Molecular Pharmacology, Vol 17, 279-282, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

The Effect of 5-Fluorouridine 5'-Triphosphate on RNA Transcribed in Isolated Nuclei in Vitro

¹ National Cancer Institute, Laboratory of Medicinal Chemistry and Biology, Applied Pharmacology Section, Bethesda, Maryland 20205

Using nuclei prepared from rat liver, the effect of 5-fluorouridine 5'-triphosphate (FUTP) was assessed on the nearest neighbor frequency of the incorporation of [-³²P]ATP and [-³²P]GTP into nascent RNA transcribed by RNA polymerase I and II. When UTP was replaced by an equimolar concentration of FUTP, GMP was preferentially incorporated next to AMP in either the presence or the absence of -amanitin. In addition, the incorporation of AMP, but not GMP, next to UMP and GMP was significantly reduced. The effect of FUTP on GMP incorporation into nearest neighbors was particularly evident in the presence of -amanitin. These effects were virtually completely reversed by the addition of UTP to the reaction mixture. When endogenous template activity was inhibited by actinomycin D and RNA was transcribed from poly(dA-dT) · poly(dA-dT), misincorporation of AMP by the presence of FUTP was greatly enhanced. These results show that FUTP is capable of producing base-pair transformations with mammalian RNA polymerases, and suggest that this effect may account, in part, for the aberrant effects of 5-fluorouracil on RNA synthesis and processing in vivo.

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ACKNOWLEDGMENT The authors wish to express their appreciation to Mrs. Margaret Green for the preparation of this manuscript.