Tsujimoto Hiroaki, Tsukioka Sayaka, Ono Satoru, Sakamoto Etsuko, Sakamoto Kazuki, Tsuta Kohji, Nakagawa Fumio, Saito Hitoshi, Uchida Junji, Kiniwa Mamoru, Fukushima Masakazu
Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan.
Oncol Lett. 2010 Nov;1(6):973-980. doi: 10.3892/ol.2010.172. Epub 2010 Sep 17.
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.
根据术后随机研究结果，口服替加氟-尿嘧啶（UFT）联合亚叶酸钙（LV）用于治疗II至III期结肠癌患者，其中UFT/LV治疗显示出与静脉注射5-氟尿嘧啶加LV疗法相当的疗效。然而，在胸苷酸合成酶（TS）高表达的结直肠肿瘤中，LV添加到UFT中是否能提高UFT的抗肿瘤活性，这一点仍有待阐明，TS会影响5-氟尿嘧啶的疗效。本研究使用具有不同TS表达水平的人结直肠癌异种移植模型，研究了LV对低叶酸饮食喂养的裸鼠中UFT和/或5-氟尿嘧啶前体药物抗肿瘤活性的影响。在11种结直肠肿瘤异种移植模型中，UFT联合LV可使肿瘤生长抑制55%-79%，而单独使用UFT时抗肿瘤活性为23%-67%。尽管单独使用UFT和UFT加LV的抗肿瘤作用与肿瘤TS活性之间存在负相关，但UFT加LV对TS高表达的结直肠肿瘤如Co-3和KM12C/5-FU似乎比单独使用UFT具有更强的抗肿瘤作用。UFT/LV相对于单独使用UFT的相对抑制率与肿瘤中TS水平之间的显著正相关证实了这一发现。为了研究UFT/LV对TS活性高的结直肠癌异种移植模型疗效更高的原因，使用Co-3异种移植模型测量了口服UFT加或不加LV后肿瘤内还原型叶酸水平和TS三元复合物水平。在LV治疗的肿瘤中，观察到还原型叶酸水平升高和TS三元复合物增加。我们的结果表明，UFT与LV联合治疗可能有助于治疗肿瘤TS低表达和高表达的结直肠癌患者，通过增加TS三元复合物的形成，导致UFT的抗肿瘤疗效增强。
