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DNA-directed Actions of 3-Deazaguanine: Effects on DNA Integrity and DNA Elongation/Ligation¹

Department of Pharmacology, The George Washington University Medical Center, Washington, D.C. 20037

The cytotoxic action of the guanine analogue, 3-deazaguanine, was shown previously to be closely associated with deazaguanine-induced inhibition of DNA synthesis and incorporation of deazaguanine into DNA. The DNA-directed effects of the compound have been further investigated by studying the effect of deazaguanine on DNA integrity, and on the ability of pulse-labeled L1210 cells to synthesize full length DNA. Deazaguanine caused DNA single strand breaks in newly synthesized DNA but not in preformed DNA. The amount of DNA single strand breaks correlated with both deazaguanine exposure and with the amount of deazaguanine incorporated into the DNA. When cells were allowed to recover in drug-free medium for 12 or 24 h after drug exposure little effect on either the amount of DNA single strand breaks or cell viability relative to controls was observed. Deazaguanine also inhibited the ability of L1210 cells to synthesize full length DNA after pulse labeling of DNA. This effect was temporally related to the inhibition by deazaguanine of total DNA synthesis.

¹ Supported in part by an Elsie McNulty grant from the American Cancer Society (CH 274) and Grant CA 36946 from the National Cancer Institute to K. A. K. Presented in part at the 1986 Joint Meeting of the American Society for Pharmacology and Experimental Therapeutics and The Society of Toxicology (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. Present address: Loyola University Medical Center, Section of Hematology/Oncology, Maywood, IL 60152.

³ To whom requests for reprints should be addressed.

Received 7/31/87. Revised 2/16/88. Accepted 2/23/88.