Camptothecin radiation sensitization: mechanisms, schedules, and timing

Based on high tumoricidal activity of the camptothecin analogs topotecan (Hycamtin), irinotecan (CPT-11[Camptosar]), and 9-aminocamptothecin (9-AC) in preclinical studies, clinical trials began testing these agents against human cancers. The cytotoxic activity of camptothecins in the clinic has been lower than predicted from the laboratory, however, and new approaches are needed. One method that holds promise is the use of the camptothecins as radiation sensitizers. The camptothecin dose, schedule, method of administration, and timing of administration, when given with irradiation, are likely to be important factors for these new S-phase radiation sensitizers. Phase I trials of the camptothecins as radiation sensitizers have begun, and multicenter phase II studies are planned by the Radiation Therapy Oncology Group (RTOG). One new approach based on preclinical observations that deserves clinical evaluation is chronomodulated camptothecin delivery with irradiation in order to widen the therapeutic window.