This invention generally relates to methods of treating cancer, and particularly to methods of treating cancer using dithiocarbamate.
Cancer, the uncontrolled growth of malignant cells, is a major health problem of the modern medical era and ranks second only to heart disease as a cause of death in the U.S. While some malignancies, such as adenocarcinoma of the breast and lymphomas such as Hodgkins Disease, respond relatively well to current chemotherapeutic antineoplastic drug regimens, other cancers are poorly responsive to chemotherapy, especially non-small cell lung cancer and pancreatic, prostate and colon cancers. Even small cell cancer of the lung, initially chemotherapy sensitive, tends to return after remission, with widespread metastatic spread leading to death of the patient. Thus, better treatment approaches are needed for this illness. Also, because almost all currently available antineoplastic agents have significant toxicities, such as bone marrow suppression, renal dysfunction, stomatitis, enteritis and hair loss, it would be of major advantage to have a relatively less toxic agent available for use alone or in combination with current drugs in order to better treat the patient without risking injury from the therapy itself.
Recently, dithiocarbamates containing a reduced sulfhydryl group, e.g., pyrrolidinedithiocarbamate, (PDTC) have been shown to inhibit the proliferation of cultured vascular smooth muscle cells as well as cultured colorectal cancer cells. See, e.g, Tsai et al., J. Biol. Chem. 271:3667-3670 (1996); Chinery et al., Nature Med. 11: 1233-1241 (1997); Chinery et al., Cancer Res. 58:2323-2327 (1998). It has been suggested that antioxidants having a reduced sulfhydryl group may be used in treating colorectal cancer.
Dithiocarbamates such as pyrrolidinedithiocarbamate (PDTC) and diethyldithiocarbamate (DEDC) have also been reported to inhibit apoptosis in different cell types, e.g., in rat thymocytes and Jurkat T lymphocytes, in short-term incubations. See, e.g. Nobel et al. Chem. Res. Toxicol. 10(6):636-643 (1997). In this article, it is disclosed that copper is required in the inhibition of apoptosis by PDTC and DEDC. It is also disclosed that thiuram disulfides such as disulfiram (oxidized disulfide of diethyldithiocarbamate which does not contain a reduced sulfhydryl group) are much more potent apoptosis inhibitors than PDTC or DEDC. In addition, as compared to the reduced molecules, disulfiram inhibition of thymocyte apoptosis is not dependent on copper.
In another report, it is however reported that upon long-term incubation with rat thymocytes, both the reduced dithiocarbamates and their disulfides are capable of inducing apoptosis. See Burkitt et al. Arch. Biochem. Biophysics 353(1):73-84 (1998). However, reduced dithiocarbamates requires copper, while the thiuram disulfide induction of apoptosis is essentially not affected by the removal of copper ions. It is suggested that copper ions are required for oxidizing dithiocarbamates to thiuram disulfides but not required for the apoptosis-inducing effect of thiuram disulfides. See Nobel et al. J. Biol. Chem. 270:26202-26208 (1995); Burkitt et al. Arch. Biochem. Biophysics 353(1):73-84 (1998).
The antioxidant effect of disulfiram has also been studied in the art. Rao et al. Jpn. J. Cancer Res. 80(12) 1171-5 (1989) examines the effect of disulfiram on transmammary carcinogenesis induction in mice by anthracene. It is disclosed that tumor incidence associated with anthracene is lower in nursing mother mice pretreated with disulfiram than those untreated. It is suggested that disulfiram can counteract the effect of carcinogen anthracene and thus inhibiting transmammary carcinogenesis in mice.
Mashiba et al. Toxicol. Lett. 61(1):75-80 (1992) discloses that the combined use of disulfiram with the antioxidant enzyme catalase induces inhibition of cell proliferation. It is suggested that the antiproliferation effect is due to the formation of compounds or metabolites with cytostatic activity as a result of the reaction of disulfiram with catalase.
Mashiba et al. Jpn J. Exp. Med. 60(4):209-14 (1990) studies the roles of oxygen free radicals in the inhibition of tumor cell proliferation. Disulfiram is used as a metal chelator to inactivate superoxide dismutase. Ascorbic acid is employed to inhibit catalase. It is disclosed that Meth A tumor cell proliferation is inhibited upon simultaneous addition of disulfiram and ascorbic acid. It is suggested that the combined use of disulfiram and ascorbic acid increases the intracellular oxygen free radicals within tumor cells.
The present invention provides a method for treating established cancer using disulfiram, either alone, or in combination with a heavy metal ion or a stimulant of a heavy metal ion.
It has been discovered that thiuram disulfide alone exhibits potent inhibitory effect on established tumor cells in absence of catalase or ascorbic acid. Disulfiram is even effective in inhibiting the growth of established melanomas cells and non-small cell lung cancer cells, which are known to be poorly responsive to currently available antineoplastic agents.
In addition, in contrast to the prior art teachings discussed above, it has further been surprisingly discovered that the antiproliferative and antineoplastic effect of disulfiram on established tumor cells is heavy metal ion-dependent. Further, the tumor cell growth inhibition effect of disulfiram can be significantly enhanced by the addition of heavy metal ions such as copper, zinc, gold, and silver ions, or a heavy metal ion stimulant, e.g., ceruloplasmin or a cytokine which can induce an acute phase response in the tumor cells.
Accordingly, this invention provides a method for treating established cancer in a patient by administering to the patient a therapeutically effective amount of a thiuram disulfide. Advantageously, a tetralkylthiuram disulfide such as tetraethylthiuram disulfide, better known as disulfiram is used.
In accordance with another aspect of this invention, a method for treating established cancer in a patient is provided comprising administering to the patient a therapeutically effective amount of a thiuram disulfide, preferably disulfiram, and a heavy metal ion. In a preferred embodiment, the heavy metal ion is administered as a complex or chelate with the thiuram disulfide. Suitable heavy metal ions include but are not limited to ions of arsenic, bismuth, cobalt, copper, chromium, gallium, gold, iron, manganese, nickel, silver, titanium, vanadium, selenium, and zinc. In another preferred embodiment, the thiuram disulfide and the heavy metal ion are administered in combination with another anticancer agent.
In accordance with another aspect of this invention, a method for treating established cancer in a patient is provided which comprises administering to the patient a therapeutically effective amount of a thiuram disulfide and a cytokine such as interferon xcex1, interferon xcex2, interferon xcex3, and IL-6. Advantageously, the thiuram disulfide administered is a tetraalkyl thiuram disulfide, preferably disulfiram. In addition, another anticancer agent can also be administered to the patient for a combination therapy.
In accordance with yet another aspect of this invention, the method for treating established cancer in a patient comprises administering to the patient a therapeutically effective amount of a thiuram disulfide, preferably disulfiram, and ceruloplasmin.
In addition, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier, and a complex between a thiuram disulfide and a heavy metal ion. Optionally, the composition can further contain another anticancer agent.
The active compounds of this invention can be administered through a variety of administration routes. For example, they can be administered orally, intravenously, indermally, subcutaneously and topically.
The present invention is effective for treating various types of cancer, including but not limited to melanoma, non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, breast cancer, pancreatic cancer, gastric cancer, bladder cancer, ovarian cancer, uterine cancer, lymphoma, and prostate cancer. In particular, the present invention will be especially effective in treating melanoma, lung cancer, breast cancer, and prostate carcinoma.
Thiuram disulfides such as disulfiram have been used clinically for many years in treating various other diseases such as alcohol abuse, and have been proved to be relatively non-toxic and safe. (Disulfiram is available as an oral formulation in the U.S. as Antabuse(copyright) from Wyeth-Ayerst Laboratories, Philadelphia, Pa.). Thus, the use of thiuram disulfides in this invention offers a readily available and easily used treatment for cancers in man and other mammals.