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In Vivo Sensitivity of Normal and Neoplastic Mouse Tissues to Azaserine^*

( McArdle Memorial Laboratory, Medical School, University of Wisconsin, Madison 6, Wis.)

It was found that normal and neoplastic mouse tissues differed widely in their sensitivity to azaserine and 6-diazo-5-oxo-L-norleucine (DON). Rapidly growing tissues required lower doses of inhibitor. When inhibited by azaserine, liver accumulated an unknown intermediate; lung, spleen, and tumor accumulated formylglycinamide ribotide (FGAR); the kidney and intestine accumulated both FGAR and the unknown intermediate. DON in low doses caused the accumulation of smaller amounts of the same intermediates, but with higher doses no accumulation was found, indicating that at higher doses DON also inhibits at a point prior to FGAR formation. Azaserine inhibition in liver and kidney was found to last approximately 9 hours, indicating that, as reported earlier for ascites tumors, a binding reaction occurs with the enzyme. Equivalent inhibitions of de novo purine synthesis were obtained with one-tenth to one-twentieth the amount of DON as compared with azaserine.

^* This research was supported in part by United States Public Health Service Grant No. C2491 and in part by the Alexander and Margaret Stewart Fund.

Received 5/ 8/57.