Metabolism-based anticancer drug design.
Many conventional anticancer drugs display relatively poor selectivity for neoplastic cells, in particular for solid tumors. Furthermore, expression or development of drug resistance, increased glutathione transferases as well as enhanced DNA repair decrease the efficacy of these drugs. Research efforts continue to overcome these problems by understanding these mechanisms and by developing more effective anticancer drugs. Cyclophosphamide is one of the most widely used alkylating anticancer agents. Because of its unique activation mechanism, numerous bioreversible prodrugs of phosphoramide mustard, the active species of cyclophosphamide, have been investigated in an attempt to improve the therapeutic index. Solid tumors are particularly resistant to radiation and chemotherapy. There has been considerable interest in designing drugs selective for hypoxic environments prevalent in solid tumors. Much of the work had been centered on nitroheterocyclics that utilize nitroreductase enzyme systems for their activation. In this article, recent developments of anticancer prodrug design are described with a particular emphasis on exploitation of selective metabolic processes for their activation.
Kwon
C H
CH
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. Johns University, Jamaica, New York 11439, USA. kwonc@stjohns.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003520:Cyclophosphamide / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000378:metabolism* / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011355:Prodrugs; D003520:Cyclophosphamide