Potentiation of the anti-tumor activity of 5FU by thymidine and its correlation with the formation of (5FU)RNA.

Abstract

Evidence is presented with two murine tumor systems (CD8F1 mammary carcinoma and CD2F1 colon tumor 26). We question the thesis that the antitumor activity of 5-fluorouracil (FU) is achieved solely by the inhibition of thymidylate synthetase by the derivative, fluorodeoxymonophosphate (FdUMP). The data described here are more consistent with the formation of FU-containing RNA (FU-RNA), an event which can adversely affect a variety of cellular mechanisms requiring RNA processing and function. These are not two mutually exclusive mechanisms. However, if the deleterious effect of FU-RNA constitutes a significant quantitative component of the anti-neoplastic activity of FU, the addition of thymidine would be expected to increase the antitumor activity of FU by the following three mechanisms: 1) protection of FU from catabolic degradation by saturation of the relevant enzymes with thymidine; 2) selective arrest by thymidine “feedback” of normal cells compared with malignant cells; 3) feedback repression of the FU anabolic pathways leading to deoxyderivatives, thus encouraging the entry of FU into RNA. The data reported here show that thymidine (as well as certain other nucleosides) does in fact markedly stimulate the incorporation of 5FU into newly synthesized nuclear RNA, an event which is paralleled by a striking increase in antitumor activity. Kinetic analysis of the events following the injection of FU reveals that DNA synthesis in the tumors is partially inhibited for up to 12 hours, although the effect on thymidylate synthetase is virtually immediate and complete, as measured by the incorporation of deoxyuridine into DNA. The earlier inhibition of DNA synthesis is reversible by thymidine. Subsequently however, cessation of DNA synthesis, due to the presence of FU, can no longer be reversed.