Symposium Report CANCER CHEMOTHERAPY AND DRUG METABOLISM

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-theart 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. Chemotherapy involving the use of cytotoxic antineoplastic agents remains an important strategy in the overall management of patients with malignant tumors. As with most therapeutic agents, drug-metabolizing enzymes and drug transporters play key roles in determining the pharmacokinetics and overall disposition of antineoplastic agents in the body. In addition, metabolism and transport can be important contributors to 1) the toxicity produced by antineoplastic agents in normal host tissues and 2) the delicate balance between drug sensitivity and resistance displayed by target tumor cells. Several features of antineoplastic drugs make the metabolism of these agents particularly significant. Many antineoplastics display steep dose-response curves and low therapeutic indices, and the toxicities that they produce can be severe and life-threatening. Since cancer chemotherapy often involves the use of multiple antineoplastic agents and supportive drugs in combination regimens, drug interactions represent a real clinical concern (Kivisto et al., 1995). Of particular importance are pharmacokinetic drug interactions that result in clinically significant alterations in host toxicity or therapeutic response. Pharmacokinetic drug interactions in cancer chemotherapy often go unrecognized because toxic reactions to these drugs are common and unpredictable, individual Supported in part by the Canadian Breast Cancer Foundation (D.S.R.), Canadian Institutes of Health Research Grant MOP-42399 (D.S.R.), and National Institutes of Health Grant CA49248 (D.J.W.). Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.105.004374. ABBREVIATIONS: GDEPT, gene-directed enzyme prodrug therapy; ABC, ATP-binding cassette; CDNB, 1-chloro-2,4-dintrobenzene; 15-d-PGJ2, 15-deoxy 12,14 -prostaglandin J2; E09, 3-hydroxymethyl-5-aziridin-1-yl-methyl-2[1H-indole-4,7-dione]prop-2-en-1-ol; RSU1069, 1-[3-aziridinyl2-hydroxypropyl]-2-nitroimidazole; CB1954, 5-[aziridin-1-yl]-2,4-dinitrobenzamide; AQ4N, 1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}5,8dihydroxyanthracene-9,10-dione; GSH, reduced glutathione; GST, glutathione S-transferase; GS-X, glutathione conjugate; HIF, hypoxia-inducible factor; HRE, hypoxia-response element; LDH, lactate dehydrogenase A; MRP, multidrug resistance-associated protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NOS, nitric oxide synthase; iNOS or NOSII, inducible nitric oxide synthase; NOSR, reductase activity of nitric oxide synthase; NQO, 4-nitroquinoline 1-oxide; NQO1, NAD(P)H:quinone oxidoreductase 1; P450, cytochrome P450; P450R, NADPH-cytochrome P450 reductase; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator-activated receptor-responsive element; QO-SG, 4-Sglutathionyl quinoline 1-oxide; ROS, reactive oxygen species; RTV4, four-times treatment size; SR4317, 3-amino-1,2,4-benzotrizine-1-N-oxide. 0090-9556/05/3308-1083–1096$20.00 DRUG METABOLISM AND DISPOSITION Vol. 33, No. 8 Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics 4374/3043919 DMD 33:1083–1096, 2005 Printed in U.S.A. 1083 at A PE T Jornals on Jne 4, 2017 dm d.aspurnals.org D ow nladed from