Fluorouracil catabolism in the combination treatment of cyclophosphamide, methotrexate and fluorouracil.

The CMF-regimen is amongst the most effective chemotherapeutic approaches in the treatment of breast cancer. It is generally accepted that the efficacy of the combination of the three agents used in the regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), is based on interactions between the drugs at the intratumoral level. In WAG/Rij rats we previously demonstrated that change of FUra clearance at the first day of the CMF-regimen occurs owing to concomitant CY + MTX. In the present study clearance of FUra and the first product of FUra catabolism, FUraH2, were monitored at day 1 and day 8 of the regimen upon treatment with single agent FUra (F), MTX + FUra (MF), CY + FUra (CF), and CY + MTX + FUra (CMF). At the first day of treatment, FUra and FUraH2 systemic exposure was demonstrated to be increased in CMF-treated rats owing to concomitant CY+MTX. At the eighth day of treatment it was found that repeated CY administration during the previous seven days in CF-treated rats resulted in increased FUra and FUraH2 systemic exposure and therefore increased the dose of FUra artificially. It is concluded that altered FUra clearance owing to extratumoral interactions by concomitant CY and MTX contributes to the efficacy of the CMF-regimen.