DNA topoisomerase I-targeting drugs as radiation sensitizers

Abstract

Combination chemoradiation, alone or as an adjuvant to surgery, has been shown to improve treatment outcomes in a number of human malignancies, but may be limited by normal tissue toxicities. A primary challenge in radiation oncology is the development of drugs that can selectively enhance the cytotoxicity of ionizing radiation against tumor cells. Mammalian DNA topoisomerase I is the major cytotoxic target of a number of newly developed anticancer drugs that have shown efficacy against solid tumors, including colon cancer, ovarian cancer, lung cancer, cancer of the head and neck, and pediatric cancers. Topoisomerase I-targeting drugs exert their cytotoxic effect by producing enzyme-mediated DNA damage, rather than by directly inhibiting enzyme 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 radiosensitization with topoisomerase I-targeting drugs are pivotal to the clinical application of these agents, as well as in guiding the development of more effective radiosensitizers.