Ledoux S P, Wilson G L
Biochim Biophys Acta. 1984 Aug 17;804(4):387-92. doi: 10.1016/0167-4889(84)90064-8.
Cytotoxic effects and DNA damage caused by streptozotocin, a potent beta-cell toxin and an important chemotherapeutic agent, in an insulin-secreting clonal isolate of a rat insulinoma cell line were evaluated. Cytotoxicity was monitored by phase-contrast microscopy and measurement of insulin release into the culture medium. DNA damage and repair were assessed by changes in nucleoid sedimentation rates. The insulinoma cells were resistant to streptozotocin toxicity as compared to normal rat beta-cells. They were also resistant to the stimulatory effects of glucose on insulin release. However, streptozotocin did cause DNA damage that was both dose- and time-dependent. Comparative analysis of streptozotocin-induced DNA damage and that produced by the aglycone N-methyl-N-nitrosourea revealed greater damage with the latter. Thus, streptozotocin, like N-methyl-N-nitrosourea, may enter these cells by passive diffusion rather than selective transport. DNA repair studies indicate that the nicks caused by streptozotocin are sealed and that the DNA is again supercoiled by 14 h. Therefore, overt toxicity may be avoided by a decreased drug uptake compared to normal beta-cells and efficient repair mechanisms. These studies suggest that an active glucose-sensing mechanism is necessary to enhance streptozotocin cytotoxicity in both normal and neoplastic beta-cells.
评估了链脲佐菌素（一种强效的β细胞毒素和重要的化疗药物）对大鼠胰岛素瘤细胞系胰岛素分泌克隆分离株产生的细胞毒性作用和DNA损伤。通过相差显微镜和测量释放到培养基中的胰岛素来监测细胞毒性。通过类核沉降速率的变化评估DNA损伤和修复情况。与正常大鼠β细胞相比，胰岛素瘤细胞对链脲佐菌素毒性具有抗性。它们对葡萄糖刺激胰岛素释放的作用也具有抗性。然而，链脲佐菌素确实会导致DNA损伤，且这种损伤具有剂量和时间依赖性。对链脲佐菌素诱导的DNA损伤与苷元N-甲基-N-亚硝基脲产生的DNA损伤进行比较分析发现，后者造成的损伤更大。因此，链脲佐菌素与N-甲基-N-亚硝基脲一样，可能通过被动扩散而非选择性转运进入这些细胞。DNA修复研究表明，链脲佐菌素造成的切口会被封闭，并且DNA在14小时后会再次超螺旋化。因此，与正常β细胞相比，通过减少药物摄取和有效的修复机制，可能避免明显的毒性。这些研究表明，活跃的葡萄糖感应机制对于增强链脲佐菌素对正常和肿瘤性β细胞的细胞毒性是必要的。
