Studies on fluorinated pyrimidines. X. In vivo studies on tumor resistance.

Abstract

Summary 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-C 14 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-C 14 into DNA thymine in the susceptible than in the resistant tumor. In the susceptible tumor, the incorporation of uracil-2-C 14 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-C 14 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.