Many clinically useful drugs and other foreign compounds are metabolized in the liver by pathways that lead to their bioactivation and/or detoxification and elimination. In particular, several widely used anti-cancer drugs, 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 provide a detailed understanding of the effects of anti-cancer drugs on the expression and activity of the drug-metabolizing P450 enzymes, and in addition, to elucidate the roles played by these enzymes in anti-cancer drug biotransformation. Previous studies carried out in this laboratory using the rat model have established that administration of cyclophosphamide, cisplatin or CCNU [1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea] dramatically alters the profile of P-450 enzymes expressed in the liver, in a manner that perturbs endogenous steroid metabolism and that may seriously compromise the animal's capacity for hepatic drug activation. In other studies the polyfunctional alkylating agent thio-TEPA has been shown to be oxidatively desulfurated to TEPA by liver P450, a reaction that prolongs systemic exposure to alkylating metabolites with anti-tumor activity. The goals of the first project period are three-fold: (a) The underlying mechanisms for the effects of cyclophosphamide and CCNU on hepatic P-450 expression will be established. Included are experiments to ascertain whether the actions of cyclophosphamide on P450 are due to the action of the metabolite acrolein or of phosphoramide mustard, and whether the effects of cyclophosphamide or CCNU reflect, in part, changes in circulating levels of the gonadal and pituitary hormones that are known to play a major role in regulating hepatic P450 expression. (b) The contribution of rat and human P-450 enzymes to the metabolic activation and cytotoxicity of ifosphamide, cyclophosphamide and thio-TEPA will be elucidated through biochemical and cellular studies using liver microsomes, purified enzyme systems, and tumor cells in culture. (c) In vivo models will be developed to ascertain whether improved therapeutic effects can be achieved through the modulation of thio-TEPA metabolism and pharmacokinetics by alteration of liver P450 enzyme levels. These studies will provide a better understanding of the interactions at the level of metabolism among anti-cancer drugs given in combination, and may thereby help to elucidate the molecular basis for some of the toxic, synergistic and antagonistic effects exhibited by these drugs. This knowledge may facilitate more effective drug sequencing, and may lead to useful ways to modulate anti-cancer drug metabolizing enzymes in hepatic and/or tumor tissue in order to achieve decreased toxic responses and improved therapeutic effects.
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