Prodrugs of anticancer agents

Anticancer drugs are primarily cytotoxic agents, and exert their antitumor activity by interfering with some aspects of DNA replication, repair, translation, or cell division. Hence, cancer chemotherapy is typically associated with severe side effects. An important approach to alleviate toxicity of the anticancer agents is to prepare covalent derivatives, i.e., prodrugs, which lack the cytotoxic activity, but which can be converted enzymatically or non-enzymatically to the cytotoxic agents upon administration to patients. Prodrugs have been used to improve the solubility, transport properties, and pharmacokinetic properties of anticancer agents. More importantly, several prodrug strategies have been developed that enable selective delivery of the cytotoxic agents 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 environment inside the core of solid tumors, and tumor-specific antigens expressed on the surface of tumor cells. The utility of various prodrug strategies in improving the therapeutic index of anticancer agents as well as the limitations of these prodrug strategies are reviewed in this chapter.