Takechi Teiji, Okabe Hiroyuki, Ikeda Kazumasa, Fujioka Akio, Nakagawa Fumio, Ohshimo Hideyuki, Kitazato Kenji, Fukushima Masakazu
Cancer Research Laboratory, Product Lifecycle Management Department, Taiho Pharmaceutical Co., Ltd., 1-27 Kanda-Nishikicho, Chiyoda-ku, Tokyo 101-8444, Japan.
Oncol Rep. 2005 Jul;14(1):33-9.
The purposes of this study were to evaluate the antitumor activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2,4-dihydroxypyridine and 1 M potassium oxonate) on human lung tumor xenografts, as compared with other fluoro-pyrimidines, and to investigate the relationships between fluoropyrimidine antitumor activities and four distinct enzymatic activities involved in the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism. S-1, UFT (1 M tegafur-4 M uracil), 5'-deoxy-5-fluorouridine (5'-DFUR), capecitabine and 5-FU were administered for 14 consecutive days to nude mice bearing lung tumor xenografts. S-1 showed stronger tumor growth inhibition in four of the seven tumors than the other drugs. Cluster analysis, on the basis of antitumor activity, indicated that S-1/UFT and 5'-DFUR/capecitabine/5-FU could be classified into another group. We investigated tumor thymidylate synthase content, dihydropyrimidine dehydrogenase (DPD) activity, thymidine phosphorylase (TP) activity and orotate phosphoribosyl transferase activity in seven human lung tumor xenografts and performed regression analyses for the antitumor activities of fluoropyrimidines. There were inverse correlations between antitumor and DPD activities for 5'-DFUR (r=-0.79, P=0.034), capecitabine (r=-0.56, P=0.19) and 5-FU (r=-0.86, P=0.013). However, no such correlations were observed for S-1 and UFT. These findings suggest that S-1 containing a potent DPD inhibitor may have an antitumor effect on lung tumors, with high basal DPD activity, superior to those of other fluoropyrimidines.
本研究的目的是评估S-1（1M替加氟、0.4M 5-氯-2,4-二羟基吡啶和1M奥替拉西钾）对人肺肿瘤异种移植瘤的抗肿瘤活性，并与其他氟嘧啶类药物进行比较，同时研究氟嘧啶类药物的抗肿瘤活性与5-氟尿嘧啶（5-FU）代谢的磷酸化和降解途径中涉及的四种不同酶活性之间的关系。将S-1、优福定（1M替加氟-4M尿嘧啶）、5'-脱氧-5-氟尿苷（5'-DFUR）、卡培他滨和5-FU连续14天给予荷人肺肿瘤异种移植瘤的裸鼠。在七种肿瘤中的四种中，S-1显示出比其他药物更强的肿瘤生长抑制作用。基于抗肿瘤活性的聚类分析表明，S-1/优福定和5'-DFUR/卡培他滨/5-FU可分为另一组。我们研究了七种人肺肿瘤异种移植瘤中的肿瘤胸苷酸合成酶含量、二氢嘧啶脱氢酶（DPD）活性、胸苷磷酸化酶（TP）活性和乳清酸磷酸核糖基转移酶活性，并对氟嘧啶类药物的抗肿瘤活性进行了回归分析。5'-DFUR（r=-0.79，P=0.034）、卡培他滨（r=-0.56，P=0.19）和5-FU（r=-0.86，P=0.013）的抗肿瘤活性与DPD活性之间存在负相关。然而，S-1和优福定未观察到此类相关性。这些发现表明，含有强效DPD抑制剂的S-1可能对具有高基础DPD活性的肺肿瘤具有抗肿瘤作用，优于其他氟嘧啶类药物。
