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Studies on Fluorinated Pyrimidines X. In Vivo Studies on Tumor Resistance^*

( McArdle Memorial Laboratory, The Medical School, University of Wisconsin, Madison 6, Wis.)

The biochemical mechanism of resistance has been studied at chemotherapeutic doses in mice bearing 5-fluorouracil-sensitive and- resistant Ehrlich ascites carcinomas. The 5-fluorouracil-resistant tumor is also resistant to 5-fluorouridine and 5-fluoro-2'-deoxyuridine. The incorporation of formate-C¹⁴ into DNA thymine is inhibited to a much greater extent and for a longer duration in the susceptible than in the resistant tumor. Biochemical dose-response studies in mice treated with 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2'-deoxyuridine show a much greater inhibition of the incorporation of formate-C¹⁴ into DNA thymine in the susceptible than in the resistant tumor. In the susceptible tumor, the incorporation of uracil-2-C¹⁴ into DNA thymine was inhibited by 5-fluorouracil and 5-fluoro-2'-deoxyuridine, but not by 5-fluorouridine, whereas none of the drugs inhibited this incorporation in the resistant cells. None of the drugs significantly affected the incorporation of uracil-2-C¹⁴ into RNA uracil in either tumor. There was a minor decrease in the conversion of 5-fluorouracil into 5-fluorouridylic acid and RNA in the resistant tumor, but the amount of 5-fluoro-2'-deoxyuridylic acid produced was about the same in both tumors. These results show that, administered in therapeutic doses to intact animals, the fluorinated pyrimidines inhibit the synthesis of DNA thymine in the susceptible but not in the resistant tumor.

^* This work was supported in part by a grant-in-aid of the Wisconsin Division of the American Cancer Society; a grant, C-2832, from the National Cancer Institute, National Institutes of Health, U.S. Public Health Service; and by a grant-in-aid from Hoffmann-LaRoche, Inc. A preliminary account of part of this work appeared in Fed. Proc., 18: 244, 1959. Paper IX is in J. Biol. Chem. (16).

Received 12/31/59.