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-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.
Riddick
David S
DS
Department of Pharmacology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada. david.riddick@utoronto.ca
Lee
Chunja
C
Ramji
Shairoz
S
Chinje
Edwin C
EC
Cowen
Rachel L
RL
Williams
Kaye J
KJ
Patterson
Adam V
AV
Stratford
Ian J
IJ
Morrow
Charles S
CS
Townsend
Alan J
AJ
Jounaidi
Youssef
Y
Chen
Chong-Sheng
CS
Su
Ting
T
Lu
Hong
H
Schwartz
Pamela S
PS
Waxman
David J
DJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D004317:Doxorubicin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D015316:Genetic Therapy; D005822:Genetic Vectors; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000145:classification / Q000378:metabolism* / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D011355:Prodrugs; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D005978:Glutathione