The combination of oral
tegafur-
uracil (UFT) with
leucovorin (LV) is used to treat patients with stage II to III
colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous
5-FU plus LV
therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in
colorectal tumors with high expression levels of
thymidylate synthase (TS), which affects
5-FU efficacy, remains to be clarified. This study investigated the effect of LV on the antitumor activity of UFT and/or
5-FU prodrugs in low
folate diet-fed nude mice using human
colorectal cancer xenografts with various expression levels of TS. The addition of LV to UFT resulted in a 55-79% inhibition of
tumor growth among 11 types of
colorectal tumor xenograft, whereas UFT alone showed 23-67% antitumor activity. Although there was an inverse relationship between the antitumor effect of UFT alone and UFT plus LV and tumoral TS activity, UFT plus LV appeared to have a more potent antitumor effect than UFT alone on
colorectal tumors such as Co-3 and KM12C/5-FU with high expression levels of TS. This finding was confirmed by the significant positive correlation between the relative inhibition ratio of UFT/LV to UFT alone and TS levels in
tumors. To investigate the reason for the higher efficacy of UFT/LV on
colorectal cancer xenografts with high TS activity, intratumoral levels of reduced folates and a ternary complex of TS after oral UFT with or without LV were measured using Co-3 xenografts. Elevated levels of reduced folates and an increased ternary complex of TS in LV-treated
tumors were noted. Our results indicate that a combined
therapy of UFT with LV may contribute to the treatment of
colorectal cancer patients with low and high expression levels of tumoral TS by increased formation of the ternary complex of TS leading to potentiated antitumor efficacy of UFT.