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Correlation of Biochemical Effects and Incorporation of 3-Deazaguanine into Nucleic Acids to Cytotoxicity in L1210 Cells¹

Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037

3-Deazaguanine, a tumor-inhibitory purine antimetabolite, is cytotoxic to L1210 leukemic cells in culture. The log percentage of viability correlated strongly (r² = 0.986) with the product of the concentration of 3-deazaguanine, or [3-deazaguanine], and period of exposure (t) when [3-deazaguanine] was between 3 and 50 µM, and t was 12 or 24 hr. We wished to relate this cytotoxicity to biochemical effects mediated by 3-deazaguanine. 3-Deazaguanine inhibited both DNA and protein synthesis, and both log DNA synthesis and log protein synthesis correlated inversely with [3-deazaguanine] x t and directly with cell viability (P < 0.001). L1210 cells accumulated 3-deazaguanine 5'-triphosphate to a level of 1.5 nmol/10⁶ cells. 3-Deazaguanine treatment had no effect on intracellular cytidine 5'-triphosphate levels, but reduced adenosine 5'-triphosphate and uridine 5'-triphosphate levels by 40% relative to control and guanosine 5'-triphosphate levels by 85% relative to control at a [3-deazaguanine] x t value at which 3-deazaguanine 5'-triphosphate accumulation was near maximal. Incorporation of 2-¹⁴C-labeled 3-deazaguanine into DNA and RNA, separated by Cs₂SO₄ density gradient centrifugation, was demonstrated. Incorporation into DNA was linear versus [3-deazaguanine] x t and correlated inversely with cell viability (P < 0.001). These data suggest that 3-deazaguanine is anabolized and incorporated into DNA, and that this incorporation is related to decreased DNA synthesis and cell death. The decrease in protein synthesis and diminution of guanosine 5'-triphosphate levels following drug treatment may also contribute to the growth-inhibitory actions of 3-deazaguanine.

¹ Presented in part at the 77^th Annual Meeting of the American Association for Cancer Research, 1986 (1).

² From a dissertation presented to the Department of Pharmacology, the Graduate School of Arts and Sciences, The George Washington University, in partial fulfillment of the requirements for the Ph.D.

³ To whom requests for reprints should be addressed.

Received 3/10/86. Revised 7/14/86. Accepted 7/14/86.