Yoshizawa Jun, Takizawa Asako, Takeuchi Osamu, Hiraku Osamu, Sasaki Ken, Morimoto Yoshihito, Atsuda Koichiro, Inoue Gaku, Suzuki Yukio, Asanuma Fumiki, Yamada Yoshinori
Department of Pharmacy, Yokohama Rosai Hospital, Yokohama, Japan.
Cancer Chemother Pharmacol. 2009 Nov;64(6):1211-9. doi: 10.1007/s00280-009-0990-0. Epub 2009 Apr 1.
To determine the most effective combination chemotherapy with S-1 against pancreatic cancer and to clarify the mechanism of synergy between S-1 and the partner drug.
We tested a combination of S-1 with the following antitumor drugs in an in vitro MTT assay against pancreatic cancer cell line MIA PaCa-2: gemcitabine (GEM), cisplatin (CDDP), irinotecan (CPT-11), mitomycin C, adriamycin, and paclitaxel. The efficacy of S-1, GEM, and a combination of S-1 and GEM was also tested in vivo by administering S-1 (10 mg/kg) orally to nude mice five times a week for 3 weeks, and GEM (100 mg/kg) intravenously every 2-3 days for a total of six times. A treated-to-control ratio (T/C) of relative mean tumor weight values less than 50% was determined to be effective. Furthermore, we investigated the mechanism of the synergistic effect of S-1 and GEM on the cell cycle by flow cytometry, because both S-1 and GEM are known as antimetabolic drugs. To verify cell death induced by a change in the distribution of the cell cycle phases, we investigated apoptosis by sub-G1 analysis and a TUNEL assay.
From classical isobolography analysis of the in vitro MTT assay, the combination of S-1 plus GEM was found to be the most effective of the combinations tested. In vivo, T/C (percentage) with the combination of S-1 plus GEM was 48.2%, which was lower than that of S-1 or GEM alone, and the combination enhanced antitumor activity. Cell cycle analysis showed greater cell cycle delay with the combination treatment (S-1 plus GEM) than for each single drug treatment, and apoptotic cells were detected only in treatments including GEM.
The combination chemotherapy of S-1 and GEM appears to be useful for pancreatic cancer. Both cycle delay by S-1 plus GEM and apoptosis induced by GEM are involved in this synergistic mechanism.
确定与S-1联合使用治疗胰腺癌最有效的化疗方案，并阐明S-1与联合用药之间的协同作用机制。
我们在体外MTT试验中，用S-1与以下抗肿瘤药物联合，作用于胰腺癌细胞系MIA PaCa-2：吉西他滨（GEM）、顺铂（CDDP）、伊立替康（CPT-11）、丝裂霉素C、阿霉素和紫杉醇。通过每周5次口服给予裸鼠S-1（10 mg/kg），持续3周，以及每2-3天静脉注射GEM（100 mg/kg），共6次，来检测S-1、GEM以及S-1与GEM联合用药在体内的疗效。相对平均肿瘤重量的治疗组与对照组比值（T/C）小于50%被判定为有效。此外，由于S-1和GEM均为抗代谢药物，我们通过流式细胞术研究了S-1与GEM对细胞周期协同作用的机制。为了验证细胞周期阶段分布变化诱导的细胞死亡，我们通过亚G1期分析和TUNEL试验研究细胞凋亡情况。
通过体外MTT试验的经典等效线图分析，发现S-1加GEM的联合用药是所测试联合用药中最有效的。在体内，S-1加GEM联合用药的T/C（百分比）为48.2%，低于单独使用S-1或GEM，联合用药增强了抗肿瘤活性。细胞周期分析显示，联合治疗（S-1加GEM）比每种单一药物治疗导致更大的细胞周期延迟，并且仅在包含GEM的治疗中检测到凋亡细胞。
S-1与GEM联合化疗似乎对胰腺癌有效。S-1加GEM导致的周期延迟和GEM诱导的凋亡均参与了这种协同机制。
