This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Pieper, R. O. Articles by Mandel, H. G. Search for Related Content PubMed PubMed Citation Articles by Pieper, R. O. Articles by Mandel, H. G.

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.