EFFECT OF RADIOPROTECTORS AND RADIOSENSITIZERS ON DNA DAMAGE PRODUCED BY X-RAYS

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We have completed studies with the halogenated pyrimidine radiosensitizers, IUdR and BUdR. IUdR is currently in clinical trials as a radiosensitizer. This agent sensitizes cells to radiation after incorporation into cellular DNA in place of thymidine. We have previously shown that the yield of DNA strand breaks was increased in cell containing IUdR after x-irradiation. Current models of IUdR and BUdR radiolysis predict that only single strand damage should be produced in DNA. However, the lesion most important in x-ray lethality is probably DNA double strand breaks. We have found that radiolysis of IUdR in DNA of cells x-irradiated leads to mobile reactive intermediates which damage both the strand containing the IUdR and also the complementary strand which did not contain IUdR in these experiments. IUdR-induced strand breaks were almost as frequent in the unsubstituted strand as in the substituted strand. There was also a smaller increase in strand breaks in unsubstituted duplex DNA in cells containing IUdR-DNA. In cell survival experiments, cells undergoing only 1 doubling with IUdR showed almost as much radiosensitization as cells undergoing 2 doublings where both strands were substituted. Cellular radiosensitivity is affected by many factors which may be clinically important. For example, cellular oxygen concentration and the redox potential of the cell affect cellular radiosensitivity and probably are also important clinically. Several agents, BSO or SR 2508, have been shown to decrease the effective sulfhydryl concentration in the cell and to act as hypoxic cell sensitizers. Addition of cysteamine, on the other hand, protects cells x-irradiated under oxic conditions. Previously, we have shown by alkaline and neutral elution that the above agents altered the yield of radiation-induced DNA damage.