MGMT is a DNA repair protein that interferes with the cytotoxic action of alkylating chemotherapy agents. Because of the prevalence of this protein in tumors, especially brain tumors, there is a great need for the discovery of an inhibitor that will not harm bone marrow stem cells. This invention has solved this problem through the discovery of a novel use for an existing FDA approved drug used for the treatment of alcoholism, disulfiram.
• Cancer Therapeutics
Features, Benefits, and Advantages:
The alcohol aversion drug disulfiram (DSF) reacts and conjugates with the protein-bound nucleophilic cysteines and is known to elicit anticancer effects alone or improve the efficacy of many cancer drugs. This invention investigated the effects of disulfiram on human MGMT, a DNA repair protein and chemotherapy target that removes the mutagenic O6-akyl groups from guanines, and thus confers resistance to alkylating agents in brain tumors. Treatment with DSF inhibited the MGMT activity in two brain tumor cell lines in a rapid and dose-dependent manner. DSF was a weaker inhibitor of MGMT, compared to the established O6-benzylguanine, nevertheless, the 24-36 h suppression of MGMT activity in cell cultures vastly increased the alkylation-induced DNA interstrand crosslinking, G2/M cell cycle blockade, cytotoxicity, and the levels of apoptotic markers.
• Increased efficacy of cancer treatment
• Decreased side-effects, as compared to existing MGMT inhibitors
This technology has been produced and tested.