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SYMPOSIUM REPORT

CANCER CHEMOTHERAPY AND DRUG METABOLISM

Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada(D.S.R., C.L., S.R.); School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (E.C.C., R.L.C., K.J.W., I.J.S.); Auckland Cancer Society Research Center, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (A.V.P.); Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina (C.S.M., A.J.T.); and Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts(Y.J., C.-S.C., T.S., H.L., P.S.S., D.J.W.)

Abstract

Drug-metabolizing enzymes and drug transporters are key determinants of the pharmacokinetics and pharmacodynamics of many antineoplastic agents. Metabolism and transport influence the cytotoxic effects of antineoplastic agents in target tumor cells and normal host tissues. This article summarizes several state-of-the-art approaches to enhancing the effectiveness and safety of cancer therapy based on recent developments in our understanding of antineoplastic drug metabolism and transport. Advances in four interrelated research areas presented at a recent symposium sponsored by the Division for Drug Metabolism of the American Society for Pharmacology and Experimental Therapeutics (Experimental Biology 2004; Washington D.C., April 17–21, 2004) are discussed: 1) interactions of anthracyclines with drug-metabolizing enzymes; 2) use of hypoxia-selective gene-directed enzyme prodrug therapy (GDEPT) in combination with bioreductive prodrugs; 3) synergy between glutathione conjugation and conjugate efflux in conferring resistance to electrophilic toxins; and 4) use of cytochromes P450 as prodrug-activating enzymes in GDEPT strategies. A clear theme emerged from this symposium: drug metabolism and transport processes can be modulated and exploited in ways that may offer distinct therapeutic advantages in the management of patients with cancer.

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