CRITICAL FACTORS FOR OPTIMIZING THE 5-FLUOROURACIL-FOLINIC ACID ASSOCIATION IN CANCER-CHEMOTHERAPY

Background: The 5-fluorouracil (FU)-folinic acid (FA) association has demonstrated clinical efficacy in colorectal cancer, both in adjuvant and metastatic situations. However, there is no clear consensus about the optimal FU-FA schedule and dose. In addition, it would be of inter est to identify FU-FA-responsive tumors. Design: Our purpose was to re view preclinical and clinical data dealing with prediction of FU-FA se nsitivity and optimization of FU-FA schedules. Results: Preclinical st udies have highlighted the importance of thymidylate synthase (TS), th e cellular target of the FU-FA mechanism of action, for predicting FU sensitivity. It appears that the more sensitive cell lines express the lowest TS activity. Interestingly, the cell lines sensitive to FA sup plementation are those more sensitive to FU. The role of TS in FU-FA r esponsiveness has been clearly demonstrated in patients with colorecta l and gastric cancers. Preliminary in vitro and clinical data have sho wn that the folylpolyglutamate synthetase (FPGS), the enzyme responsib le for folate polyglutamylation, is another promising tool for identif ying FU-FA-responsive tumors. So far, results of clinical trials do no t form a clear consensus regarding the need to administer high FA dose s for improving FU-FA treatment. Experimental studies on human cancer cell lines have demonstrated the wide variability among cell lines, ra nging from 0.05 to 200 mu m, of 1 FA concentrations required for maxim al FU potentiation. In addition, pharmacokinetic studies have reported a significant variability of active folates in plasma after administr ation of standard-dose FA. Altogether, these observations favour high- dose FA administration to achieve high folate concentrations in plasma and thus to counteract the variability of the 1 FA concentrations req uired. With respect to the choice of FU-FA schedule, it appears from e xperimental data that increasing the duration of exposure to FA enhanc es FU-FA cytotoxicity, probably through an increased formation of redu ced folate polyglutamate forms. Considering the S-phase specificity of FU cytotoxicity as well as its rapid elimination from plasma, a sched ule of prolonged exposure to both FU and FA should be considered prefe rable. Conclusions: Results of the new FU-FA administration schedules such as the one consisting of a 2-hour FA administration followed by a combination of FU bolus and FU infusion, or the chronomodulated FU-FA infusion, open up promising approaches for improving the therapeutic index of FU-FA chemotherapy. Finally, future clinical studies should i nvestigate tumoral parameters pharmacologically linked to FU-FA sensit ivity such as pre-treatment TS and FPGS activities. Such tumoral inves tigations along with FU and FA pharmacokinetic investigations should p rovide a better understanding of inter-patient variability in response to FU-FA therapy and an optimal management of this chemotherapy regim en.