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Selective Metabolic Effects of 1,3-Bis(2-chloroethyl)-1-nitrosourea upon de Novo Purine Biosynthesis¹

Department of Biochemistry [D. G.], Division of Basic Health Sciences, and the Department of Medicine, Division of Hematology [J. M. D., W. R. V., E. S. M., B. B.], Emory University School of Medicine, Emory University, Atlanta, Georgia 30322

The rate of incorporation of formate-¹⁴C into the nucleic acid purines of leukemic cells was stimulated by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This observation indicated that BCNU had an effect on de novo purine biosynthesis, affecting a certain reaction(s) involved with the insertion of either the C-2 or C-8 position of the purine ring. Studies with aminoimidazolecarboxamide riboside showed no direct effect of BCNU on the insertion of formate-¹⁴C into the C-2 position. The rate of incorporation of histidine-2-¹⁴C into the nucleic acid purines of leukemic cells was inhibited by BCNU. Excretion of formiminoglutamate was increased and excretion of aminoimidazolecarboxamide was decreased in patients receiving BCNU. These findings suggest that BCNU inhibits a reaction(s) involved with the insertion of the C-8 position of the purine ring.

¹ This investigation was supported by USPHS Research Grants CA-03528 and CA-05733 from the National Cancer Institute and FR-39 from the General Clinical Research Centers Branch, Division of Research Facilities and Resources. Publication No. 980 of the Division of Basic Health Sciences, Emory University School of Medicine.

² Supported by a Cancer Research Training Grant 5-TO1 CA-05127.

Received 9/ 8/70. Accepted 11/16/70.