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Comparative Studies of Fluorinated Pyrimidines with Various Cell Lines¹

McArdle Laboratory for Cancer Research, The Medical School, University of Wisconsin, Madison, Wisconsin 53706

The effects of a number of pyrimidine nucleoside analogs on the growth of HeLa, Novikoff hepatoma, and L 5178 leukemia cells in culture have been determined. Information on the biochemical mechanisms of action has been obtained by experiments on the prevention of the inhibition by normal metabolites and by reversal from inhibition by delayed addition of the normal metabolites. In HeLa cells the appropriate normal metabolites prevented the inhibition produced by 5-fluorouracil, 5-fluoro-2'-deoxyuridine (FUDR), 5-fluorouridine, 2',3'-dehydro-5-fluoro-2'-deoxyuridine, 5-iodo-2'-deoxyuridine, 5-trifluoromethyl-2'-deoxyuridine, and arabinofuranosylcytosine. Delayed addition of the normal metabolites reversed the inhibition produced by the above compounds with the exception of 5-trifluoromethyl-2'-deoxyuridine and 5-iodo-2'-deoxyuridine, which were not reversed by thymidine, and the inhibition by 5-fluorouridine, which was not reversed by uridine, suggesting that the irreversible toxicity was the consequence of incorporation of these analogs into nucleic acids. Cell lines of the Novikoff hepatoma and L 5178Y leukemias were studied that were resistant to FUDR as a result of a loss of thymidine kinase. These cells were effectively inhibited by 2',3-dehydro-5-fluoro-2'-deoxyuridine, a new analog that is not phosphorylated by thymidine kinase. With the exception of arabinofuranosylcytosine, all the compounds exerted widely differing toxicities to the various cell lines.

¹ This work was supported in part by Grant CA 7175 from the National Cancer Institute. NIH, USPHS. A preliminary abstract of part of this work appeared in Abstracts. Seventh International Congress of Biochemistry, Tokyo, Japan, Aug. 1967, p. 1033. This is Paper No. 30 of a series on fluorinated pyrimidines.

² Holder of National Institutes of Health International Research Fellowship 2 F05 TW-950-02. Present address: Tissue Culture Laboratory, Yokohama City University, Yokohama, Japan.

³ American Cancer Society Professor of Oncology.

Received 5/ 2/68. Accepted 8/28/68.