Several widely used anti-cancer drug alkylating agents, including cyclophosphamide, ifosphamide, procarbazine, and thio-TEPA, are oxidatively metabolized to therapeutically significant cytotoxic metabolites in reactions catalyzed by liver cytochrome P450 enzymes. The overall goal of this project is to elucidate the roles played by cytochrome P450 and other drug-metabolizing enzymes in anti-cancer drug biotransformation, and then to apply this information to the development of improved chemotherapeutic regimens based on modulation of competing pathways of prodrug activation, drug inactivation and drug toxication. The specific goals of the next project period are centered on the oxazaphosphorines cyclophosphamide and ifosphamide, and are designed to accomplish the following objectives: (1) To identify the specific rat and human liver P450 enzymes that inactivate ifosphamide via N- dechloroethylation reactions that generate the toxic metabolite chloroacetaldehyde; (2) to establish the role of prostaglandin H synthase in the activation of cyclophosphamide and ifosphamide to DNA-crosslinking, cytotoxic species that may contribute to anti-tumor activity; (3) to evaluate the impact of liver P450 inducers on the therapeutic activity of high-dose cyclophosphamide using a rat mammary tumor model, and to ascertain whether an increase in therapeutic index for ifosphamide can be achieved by modulation of the pathways leading to drug activation versus toxification using P450 form-selective inducers and inhibitors; (4) to identify efficacious inducers of the human P450 enzymes that activate ifosphamide and cyclophosphamide using a primary human hepatocyte culture system, and to elucidate the underlying mechanism for the autoinduction of hepatic oxazaphosphorine activation observed in cancer patients; (5) to employ P450 gene transfer for the sensitization of solid tumors to the cytotoxic effects of cyclophosphamide and ifosphamide. Together, these studies will help elucidate the underlying metabolic basis for the large interindividual differences in pharmacokinetics and activity of this class of alkylating agent prodrugs, and in addition, may establish a rational basis for modulating the alternative and competing pathways of drug metabolism with the goal of decreasing toxic responses and improving therapeutic effects.
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