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 cells containing IUdR after x-irradiation. Current models of lUdR 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 lUdR in DNA of cells x-irradiated leads to mobile reactive intermediates which damage both the strand containing the lUdR and also the complementary strand which did not contain lUdR 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 lUdR-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.
