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

我们已经完成了对卤代嘧啶的研究 放射增敏剂、IUdR和BUDR。宫内发育迟缓目前处于临床阶段 作为放射增敏剂的试验。这种试剂使细胞对 掺入细胞DNA后的辐射 胸苷。我们之前已经证明，DNA链的产量 含IUdR的细胞经x射线照射后，断裂增加。 目前IUdR和BUDR辐射分解的模型预测只有一个 链损伤应该在DNA中产生。然而，病变最多的是 X射线致死的重要原因可能是DNA双链断裂。 我们发现，经x-射线照射的细胞DNA中IUdR的辐解 导致可移动的活性中间体，破坏两条链 含有IUdR和不含IUdR的互补链 在这些实验中包含IUdR。IUdR诱导的链断裂是 在未被取代的链中出现的频率几乎与在 取代链。链也有较小的增长。 含有IUdR-DNA的细胞中未被取代的双链DNA的断裂。 在细胞存活实验中，细胞只经历了1倍于 IUdR显示的放射增敏作用几乎与细胞 2两条链都被替换的加倍。 细胞的辐射敏感性受到许多因素的影响，这些因素可能是 临床上很重要。例如，细胞内的氧浓度 细胞的氧化还原电势影响细胞 放射敏感性和可能在临床上也很重要。 几种药物，BSO或SR 2508，已经被证明可以降低 细胞内有效的巯基浓度，并作为 低氧细胞敏感剂。另一方面，添加半胱胺 手，保护在有氧条件下经X-射线照射的细胞。 以前，我们已经通过碱性和中性洗脱表明 上述药物改变了辐射诱导的DNA损伤的产率。

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.