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Effect of Methotrexate and 5-Fluorodeoxyuridine on Ribonucleotide Reductase Activity in Mammalian Cells¹

Department of Biochemistry and MCV/VCU Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298 [H. L. E.]; Department of Physiology and Pharmacology, Duke University Medical School, Durham, North Carolina 27710 [H. L. E., E. L. B., B. H. K., S. D. H.]; and Department of Biochemistry, Georgetown University, Schools of Medicine and Dentistry, Washington, D. C. 20007 [M. S.]

A number of studies in bacteria have indicated that deoxythymidine 5'-triphosphate may be a repressor or corepressor of ribonucleotide reductase. For determination of whether a similar regulating mechanism exists in mammalian cells, HeLa cells and partially hepatectomized rats were treated with either methotrexate, 5-fluorouracil, or 5-fluorodeoxyuridine in order to block thymidylate synthesis and consequently lower the intracellular pools of deoxy-thymidine 5'-triphosphate. In HeLa cells there was a significant (360 to 400%) increase in reductase activity in both the methotrexate and 5-fluorodeoxyuridine-treated cells. The administration of methotrexate to partially hepatectomized rats resulted in a 2.7-fold enhancement of the hepatectomy-induced increase in reductase activity, and the 5-fluorouracil treatment yielded a 60% increment in the increase of ribonucleotide reductase activity after partial hepatectomy.

Cycloheximide prevented the increase in reductase activity after the exposure of HeLa cells to methotrexate and 5-fluorodeoxyuridine, indicating that the stimulation of ribonucleotide reductase activity was the result of enhancement of de novo enzyme synthesis rather than of enzyme activation. The data support the thesis that deoxythymidine 5'-triphosphate or a thymidylate metabolite may be involved in the regulation of ribonucleotide reductase levels in mammalian cells.

¹ This work was presented in part at the Fall Meeting of the American Society for Pharmacology and Experimental Therapeutics, Inc., Université de Montréal, Montreal, Canada, 1974 (13), and the 67th Annual Meeting of the American Association for Cancer Research, Toronto, Canada, 1976 (15).

² Recipient of NIH Grant CA 11978. To whom requests for reprints should be addressed at: Department of Biochemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond, Va. 23298.

³ Recipient of NIH Grant CA 13195 and CA 11950.

Received 5/ 3/76. Accepted 9/ 8/77.