Effects of streptozotocin on a clonal isolate of rat insulinoma cells

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.