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

我们已经完成了卤代嘧啶放射增敏剂的研究， IUdR和BUDR。IUdR目前正在作为放射增敏剂进行临床试验。 这种试剂掺入细胞后使细胞对辐射敏感。 DNA取代胸腺嘧啶核苷。我们之前已经证明，DNA的产量 含IUdR的细胞经x射线照射后，断链增加。 目前的lUdR和budr辐射分解模型预测，只有单链 损伤应该在DNA中产生。然而，最重要的病变是 X射线致死很可能是DNA双链断裂。我们发现， X射线照射细胞DNA中lUdR的辐解导致流动反应 中间体，既破坏含有lUdR的链，也破坏 在这些实验中不含lUdR的互补链。 IUdR诱导的链断裂在未被取代的 被取代的链中的链。另有较小的升幅。 在含有lUdR-DNA的细胞中，未被取代的双链DNA中的链断裂。在……里面 细胞存活实验，细胞仅经历1次IUDR倍增 显示的放射增敏作用几乎与经历2次倍增的细胞相同 其中两条都被替换了。

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.