title: Production of DNA double-strand breaks by interactions between carboplatin and radiation: a potential mechanism for radiopotentiation.
abstract: The production of DNA double-strand breaks (DSBs) was studied in cells of four CHO cell lines under conditions where combining radiation with carboplatin enhanced cell killing (radiosensitization and radiopotentiation). The cell lines included repair-proficient (AA8 and K1), excision repair-deficient (UV41) and DSB repair-deficient (xrs-5) cells. Double-strand breaks were analyzed by neutral elution either immediately after or 4 h after a single 55-Gy radiation dose delivered under hypoxic 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 in AA8, K1 and xrs-5 cells was significantly higher 4 h after carboplatin-radiation treatment; no such increase was found at 4h in UV41 cells. Strand scission factors (SSFs) were calculated as SSF = -log [percentage DNA remaining on filter at 8 h elution (treated cells)/percentage DNA remaining at 8 h elution (untreated cells)]. The ratios of the SSF 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 results support a possible explanation for the enhanced killing of irradiated cells by platinum chemotherapeutic agents, namely enhanced production of DSBs.
authors.affiliation: Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
authors.forename: L X
authors.initials: LX
authors.lastname: Yang
authors.forename: E B
authors.initials: EB
authors.lastname: Douple
authors.forename: J A
authors.initials: JA
authors.lastname: O'Hara
authors.forename: H J
authors.initials: HJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D016466:CHO Cells; D016190:Carboplatin / Q000494:pharmacology*; D006224:Cricetinae; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D011836:Radiation Tolerance / Q000187:drug effects*
chemical_list: D004247:DNA; D016190:Carboplatin