DNA topoisomerase I-targeting drugs as radiation sensitizers

Combination chemoradiation, alone or as an adjuvant to surgery, has been sh own to improve treatment outcomes in a number of human malignancies, but ma y be limited by normal tissue toxicities. A primary challenge in radiation oncology is the development of drugs that can selectively enhance the cytot oxicity of ionizing radiation against tumor cells. Mammalian DNA topoisomer ase I is the major cytotoxic target of a number of newly developed anticanc er drugs that have shown efficacy against solid tumors, including colon can cer, ovarian cancer, lung cancer, cancer of the head and neck, and pediatri c cancers. Topoisomerase I-targeting drugs exert their cytotoxic effect by producing enzyme-mediated DNA damage, rather than by directly inhibiting en zyme catalytic activity. DNA topoisomerase I recently has been established as a biochemical mediator of radiosensitization in cultured mammalian cells by camptothecin derivatives. Interestingly, this sensitization appears to be schedule-dependent, cell cycle phase-specific, cell line-dependent, and not strictly dependent on drug cytotoxicity. Clinical chemoradiation trials using camptothecin derivatives are currently ongoing. Future studies aimed at better understanding the underlying mechanisms of molecular radiosensit ization with topoisomerase I-targeting drugs are pivotal to the clinical ap plication of these agents, as well as in guiding the development of more ef fective radiosensitizers.