Calcium leucovorin and 5-fluorouridine cytotoxicity

The action of fluoropyrimidine (FP) drugs at thymidylate synthase (TS) is associated with enhanced chemotherapeutic response. Calcium leucovorin (CF) increases the cytotoxicity of the FP drugs, 5-fluorouracil and 5-fluorodeoxyuridine, in human laryngeal carcinoma HEp-2 cells by directing the action of these drugs at TS. Thus, the effect of CF on the cytotoxicity and site of action of the FP, 5-fluorouridine (FUrd), was investigated in HEp-2 cells. The cytotoxicity of FUrd was unaffected by CF. Moreover, CF was unable to alter the growth-limiting target of FUrd to TS. HEp-2 cells convert FUrd to FdUMP, the FP metabolite that is the direct inhibitor of TS; thus, the inability of CF to modulate FUrd action is not due to lack of inhibitor formation. In addition, greater than 90 percent of TS activity is inhibited at concentrations of FUrd that inhibit HEp-2 cell growth by 50 percent. Thus, while TS is significantly inhibited by FUrd, it is not the growth-limiting target of this drug. It is likely that the RNA-directed effects of FUrd are so extensive that CF, which maximizes TS-directed action, is ineffective at reducing the cytotoxicity further. An approach to overcoming the RNA-directed effects of FUrd is suggested.