MODULATION OF RADIATION-INDUCED STRAND BREAK REPAIR BY CISPLATIN IN MAMMALIAN-CELLS

Purpose: To investigate the repair of ionizing radiation-induced DNA l esions in human skin fibroblasts in the presence of cisplatin-DNA addu cts and to determine the persistence of DNA repair inhibition by cispl atin. Materials and methods: Normal human fibroblasts (AG 1522) treate d with cisplatin were exposed to 4 Gy Co-60 gamma-radiation and assaye d for repair of radiation-induced damage under growth-permissive condi tions. DNA damage was measured by the fluorescence analysis of DNA unw inding (FADU) and cytokinesis-blocked micronucleus assays. Results: Re joining of strand breaks caused by dr Gy radiation in cells without ci splatin pre-treatment appeared to be biphasic with an initial fast com ponent (up to 15 min of repair time) followed by a slower component, a nd was completed by 90 min. Cisplatin treatment (10 mu g/ml, 30 min) i mmediately before irradiation had no effect on the fast rejoining comp onent, but inhibited the slow component (p<0.01). The same cisplatin t reatment 24 h prior to irradiation inhibited both slow and fast compon ents (p<0.01). In contrast, decreasing the cisplatin exposure to 1.0 m u g/ml for 30 min, 24 h prior to irradiation, resulted in an increased amount of strand break repair at each time point measured compared wi th irradiated control cells. This mild cisplatin treatment (95% surviv al) also resulted in a reduction of radiation-generated micronuclei in dicating an adaptive response. Conclusions: Cisplatin used in combinat ion with ionizing radiation can produce differential cellular response s depending upon the severity of the cisplatin treatment and the time interval between cisplatin and radiation exposures.