more chemotherapeutic agents, an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention.

148. A method of augmenting the anti-cancer activity of chemotherapeutic agents by acting in an additive or synergistic manner with said chemotherapeutic agent or agents to alter the intracellular oxidative/reduction potential within cancer cells in a subject with cancer, wherein said method comprises administering to a subject who has received, is receiving, or will subsequently receive one or more chemotherapeutic agents, an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention at a rate of about 0.1 g/min. to about 2.0 g/min.

149. A method of selectively altering the intracellular oxidative/reduction potential within cancer cells versus normal, non-cancerous cells in order to have a therapeutic effect on a subject with cancer, wherein said method comprises administering to said subject with cancer who has received, is receiving, or will subsequently receive one or more chemotherapeutic agents, an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention at a rate of about 0.1 g/min. to about 2.0 g/min.

150. A method of selectively altering the intracellular oxidative/reduction potential within cancer cells versus normal, non-cancerous cells in order selectively sensitize the cancer cells of a subject with cancer in order to have a therapeutic effect on said subject, wherein said method comprises administering to said subject with cancer who has received, is receiving, or will subsequently receive one or more chemotherapeutic agents, an effective amount of a pharmaceutically-acceptable form of a dithio-containing compound of the present invention at a rate of about 0.1 g/min. to about 2.0 g/min.

151. The method of any one of claims 142 to 150, wherein the dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

152. The method of any one of claims 142 to 151, wherein said one or more chemotherapeutic agents are selected from the group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

153. The method of any one of claims 142 to 150, wherein the one or more cancers are selected from the group consisting of: ovary, breast, lung, esophagus, bladder, stomach, pancreas, liver (e.g., bile ducts, gall bladder, and Ampulla of Vater), testes, germ cell, bone, cartilage, head, neck, oral mucosa, colorectal area, anus, kidney, uroepithelium, central nervous system, prostate, endometrium, cervix, uterus, fallopian tube, peripheral nervous system, and various other cancers including melanoma, mesothelioma, myeloma, lymphoma, leukemia, and Kaposi's sarcoma.

154. A medical device which possesses the ability to administer to a subject with cancer a composition comprising a dithio-containing compound of the present invention which possesses the ability to selectively alter the intracellular oxidative/reduction potential within cancer cells versus normal, non-cancerous cells in order to have a therapeutic effect on said subject, wherein said device utilizes the method set forth in any one of claims 1, 37, 73, 106, 142, or 142 to 150.

155. The medical device of claim 154, wherein said device is an implantable infusion device.

156. The medical device of claim 155, wherein said implantable infusion device is a passive infusion device.

157. The medical device of claim 155, wherein said implantable infusion device is an active infusion device.

158. The device of any one of claim 154-157, wherein said composition further comprises one or more chemotherapeutic agents selected from the group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

159. The medical device of claim 154, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

160. A medical device which possesses the ability to administer to a subject in need thereof a composition comprising a dithio-containing compound of the present invention, wherein said composition is administered to said subject at a rate of about 0.1 g/min. to about 4.6 g/mL/min., for a total dose of about 4 g/m2 to about 41 g/m2.

161. The device of claim 160, wherein said device is an implantable infusion device.

162. The device of claim 161, wherein said implantable infusion device is a passive infusion device.

163. The device of claim 161, wherein said implantable infusion device is an active infusion device.

164. The device of any one of claim 160-163, wherein said composition further comprises one or more chemotherapeutic agents selected from the group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

165. The method of claim 160, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

166. A medical device which possesses the ability to administer to a subject in need thereof a composition comprising a dithio-containing compound of the present invention, wherein said composition is administered to said subject at a rate of about 1 g/mULmin. to about 50 g/mL/min.

167. The medical device of claim 166, wherein said device is an implantable infusion device.

168. The medical device of claim 167, wherein said implantable infusion device is a passive infusion device.

169. The device of claim 167, wherein said implantable infusion device is an active infusion device.

170. The device of any one of claims 166-169, wherein said composition further comprises one or more chemotherapeutic agents selected from the group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

171. The method of claim 166, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.

172. A medical device which possesses the ability to administer to a subject in need thereof a composition comprising a dithio-containing compound of the present invention, wherein said composition is administered to said subject at a rate of about 0.1- to about 5-times the osmolarity of the normal range of plasma osmolarity.

173. The device of claim 172, wherein said device is an implantable infusion device.

174. The device of claim 173, wherein said implantable infusion device is a passive infusion device.

175. The device of claim 173, wherein said implantable infusion device is an active infusion device.

176. The device of any one of claims 172-175, wherein said composition further comprises one or more chemotherapeutic agents selected from the group consisting of: fluropyrimidines, pyrimidine nucleosides, anti-folates, purine nucleosides, nucleotides, platinum analogs, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, hormones and hormonal analogs, antihormones, enzymes, proteins, antibodies, vinca alkaloids, taxanes and taxane analogs, antimicrotubule agents, alkylating agents, epothilones, antimetabolites, topoisomerase inhibitors, aziridine-containing compounds, antiviral agents, monoclonal antibodies, proteins, peptides, enzymes, or cytostatic agents.

177. The method of claim 172, wherein said dithio-containing compound is disodium 2,2′-dithio-bis-ethane sulfonate.