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.