Wada Yoshiyuki, Yoshida Kazuhiro, Suzuki Takahisa, Mizuiri Hirozumi, Konishi Kazuo, Ukon Kei, Tanabe Kazuaki, Sakata Yu, Fukushima Masakazu
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Int J Cancer. 2006 Aug 15;119(4):783-91. doi: 10.1002/ijc.21879.
We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK-1, and MKN-1, -28, -45 and -74), in a time- and dose-dependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growth-inhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors.
我们最近在一项I/II期研究中证实，多西他赛（TXT）与S-1联合化疗对转移性胃癌有效。为阐明这些药物协同作用的潜在机制，我们在体外和体内研究了氟尿嘧啶（5-FU）代谢相关酶的生长抑制作用和表达谱。单独使用TXT以及TXT与5-FU联合使用均能以时间和剂量依赖性方式抑制我们检测的5种胃癌细胞系（TMK-1、MKN-1、-28、-45和-74）的生长。此外，在体外TMK-1细胞中观察到显著的协同作用，5-FU的IC50值在4.73至0.61 nM之间。此外，在TMK-1异种移植瘤中，5-FU/TXT联合治疗显示出协同抗肿瘤作用。然而，S-1与TXT联合使用比5-FU/TXT联合治疗表现出更强的生长抑制作用。通过对5-FU代谢酶的表达和活性分析，研究了S-1与TXT协同作用的潜在机制。胸苷酸合成酶（TS）和二氢嘧啶脱氢酶（DPD）的表达分别降至对照水平的50%和73%，乳清酸磷酸核糖转移酶（OPRT）的蛋白水平增加了3.9倍。这些发现表明两种药物发生了生化调节，活性测定结果进一步证实了这一点。这些数据有力地表明，TXT与S-1联合化疗对胃癌有效，因此是治疗这些肿瘤的标准化疗策略的良好候选方案。
