PRODUCTION OF DNA DOUBLE-STRAND BREAKS BY INTERACTIONS BETWEEN CARBOPLATIN AND RADIATION - A POTENTIAL MECHANISM FOR RADIOPOTENTIATION

The production of DNA double-strand breaks (DSBs) was studied in cells of four CHO cell lines under conditions where combining radiation wit h carboplatin enhanced cell killing (radiosensitization and radiopoten tiation). The cell lines included repair-proficient (AA8 and K1), exci sion repair-deficient (UV41) and DSB repair-deficient (xrs-5) cells. D ouble-strand breaks were analyzed by neutral elution either immediatel y after or 4 h after a single 55-Gy radiation dose delivered under hyp oxic conditions. Carboplatin (1 mM) combined with radiation produced a small increase in DSBs compared to radiation alone immediately after irradiation in AA8, UV41 and xrs-5 cells. However, the yield of DSBs i n AA8, K1 and xrs-5 cells was significantly higher 4 h after carboplat in-radiation treatment; no such increase was found at 4 h in UV41 cell s. Strand scission factors (SSFs) were calculated as SSF = -log [perce ntage DNA remaining on filter at 8 h elution (treated cells)/percentag e DNA remaining at 8 h elution (untreated cells)]. The ratios of the S SF at 4 h to 0 h postirradiation for carboplatin-treated cells were 13 .7 for K1, 4.9 for xrs-5, 2.5 for AA8 and 1.2 for UV41 cells. These re sults support a possible explanation for the enhanced killing of irrad iated cells by platinum chemotherapeutic agents, namely enhanced produ ction of DSBs. (C) 1995 by Radiation Research Society