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Effects of 6-Diazo-5-oxo-L-norleucine and Other Tumor Inhibitors on the Biosynthesis of Nicotinamide Adenine Dinucleotide in Mice¹

Division of Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research, and Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University Medical College, New York, New York

NAD² in extracts of mouse liver and tumor was determined enzymically by ADH and chemically by reaction with cyanide. The presence of Sarcoma 180 caused a decrease in the level of NAD in the host liver. Of the 16 antitumor agents tested for inhibition of nicotinamide-induced biosynthesis of NAD, DON was the most effective. 6-Fluoronicotinamide, 5-fluoronicotinic acid, azaserine, and 6-mercaptopurine were inhibitory but less effective, and mitomycin, actinomycin, and amethopterin were ineffective. DON caused a slight decrease in the normal levels of liver and tumor NAD and completely prevented the increased synthesis of NAD induced by nicotinamide. Glutamine given before administration of DON and nicotinamide did not prevent the effect of DON. An accumulation of desamido-NAD in the livers of mice treated with nicotonamide plus DON was found approximately equal to the amounts of NAD synthesized in the absence of DON. It is suggested that DON inhibits the enzyme system that converts desamido-NAD to NAD—NAD synthetase.

¹ Supported in part by Grant No. CA-03192-08 from the National Cancer Institute, NIH.

² The abbreviations used are: NAD, nicotinamide adenine dinucleotide; ADH, alcohol dehydrogenase; DON, 6-diazo-5-oxo-L-norleucine; desamido-NAD, nicotinic acid analog of NAD; TCA, trichloroacetic acid; NAm, nicotinamide; 6-AN, 6-aminonicotinamide; NMN, nicotinamide mononucleotide; NAc, nicotinic acid; and AMP, adenine monophosphate.

Received 5/24/65. Revised 8/30/65.