PRODRUGS OF ANTICANCER AGENTS

Anticancer drugs are primarily cytotoxic agents, and exert their antit umor activity by interfering with some aspects of DNA replication, rep air, translation, or cell division. Hence, cancer chemotherapy is typi cally associated with severe side effects. An important approach to al leviate toxicity of the anticancer agents is to prepare covalent deriv atives, i.e., prodrugs, which lack the cytotoxic activity, but which c an be converted enzymatically or non-enzymatically to the cytotoxic ag ents upon administration to patients. Prodrugs have been used to impro ve the solubility, transport properties, and pharmacokinetic propertie s of anticancer agents. More importantly, several prodrug strategies h ave been developed that enable selective delivery of the cytotoxic age nts to the tumor tissue, thereby significantly reducing the toxic side effects of the anticancer agents. These strategies include design of prodrugs based on elevated enzymes in tumor tissues, hypoxic environme nt inside the core of solid tumors, and tumor-specific antigens expres sed on the surface of tumor cells. The utility of various prodrug stra tegies in improving the therapeutic index of anticancer agents as well as the limitations of these prodrug strategies are reviewed in this c hapter.