COMBINATION OF CISPLATIN AND RADIATION IN CELL-CULTURE - EFFECT OF DURATION OF EXPOSURE TO DRUG AND TIMING OF IRRADIATION

Responses to the combination of cisplatin (CDDP) and radiation in expe rimental and clinical studies have been reported to vary from high rad iosensitization to clear sub-additivity. We examined the combined effe ct of CDDP with ionizing radiation in both murine mammary adenocarcino ma (EMT-6) and human ovarian carcinoma (OV-1063) cells with special re ference to the duration of CDDP exposure and timing of irradiation. Ce ll survival was measured with a colorimetric assay of cell density. Th e nature of interaction of cisplatin and radiation was evaluated using isobolograms and a combination index (CI). Exposure of both cell line s to CDDP for 24 hr before irradiation yielded an additive or slightly sub-additive response only if the exposure was extended for a few mor e hours after irradiation. In EMT-6 cells, the combination of radiatio n with subsequent continuous as well as short-term (4 to 6 hr) CDDP tr eatment was found to have a clear sub-additive effect; dose escalation of each modality reduced the additional effect of the other. The sub- additive effect may be explained by a radiation-induced arrest of cell s in late S phase, which was dose- and time-dependent. Post-radiation exposure to CDDP further increased the S-phase arrest. In contrast, a 2 hr post-radiation drug exposure resulted in a supra-additive combine d effect. Our results stress the crucial role of the timing and the do ses of both modalities as well as the duration of post-radiation drug exposure on their combined effect. (C) 1998 Wiley-Liss, Inc.