Drug metabolism in carcinogenesis and cancer chemotherapy

Cytotoxic drugs have become invaluable for the clinical oncologist in the treatment of neoplastic disease. Frequently, these therapeutic agents are used in combination in order to combat the heterogeneity imposed by the variable tumor cell biochemistry of the neoplastic cell population. Hence, one could argue polypharmacy has become the rule rather than the exception in cancer chemotherapy. The use of such regimens obviously increases the potential for drug-drug interactions and also may potentiate the effects of interindividual variation in drug metabolism. Altered expression of drug metabolizing enzymes may also predispose certain individuals to cancer through enhanced metabolic activation and decreased detoxication of environmental, dietary and possibly endogenous procarcinogens. Many anticancer drugs can be considered as prodrugs which require metabolic activation to exert their selective cytotoxic effects. Recent molecular and biochemical advances have increased our understanding of the factors which govern the regulation of drug metabolizing enzymes and have improved our knowledge of the metabolism and action of anticancer agents. The aim of this review is not to exhaustively document all the work in the area of drug metabolism in relation to cancer, but to provide a comprehensive update of some of the recent advances in drug metabolism which have helped to rationalize the mechanism of action of some anticancer drugs and which may help to optimize future patient selection for certain novel chemotherapeutic regimens. This review also discusses some of the more recent breakthroughs in the area of carcinogenesis and highlights directions for future studies.