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1-Methyl-1-nitrosourea and Dialkylnitrosamine Depression of Nicotinamide Adenine Dinucleotide

Laboratory of Chemical Pharmacology, National Cancer Institute, Bethesda, Maryland 20014

1-Methyl-1-nitrosourea (MNU), the active moiety of the Streptozotocin molecule, produces a dose-related depression of nicotinamide adenine dinucleotide (NAD) concentrations in mouse liver and L1210 ascities, similar to that produced by the latter compound. There was early increase in liver NAD glycohydrolase activity, but no significant change in NAD pyrophosphorylase. While pretreatment with nicotinamide prevented the decrease in NAD, it did not influence either toxicity or antitumor activity of MNU. Unlike Streptozotocin, MNU is nondiabetogenic but does produce severe leukopenia and an acute neurologic syndrome consisting of spasmodic arching of the back and spreading of the limbs. A colorimetric method for the determination of MNU in biologic materials is presented. Eighty-five percent of a 100 mg/kg dose could be accounted for in serum at five minutes, with a half-life of twenty-five minutes. The liver retained 3.6 percent of the total dose at five minutes, with a half-life of 12 minutes, and no drug detectable at two hours. N-Nitrosodimethylamine, N-nitrosodiethylamine, 2-chloro-N-methyl-N-nitrosoethylamine, and N-methyl-N-nitrosourethane have been found to significantly lower liver, but not L1210, NAD concentrations. The possibility of a common mechanism of alkylation, through a diazoalkane intermediate, for the phenomenon of NAD depression is discussed.

¹ Present address: Department of Medicine, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215.

Received 6/17/68. Accepted 1/19/69.