This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bennett, L. L. Articles by Barker, T. L. Search for Related Content PubMed PubMed Citation Articles by Bennett, L. L., Jr. Articles by Barker, T. L.

The Primary Site of Inhibition by 6-Mercaptopurine on the Purine Biosynthetic Pathway in Some Tumors in Vivo^*

( Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Ala.)

The effects of 6-mercaptopurine on the incorporation of a number of C¹⁴-labeled precursors into soluble purines and into purines of DNA and of RNA have been studied in leukemia L1210 cells, Ehrlich ascites cells, and solid Sarcoma 180, with the purpose of determining which of the several sites at which 6-mercaptopurine may inhibit the biosynthesis of purine nucleotides is the most sensitive in the intact cell in vivo.

6-Mercaptopurine inhibited markedly the incorporation of formate and glycine and did not inhibit the utilization of adenine or 2,6-diaminopurine. There was no inhibition of the incorporation of 4-amino-5-imidazolecarboxamide into adenine derivatives and no consistent and marked inhibition of incorporation into guanine derivatives. In the ascites cell lines, the conversion of 4-amino-5-imidazolecarboxamide to purines was essentially uninhibited by levels of 6-mercaptopurine 8–20 times those that produced a 50 per cent or greater inhibition of synthesis de novo.

These results suggest that, in these tumor systems in vivo, the principal site at which 6-mercaptopurine inhibits biosynthesis of purines is at a point prior to the formation of the ribonucleotide of 4-aminoimidazole-5-carboxamide and that the interconversion of purine ribonucleotides is not a primary site of action.

^* This work was supported by grant No. T-13E from the American Cancer Society; by the Cancer Chemotherapy National Service Center, National Cancer Institute, under National Institutes of Health Contract No. SA-43-ph-2433; and grants from the Charles F. Kettering Foundation and the Alfred P. Sloan Foundation.

Affiliated with the Sloan-Kettering Institute for Cancer Research, New York.

Received 5/13/63.