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Study of the Cytotoxicity and Metabolism of 4-Amino-3-carboxamido-1-(ß-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine Using Inhibitors of Adenosine Kinase and Adenosine Deaminase¹

Departments of Biochemical Pharmacology and Toxicology [L. L. W.] and Medicinal Chemistry [L. B. T.], College of Pharmacy, University of Utah, Salt Lake City, Utah 84112

The greater in vivo antitumor activity of 4-amino-3-carboxamido-1-(ß-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (APPCR) in comparison to the parent compound 4-amino-1-(ß-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (APPR) may involve intrinsic differences in the effects of these two compounds on cells, as well as in their metabolisms. In studies with L1210 cells in vitro, growth inhibition by APPCR for 36 hr or more was found to be cytocidal, while growth inhibition by APPR was cytostatic in that a substantial fraction of the cells survived 36 or 72 hr of exposure to growth-inhibiting concentrations of APPR. It appears that this difference in the cellular effects of APPCR and APPR is not related to differences in the requirement for activation by phosphorylation or in susceptibility to inactivation by deamination. However, deamination may limit the effectiveness of APPR in vivo since it is a substrate for adenosine deaminase, while deamination of APPCR is not detectable.

¹ This work was supported by Contracts N01-CM-43806 and NCI-CM-77142 from the Division of Cancer Treatment, National Cancer Institute, NIH. A portion of this material has been reported previously in abstract form (26).

² To whom requests for reprints should be addressed, at College of Pharmacy, 1010 Pharmacy, University of Michigan, Ann Arbor, Mich. 48109.

³ Present address: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Mich. 48109.

Received 11/10/78. Accepted 4/26/79.