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Purine Biosynthesis and Inhibitors in Ascites Cell Tumors^*

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

In vitro incorporation of glycine-2-C¹⁴ into nucleic acid purines was partially inhibited by 6-mercaptopurine (6-MP) in all four of the ascites tumors tested. Only two of these tumors were susceptible to 6-MP as measured by prolongation of survival in tumor-bearing mice.

Azaserine was demonstrated to react with a tumor cell constituent, in vivo or in vitro, during the first 8–10 minutes of contact and to give essentially complete inhibition of de novo purine synthesis thereafter by what appears to be an irreversible binding to an enzyme or enzymes necessary to the synthesis. This results in a relatively large accumulation of an intermediate, which gives analyses corresponding to those for glycinamide ribotide.

Partial inhibition of the in vitro utilization of adenosine monophosphate as a nucleic acid purine precursor was achieved with L(+)-threochloramphenicol. This drug gave additive effects with azaserine on prolongation of life in tumor-bearing mice.

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

Received 5/ 2/56.