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.
Footnotes
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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.).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.004374.
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ABBREVIATIONS: GDEPT, gene-directed enzyme prodrug therapy; ABC, ATP-binding cassette; CDNB, 1-chloro-2,4-dintrobenzene; 15-d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; E09, 3-hydroxymethyl-5-aziridin-1-yl-methyl-2[1H-indole-4,7-dione]prop-2-en-1-ol; RSU1069, 1-[3-aziridinyl-2-hydroxypropyl]-2-nitroimidazole; CB1954, 5-[aziridin-1-yl]-2,4-dinitrobenzamide; AQ4N, 1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}5,8-dihydroxyanthracene-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-S-glutathionyl quinoline 1-oxide; ROS, reactive oxygen species; RTV4, four-times treatment size; SR4317, 3-amino-1,2,4-benzotrizine-1-N-oxide.
- Received February 18, 2005.
- Accepted May 13, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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- Article
- Abstract
- Interactions of Anthracyclines with Drug-Metabolizing Enzymes (D.S.R., C.L., S.R.)
- Bioreductive Prodrugs: Routes of Activation and Potential Application in Gene Therapy (E.C.C., R.L.C., K.J.W., A.V.P., I.J.S.)
- Role of Glutathione Conjugation and Conjugate Efflux in Cellular Resistance to Alkylating Agents and Other Reactive Electrophiles (C.S.M., A.J.T.)
- P450-Based Gene-Directed Enzyme Prodrug Therapy (Y.J., C.-S.C., T.S., H.L., P.S.S., D.J.W.)
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