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Stimulatory Effects of Inosine and Deoxyinosine on the Incorporation of Uracil-2-¹⁴C, 5-Fluorouracil-2-¹⁴C, and 5-Bromouracil-2-¹⁴C into Nucleic Acids by Ehrlich Ascites Tumor Cells in Vitro¹

Department of Molecular Biology, Vanderbilt University, Nashville, Tennessee 37203

The incorporation of uracil-2-¹⁴C into the nucleic acids of Ehrlich ascites tumor cells is increased 10- to 50-fold by the addition of inosine. Maximum stimulation is obtained at an inosine concentration of 1 mM. Actinomycin D (50 µg/ml) abolishes incorporation. The effect of inosine seems unlikely to be mediated by an enhancement of synthesis of ATP, 5-phosphoribosyl-1-pyrophosphate, or nucleic acids by de novo pathways. Unlike uracil incorporation, the labeling of nucleic acid by uridine-2-¹⁴C is extensive in the absence of inosine. The incorporation of 5-fluorouracil-2-¹⁴C into RNA also is greatly increased by inosine. Inosine has little effect on the incorporation of 5-bromouracil-2-¹⁴C into nucleic acids, whereas deoxyinosine is a potent stimulator. Deoxyinosine, on the other hand, is a relatively weak enhancer of uracil incorporation. These results suggest that ribose-1-phosphate and deoxyribose-1-phosphate may be rate limiting for the incorporation of uracil (or 5-fluorouracil) and 5-bromouracil into RNA and DNA respectively. Inosine and deoxyinosine serve as precursors of ribose-1-phosphate and deoxyribose-1-phosphate. These interconversions involve purine and pyrimidine nucleoside phosphorylases. The possible application of these findings in chemotherapy is discussed.

¹ This study was supported in part by grants from the National Science Foundation (G-25126), the National Cancer Institute of the USPHS (CA-07489), and an Institutional Grant from the American Cancer Society.

² Aided by a grant for a Postdoctoral Research Scholarship from the American Cancer Society. Present address: Molecular Disease Branch, National Heart Institute, NIH, Bethesda, Maryland.

³ Present address: Radiation Protection Division, Department of National Health and Welfare, Ottawa, Canada.

Received 6/10/68. Accepted 11/22/68.

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