[Augmentation of chemotherapeutic efficaciousness of UFT by oral l-leucovorin--l-leucovorin factors enhancing cytotoxic activity of 5-fluorouracil].

The relationship between augmentation of cytotoxic activity of 5-fluorouracil (FUra) by l-leucovorin (l-LV) and combination schedule was investigated using human colon adenocarcinoma KM 20 C cell line. The enhancement of cytotoxic activity of FUra by l-LV or 5-CH3FH4, a main metabolite after oral administration of l-LV, was observed after 96-hr exposure to either l-LV or 5-CH3FH4 at concentrations of greater 0.001 microM or 0.3 microM, respectively. We found that 1.5 microM FUra, which has no effect on cell-growth without l-LV, could suppress strongly the proliferation if cells were co-treated with l-LV for more than 8 hr. Therefore, enhancement of cytotoxic activity of FUra by l-LV depended on the time cell exposure to l-LV. Moreover, this effect was observed even at a concentration of 0.01 microM l-LV after 48-hr exposure. Likewise, it is known that the antitumor activity of FUra correlates with the time-schedule of treatment with FUra. These results suggest that in addition to FUra derivatives which continuously release FUra, it is beneficial for the combination therapy of FUra with l-LV to consider continuous administration of l-LV as well.