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Interaction among the Distinct Effects of Adenine and Guanine Depletion in Mouse Lymphoma Cells¹

Departments of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94143

Toxic guanine depletion was shown previously to result in a dramatic reduction of DNA synthesis, while toxic adenine depletion failed to affect DNA synthesis (M. B. Cohen and W. Sadée, Cancer Res., 43: 1587–1591, 1983). In this study, relative DNA synthesis rates were measured in mouse lymphoma S49 cells over 24 hr after drug exposure and were compared to cell growth curves. DNA synthesis inhibition by mycophenolic acid (guanine starvation) was achieved at lower drug concentrations than was the inhibition of cell growth. This result further supports the hypothesis (reference above) that guanine starvation specifically affects cells in S phase while it allows cells with full DNA complement to divide. In contrast, L-alanosine (adenine starvation) failed to affect DNA synthesis for at least 24 hr at a concentration that inhibits cell growth by 80%. The dramatically different effects of guanine and adenine starvation on DNA synthesis can thus be used to assess the magnitude of each when blocking early de novo purine biosynthesis by 6-methyl-mercaptopurine ribonucleoside (6-MMPR). The results suggest that, although 6-MMPR effects primarily resemble those of guanine depletion, adenine starvation measurably contributes to the overall toxicity of 6-MMPR. Drug combination experiments with L-alanosine, mycophenolic acid, and 6-MMPR suggest that the basic mechanisms underlying the toxic effects of guanine and adenine starvation act synergistically.

¹ This work was supported by Grant CA 27866 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 8/18/83. Accepted 2/24/84.