CA2384059A1 - Method of treating cancer using tetraethyl thiuram disulfide - Google Patents

Method of treating cancer using tetraethyl thiuram disulfide Download PDF

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Publication number
CA2384059A1
CA2384059A1 CA002384059A CA2384059A CA2384059A1 CA 2384059 A1 CA2384059 A1 CA 2384059A1 CA 002384059 A CA002384059 A CA 002384059A CA 2384059 A CA2384059 A CA 2384059A CA 2384059 A1 CA2384059 A1 CA 2384059A1
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Prior art keywords
thiuram disulfide
administered
cancer
dosage
heavy metal
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CA002384059A
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French (fr)
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CA2384059C (en
Inventor
Thomas Preston Kennedy
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CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY D/B/A CAROLINAS MEDICAL CENTE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/36—Arsenic; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y116/00—Oxidoreductases oxidizing metal ions (1.16)
    • C12Y116/03—Oxidoreductases oxidizing metal ions (1.16) with oxygen as acceptor (1.16.3)
    • C12Y116/03001—Ferroxidase (1.16.3.1), i.e. ceruloplasmin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof

Abstract

Dithiocarbamate, particularly tetraethylthiuram disulfide strongly inhibits the growth of cancer cells of a variety of cell types. Such inhibitory effec t is enhanced by heavy metal ions such as copper ions, cytokines and ceruloplasmin. A method is presented for using tetraethylthiuram disulfide t o reduce tumor growth, and to potentiate the effect of other anticancer agents .

Claims (53)

1 . A method for treating established cancer in a mammal comprising administering to said mammal a therapeutically effective amount of a thiuram disulfide and a heavy metal ion.
2. The method of Claim 1, wherein said thiuram disulfide is a tetraalkyl thiuram disulfide.
3. The method of Claim 1, wherein said tetraalkyl thiuram disulfide is tetraethyl thiuram disulfide.
4. The method of Claim 1, wherein said heavy metal ion is administered as a complex with said thiuram disulfide.
5. The method of Claim 1, wherein said heavy metal ion is selected from the group consisting of ions of arsenic, bismuth, cobalt, copper, chromium, gallium, gold, iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc.
6. The method of Claim 1, wherein said heavy metal ion is selected from the group consisting of ions of gold, silver, and zinc.
7. The method of Claim 1, wherein said heavy metal ion is a copper ion.
8. The method of Claim 1, wherein the thiuram disulfide and the heavy metal ion are administered orally.
9. The method of Claim 1, wherein said thiuram disulfide and said heavy metal ion are administered intravenously.
10. The method of Claim 1, wherein said thiuram disulfide is administered a dosage of from about 125 to about 1000 mg.
11. The method of Claim 1, wherein the cancer is melanoma, lung cancer, breast cancer, or prostatic carcinoma.
12. The method of Claim 1, wherein said thiuram disulfide and said heavy metal ion are administered in combination with another anticancer agent.
13. The method of Claim 12, wherein said other anticancer agent is selected from group consisting of cisplatin, carboplatin, cyclophosphamide, nitrosoureas, fotemustine, herceptin, carmustine, vindesine, etoposide, daunorubicin, adriamycin, taxol, taxotere, fluorouracil, methotrexate, melphalan, bleomycin, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, maprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin, and doxirubincin.
14. The method of Claim 12, wherein said other anticancer agent is cisplatin or carmustine.
15. A method for treating in human established cancer selected from the group consisting of melanoma, lung cancer, breast cancer, and prostatic carcinoma, said method comprising administering to said human a complex of tetraethyl thiuram disulfide and copper ion at a dosage of from about 125 to about 1000 mg.
16. A method for treating established cancer in a mammal comprising administering to said mammal a therapeutically effective amount of a thiuram disulfide and a cytokine selected from the group consisting of interferon .alpha., interferon .beta., interferon .gamma., and IL-6.
17. The method of Claim 16, wherein said thiuram disulfide is a tetraalkyl thiuram disulfide.
18. The method of Claim 16, wherein said thiuram disulfide is tetraethyl thiuram disulfide.
19. The method of Claim 16, wherein said thiuram disulfide is administered orally.
20. The method of Claim 16, wherein said thiuram disulfide and said cytokine are administered intravenously.
21. The method of Claim 16, wherein said thiuram disulfide is administered a dosage of from about 125 to about 1000 mg.
22. The method of Claim 16, wherein said IL-6 is administered at a dosage of from about 1 to about 100 mg/Kg per day.
23. The method of Claim 16, wherein the interferon .alpha. is administered at a dosage of about 3 x 10 6 to 8 x 10 6 international units per day.
24. The method of Claim 16, wherein the interferon .beta. is administered at a dosage of from about 15 to about 60 µg per day.
25. The method of Claim 16, wherein the interferon .gamma. is administered at a dosage of from about 50 to about 250 µg per day.
26. The method of Claim 16, wherein the cancer is melanoma, lung cancer, breast cancer, or prostatic carcinoma.
27. The method of Claim 16, further comprising administering to said mammal a therapeutically effective amount of another anticancer agent.
28. The method of Claim 27, wherein said other anticancer agent is selected from group consisting of cisplatin, carboplatin, cyclophosphamide, nitrosoureas, fotemustine, herceptin, carmustine, vindesine, etoposide, daunorubicin, adriamycin, taxol, taxotere, fluorouracil, methotrexate, melphalan, bleomycin, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, maprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin, and doxirubincin.
29. The method of Claim 27, wherein the other anticancer agent is cisplatin or carmustine.
30. A method for treating established cancer in a mammal comprising administering to said mammal a therapeutically effective amount of a thiuram disulfide and ceruloplasmin.
31. The method of Claim 30, wherein said thiuram disulfide is a tetraalkyl thiuram disulfide.
32. The method of Claim 31, wherein said tetraalkyl thiuram disulfide is tetraethyl thiuram disulfide.
33. The method of Claim 30, wherein said thiuram disulfide is administered orally.
34. The method of Claim 30, wherein said thiuram disulfide and said ceruloplasmin are administered intravenously.
35. The method of Claim 30, wherein said thiuram disulfide is administered a dosage of from about 125 to about 1000 mg.
36. The method of Claim 30, wherein said ceruloplasmin is administered at a dosage of from about 5 to about 30 mg per day.
37. The method of Claim 30, wherein the established cancer is melanoma, lung cancer, breast cancer, or prostatic carcinoma.
38. The method of Claim 30, further comprising administering to the mammal a therapeutically effective amount of another anticancer agent.
39. The method of Claim 38, where the other anticancer agent is ciplatin or carmustine.
40. A method for treating an established cancer of melanoma, lung cancer, breast cancer, or prostatic carcinoma in a human, comprising administering to said human tetraethyl thiuram disulfide at a dosage of from about 125 to about 1000 mg, and ceruloplasmin at an amount of from about 5 to about 30 mg per day.
41. A method for treating established cancer in a mammal comprising administering to said mammal a therapeutically active amount of a thiuram disulfide.
42. The method according to Claim 41, wherein the established cancer is melanoma, lung cancer, breast cancer, or prostatic carcinoma.
43. The method of Claim 41, wherein said thiuram disulfide is a tetraalkyl thiuram disulfide.
44. The method of Claim 41, wherein said thiuram disulfide is tetraethyl thiuram disulfide.
45. The method of Claim 41, wherein said tetraethyl thiuram disulfide is administered at a dosage of from about 125 to about 1000 mg.
46. The method of Claim 41, wherein said thiuram disulfide is administered orally.
47. The method of Claim 41, wherein said thiuram disulfide is administered in combination with another anticancer agent.
48. A method for treating an established cancer in human selected from the group consisting of melanoma, lung cancer, breast cancer, and prostatic carcinoma, said method comprising administering to said human tetraethyl thiuram disulfide at a dosage of from about 125 to about 1000 mg.
49. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a complex between a thiuram disulfide and a heavy metal ion.
50. The pharmaceutical composition of Claim 49, wherein said thiuram disulfide is tetraethyl thiuram disulfide.
51. The composition of Claim 49, wherein said heavy metal ion is selected from the group consisting of gold, silver, selenium and zinc ions.
52. The composition of Claim 49, wherein said heavy metal ion is a copper ion.
53. The composition of Claim 49, further comprising another anticancer agent.
CA2384059A 1999-09-08 1999-11-15 Method of treating cancer using tetraethyl thiuram disulfide Expired - Lifetime CA2384059C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/392,122 US6589987B2 (en) 1998-09-08 1999-09-08 Method of treating cancer using tetraethyl thiuram disulfide
US09/392,122 1999-09-08
PCT/US1999/027193 WO2001017522A1 (en) 1999-09-08 1999-11-15 Method of treating cancer using tetraethyl thiuram disulfide

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CA2384059A1 true CA2384059A1 (en) 2001-03-15
CA2384059C CA2384059C (en) 2010-06-22

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US (1) US6589987B2 (en)
EP (1) EP1214063B1 (en)
JP (1) JP2003514769A (en)
AT (1) ATE300291T1 (en)
AU (1) AU782029B2 (en)
CA (1) CA2384059C (en)
DE (1) DE69926407T2 (en)
ES (1) ES2244237T3 (en)
WO (1) WO2001017522A1 (en)

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Publication number Publication date
ES2244237T3 (en) 2005-12-01
DE69926407D1 (en) 2005-09-01
JP2003514769A (en) 2003-04-22
CA2384059C (en) 2010-06-22
AU782029B2 (en) 2005-06-30
US6589987B2 (en) 2003-07-08
AU2025500A (en) 2001-04-10
DE69926407T2 (en) 2006-05-24
ATE300291T1 (en) 2005-08-15
WO2001017522A1 (en) 2001-03-15
EP1214063A1 (en) 2002-06-19
US20030065026A1 (en) 2003-04-03
EP1214063B1 (en) 2005-07-27

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