Murray D, VanAnkeren S C, Milas L, Meyn R E
Department of Experimental Radiotherapy, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Radiat Res. 1988 Jan;113(1):155-70.
We have examined the radioprotective effect of WR-1065 on cultured Chinese hamster ovary cells. The effects of the drug on the induction and rejoining of gamma-ray-induced DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) were measured using alkaline (pH 12.1) and neutral (pH 7.0) elution, respectively. Molecular protection factors (PFs) calculated from these data allowed us to determine whether the degree of modification of strand breakage accurately predicted the PFs measured using the biological end point of cell survival. The drug did protect against the induction of both SSBs and DSBs, although to an extent that did not appear to fully account for the degree of radioprotection in terms of cell killing measured under identical conditions. It is therefore unlikely that radioprotection by WR-1065 occurs simply as a consequence of a general lowering of all types of gamma-ray-induced DNA lesions, and it is possible that the drug could differentially protect against the induction of subsets of these DNA lesions. The rate of SSB rejoining was retarded following preirradiation treatment of cells with WR-1065, but there was no effect on DSB rejoining. Postirradiation treatment with WR-1065 also appeared to retard SSB rejoining but without an accompanying effect on either DSB rejoining or cell survival; however, this effect was largely reversed by the addition of catalase and was therefore probably a result of H2O2 generated by autoxidation of the drug. Based on these observations, it would appear that the molecular actions of aminothiol radioprotective compounds that lead to reduced cell killing are much more complex than previously thought.
我们研究了WR-1065对培养的中国仓鼠卵巢细胞的辐射防护作用。分别使用碱性（pH 12.1）和中性（pH 7.0）洗脱法，测定了该药物对γ射线诱导的DNA单链断裂（SSB）和双链断裂（DSB）的诱导及重新连接的影响。根据这些数据计算出的分子保护因子（PF），使我们能够确定链断裂的修饰程度是否准确预测了使用细胞存活这一生物学终点测得的PF。该药物确实对SSB和DSB的诱导均有防护作用，尽管其防护程度似乎并未完全解释在相同条件下测得的细胞杀伤方面的辐射防护程度。因此，WR-1065的辐射防护作用不太可能仅仅是由于所有类型的γ射线诱导的DNA损伤普遍减少所致，而且该药物有可能对这些DNA损伤子集的诱导具有差异性保护作用。在用WR-1065对细胞进行预照射处理后，SSB重新连接的速率减慢，但对DSB重新连接没有影响。用WR-1065进行照射后处理似乎也会减慢SSB重新连接，但对DSB重新连接或细胞存活均无伴随影响；然而，加入过氧化氢酶后这种影响在很大程度上得到了逆转，因此这可能是药物自氧化产生H2O2的结果。基于这些观察结果，导致细胞杀伤减少的氨基硫醇辐射防护化合物的分子作用似乎比以前认为的要复杂得多。
