The action of streptozotocin in mouse leukaemia cells.

Streptozotocin, the glucose derivative of N-methyl-N-nitrosourea, is, in addition to being carcinogenic, a powerful diabetogen. When administered to mice, it rapidly lowers the amount of islet-cell NAD and causes considerable 8-cell toxicity (Schein ef a/., 1973 ; Gunnarsson et al., 1974). Administration of nicotinamide before streptozotocin, or up to 2h afterwards, completely inhibits the fall in NAD and prevents the diabetes. The diabetogenic action of streptozotocin is thus thought to be through the lowering of the amount of 8-cell NAD. In experimental systems, streptozotocin is a potent anti-cancer agent (Bhuyan, 1970), but it has found limited clinical use. Simultaneous administration of nicotinamide potentiates the survival of tumour-bearing animals, acting probably through a modulating effect on streptozotocin toxicity (Schein et al., 1967). However, nicotinamide can potentiate the carcinogenic action of the drug (Rakieten et al., 1971). There is a large literature associating changes in NAD concentrations with changes in the growth state of cells. An increasing amount of evidence associates such changes with the chromosomal enzyme, poly(ADP-ribose) polymerase, which degrades NAD. 5-Methylnicotinamide, which inhibits NAD degradation, but is not a precursor for its synthesis, will block the diabetogenic action of streptozotocin in mouse islets (Hinz et al., 1973). Whish et al. (1975) showed that administration of streptozotocin to Physarum polycephalum causes a marked decrease in NAD, which correlates with a twofold