Murray D, Milas L, Meyn R E
Department of Experimental Radiotherapy, University of Texas, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Radiat Res. 1988 May;114(2):268-80.
WR-2721 and its free-thiol metabolite WR-1065 have been characterized for their ability to protect mouse jejunal cells in vivo from the damaging effects of gamma rays with respect to both cytotoxicity and DNA single-strand break (SSB) induction. SSBs were measured both in the whole jejunal epithelium and in the proliferating crypt cells using an adaptation of the alkaline elution methodology. Protection factors (PFs) were also obtained using the microcolony assay for jejunal crypts. In mice treated with WR-1065 (400 mg/kg) 15 or 30 min prior to irradiation, there was a slight but significant reduction in the initial number of SSBs both in the whole jejunum (PF of between 1.17 and 1.22) and in the proliferating crypt cells (PF of between 1.13 and 1.28). At a dose of 200 mg/kg, the PF for SSBs in the proliferating crypt cells was 1.12 +/- 0.07 while that for crypt-cell survival was approximately 2.0. In mice treated with WR-2721 (400 mg/kg) 15 min prior to irradiation, there was little effect on the initial number of SSBs induced both in the whole jejunum (PF of 1.07 +/- 0.11) and in the proliferating crypt cells (PF of 1.04 +/- 0.07). WR-2721 protected jejunum in the microcolony assay with a much greater PF of 1.8. For each drug the PF for SSBs was therefore always much lower than that indicated by the biological end point under identical conditions. Both drugs also retarded the rate of SSB rejoining in each population of cells. These data suggest that mechanisms such as free-radical scavenging by these drugs may contribute to but not completely explain their protective action. Comparison with data obtained previously with cultured CHO cells supports the idea that the action of these drugs at the DNA lesion level may not be dose-modifying, but may also result in a shift in the spectrum of lesions induced by the radiation.
WR-2721及其游离硫醇代谢产物WR-1065的特点是，它们能够在体内保护小鼠空肠细胞免受γ射线在细胞毒性和DNA单链断裂（SSB）诱导方面的损伤作用。使用改良的碱性洗脱方法，在整个空肠上皮和增殖的隐窝细胞中测量SSB。还使用空肠隐窝的微集落测定法获得保护因子（PF）。在照射前15或30分钟用WR-1065（400mg/kg）处理的小鼠中，整个空肠（PF在1.17至1.22之间）和增殖的隐窝细胞（PF在1.13至1.28之间）中SSB的初始数量均有轻微但显著的减少。在200mg/kg的剂量下，增殖隐窝细胞中SSB的PF为1.12±0.07，而隐窝细胞存活的PF约为2.0。在照射前15分钟用WR-2721（400mg/kg）处理的小鼠中，对整个空肠（PF为1.07±0.11）和增殖的隐窝细胞（PF为1.04±0.07）中诱导的SSB初始数量几乎没有影响。在微集落测定中，WR-2721对空肠的保护作用更强，PF为1.8。因此，对于每种药物，在相同条件下，SSB的PF总是远低于生物学终点所表明的PF。两种药物还延缓了每个细胞群体中SSB重新连接的速率。这些数据表明，诸如这些药物的自由基清除等机制可能有助于但不能完全解释它们的保护作用。与先前用培养的CHO细胞获得的数据进行比较支持了这样一种观点，即这些药物在DNA损伤水平的作用可能不是剂量修饰作用，而是也可能导致辐射诱导的损伤谱发生变化。
