Modulation of 5-FU action by thymidine in murine and human tumors

The biochemical basis of, and preclinical experience with, combined chemotherapy with thymidine and 5-FU are reviewed. Phase I trial and clinical pharmacologic evaluation of a monthly schedule of thymidine and 5-FU showed marked increase in the biologic activity of 5-FU. Both toxic and antitumor effects were observed. Myelosuppression was the dose-limiting side effect. The central nervous system toxicity of 5-FU appeared increased; gastrointestinal toxicity was not. The available data do not permit an assessment of whether the therapeutic index of 5-FU has been altered by combination with thymidine. The basis for the observed increase in potency of 5-FU appears to be a thymine-induced marked slowing in its catabolism that results in a prolonged plasma half-life for 5-FU and an increased cellular exposure to the drug.