MECHANISM OF RADIOSENSITIZATION BY HALOGENATED PYRIMIDINES - BROMODEOXYURIDINE AND BETA-ARABINOFURANOSYLADENINE AFFECT SIMILAR SUBSETS OF RADIATION-INDUCED POTENTIALLY LETHAL LESIONS IN PLATEAU-PHASE CHINESE-HAMSTER OVARY CELLS

Chinese hamster ovary (CHO) cells were grown to plateau phase in the presence of various amounts of bromodeoxyuridine (BrdU) and treated after irradiation with β-arabinofuranosyl-adenine (ara-A), an inhibitor of DNA and potentially lethal damage (PLD) repair, in order to investigate the importance of repair reactions in general and of PLD repair, in particular, on the mechanism of radiosensitization by halogenated pyrimidines. The degree of BrdU-mediated radiosensitization observed in ara-A-treated cells was compared to that of cells incubated after irradiation in the absence of ara-A. A substantial reduction in BrdU-mediated radiosensitization was observed in cells treated with ara-A at concentrations that, when given alone, produced maximum potentiation in cell killing (500-1500 μM). The residual BrdU-mediated radiosensitization observed at high levels of thymidine replacement could be explained by a BrdU-mediated increase in DNA and chromosome damage induction per gray. These findings are similar to those reported previously for a repair-deficient mutant of CHO cells, the xrs-5 cell line, and consistent with the hypothesis that BrdU-mediated radiosensitization has two distinct components, one that derives from an increase in damage induction per gray, and a second one that derives from an effect of BrdU on the repair of radiation-induced damage. It is proposed that the reduction in BrdU-mediated radiosensitization observed in ara-A-treated cells is the result of ara-A-mediated expression of radiation damage, the repair of which would have been otherwise modulated by BrdU. Since ara-A is known to act by fixing a form of radiation-induced PLD (α-PLD), we further propose that BrdU acts by fixing α-PLD. A synergistic effect in the potentiation of cell killing was observed between ara-A and BrdU when ara-A was given at concentrations below 100 μM. This result suggests that a benefit may be expected in the clinic from the combined application of halogenated pyrimidines with repair inhibitors, if administered at a carefully screened range of concentrations.