The therapeutic potential of O6-alkylguanine DNA alkyltransferase inhibitors.

Resistance to O(6-)alkylating agents can be overcome by depletion of the DNA repair protein, O(6)-alkylguanine DNA alkyltransferase. Inhibitors of this protein act as pseudosubstrates and, so far, O(6)-benzylguanine and lomeguatrib have been tested in clinical trials. Inherently non-toxic, optimum doses for protein depletion have been established for both agents. Myelosuppression of alkylating agents is significantly enhanced when used in combination with these agents, necessitating significant reductions in standard doses. Consequently, no improvement in efficacy is seen. Strategies to limit myelotoxicity are complex and will be very difficult to apply clinically. O(6)-alkylguanine DNA alkyltransferase inhibition may also potentiate the toxicity of other agents such as cyclophosphamide and irinotecan. Other mechanisms of DNA repair are also important and drugs targeting some of these systems are in early phase clinical trials.