The effects of cytotoxic drugs and inhibitors of insulin secretion were examined in vivo in rats with a radiation-induced transplantable insulinoma, and in vitro using cultured rat insulinoma cells and the derived RINm5F insulin-secreting cell line. Administration of diazoxide to insulinoma-bearing rats resulted in a transient decrease of plasma insulin with a temporary rise of glucose concentrations. Mannoheptulose and somatostatin failed to affect the marked hyperinsulinaemia and hypoglycaemia. Streptozotocin produced a rapid and sustained decrease of insulin concentrations in insulinoma-bearing rats, accompanied by a progressive elevation of plasma glucose. Administration of alloxan failed to affect circulating insulin or glucose concentrations. In vitro, streptozotocin and alloxan exerted approximately equipotent time-dependent and concentration-dependent cytotoxic effects on insulinoma cells and RINm5F cells as established by cell staining with trypan blue. The cytotoxic actions of both drugs were decreased by agents believed to scavenge free radicals or to act as inhibitors of poly(ADP-ribose) synthetase. The results suggest that the cytotoxic actions of streptozotocin and alloxan on rat insulinoma cells and RINm5F cells are mediated by the generation of hydroxyl free radicals and DNA strand breaks. The ineffectiveness of alloxan in insulinoma-bearing rats probably reflects the high rate of decomposition of the drug in vivo.
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