[Mode of action of fluoropyrimidines, in relation to their clinical application]

From results which we obtained in experiments on 5-fluoropyrimidine analogs, it was demonstrated that the mode of action of these compounds was as follows: In human cancer, in contrast to experimental animal tumors, it was demonstrated that thymidine phosphorylase (Thd Pase) activity was dominant compared to that of uridine phosphorylase (Urd Pase). This observation would indicate that 5-fluorouracil (5-FU) was mainly metabolized to produce 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), via 5-flu fluoro-2'-deoxyuridine(FdUR). FdUMP would inhibit DNA synthesis by blocking thymidilate synthetase activity, resulting in the death of cancer cells. Thd Pase activity by which 5-FU is converted to FdUR would participate greatly in the antitumor effect of the compounds because of the fact that FdUR has 1,000 times greater antitumor activity than 5-FU. Moreover, some of the fluoropyrimidines are activated by this enzyme to produce 5-FU. It should be emphasized that Thd Pase activity is higher in tumor tissue than in normal tissues. This finding would mean that the compounds would exert a selective (antitumor) activity on cancer cells. In addition, a clinical trial of fluoropyrimidines showed them to be effective when administered to patients in order to maintain a lower effective level of 5-FU in tumor tissues for a longer period of time. Such experiences would also lend more weight the possible of the mode of action of the of fluoropyrimidines mentioned above.