Synthetic DNA-Targeted Chemotherapeutic Agents And Related Tumor-Activated Prodrugs

Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. The original antimetabolites such as cytosine arabinoside and 5-fluorouracil have been augmented by more recent compounds such as gemcitabine, fludarabine, cladribine, and pentostatin, which inhibit DNA polymerase action during DNA synthesis. A new development is the related compounds deazacytidine and decitabine, which inhibit reactivate silenced genes by inhibition of cytosine methylation. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene-based DNA-methylating agents are direct DNA-modifying agents that still play an important role in clinical treatment. Methotrexate and more recent lipophilic analogs, together with older drugs such as 5-fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs whose therapeutic effects are due to enzyme-mediated DNA modification. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor-activated prodrugs of DNA-active agents. Using hypoxia, gene therapy or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive nontumor cell populations. Keywords: alkylating agent; antibody; antifolate; antimetabolite; DNA intercalator; gene therapy; hypoxia; mustard; nitrosourea; platinum complex; topoisomerase inhibitor; triazene; tumor-activated prodrug