Mechanism of Radiosensitization by Halogenated Pyrimidines: The Contribution of Excess DNA and Chromosome Damage in BrdU Radiosensitization may be Minimal in Plateau-phase Cells

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Abstract
We measured the contribution of increased DNA double-strand break (dsb) and interphase chromosome break induction in BrdU-mediated radiosensitization in exponentially growing (DNA dsb measurements only) and plateau-phase Chinese hamster ovary cells using an approach developed by Webb et al. (1993). The approach is based on the scavenging capacity of acetone for hydrated electrons, which are thought to react with bromine and form excess DNA and chromosome damage in BrdU-containing cells. In irradiated exponentially growing cells, acetone (1 m) removes the majority of excess DNA dsb induced in the presence of 4 µm BrdU (∼ 40% replacement of thymidine by BrdU), but does not restore cell radiosensitivity to the levels observed in BrdU-free cells. Although BrdU radiosensitizes cells by decreasing both D0 and Dq of the survival curve, acetone only restores D0 to levels measured in BrdU-free cells, but leaves Dq at levels measured in BrdU-containing cells. In plateau-phase cells, acetone removes the majority of excess DNA dsb and interphase chromosome breaks induced in the presence of 4 µm BrdU (∼ 50% replacement of thymidine by BrdU) but has only a small effect on BrdU-mediated radiosensitization to killing. These observations suggest that increased DNA damage production has a variable contribution in BrdU radiosensitization: it constitutes a major, albeit not the sole, component in the radiosensitization of exponentially growing cells, but only a minor component in the radiosensitization of plateau-phase cells. The results suggest that BrdU radiosensitization does not derive exclusively from increased DNA damage induction and support our previous hypothesis invoking repair inhibition/damage fixation as a component in the mechanism of radiosensitization. The results further suggest that repair inhibition is a major component in BrdU radiosensitization in exponentially growing cells, but the main cause of radiosensitization in plateau-phase cells.

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