Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
Dig Dis Sci. 2013 Jan;58(1):123-31. doi: 10.1007/s10620-012-2311-4. Epub 2012 Jul 18.
Intraperitoneal (i.p.) administration of paclitaxel is useful for treating malignant tumors with peritoneal dissemination, but the therapeutic efficacy is limited. Chemoresistance due to paclitaxel-induced nuclear factor-kappa B (NF-κB) activation is an important cause of suboptimal therapeutic efficacy.
The purpose of this study was to prove that addition of nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor and an NF-κB inhibitor, to i.p. paclitaxel enhances antitumor effects of paclitaxel against gastric cancer with peritoneal dissemination.
In vitro, we assessed NF-κB activity and apoptosis in response to treatment with FUT-175 alone, paclitaxel alone, or a combination of FUT-175 and paclitaxel in a human gastric cancer cell line (MKN-45). In vivo, we established peritoneal dissemination in nude mice by i.p. injection of MKN-45 cells. The animals received i.p. injections of FUT-175 alone three times a week (FUT-175 group), of paclitaxel alone once a week (paclitaxel group), or a combination of FUT-175 and paclitaxel (combination group) three times and once a week, respectively.
In the combination group, paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both in vitro and in vivo. In the combination group, number and weight of peritoneal nodules were significantly lower than those in the paclitaxel group (p = 0.0009 and p = 0.0417, respectively). In the survival analysis, the combination group had a significantly better survival than the paclitaxel group (p = 0.0048).
FUT-175 enhances the antitumor effect of i.p. paclitaxel against gastric cancer with peritoneal dissemination by inhibiting NF-κB activation in mice.
腹腔内（i.p.）给予紫杉醇对治疗伴有腹膜扩散的恶性肿瘤是有效的，但疗效有限。紫杉醇诱导核因子-κB（NF-κB）激活导致的化疗耐药是疗效欠佳的一个重要原因。
本研究旨在证明腹腔内给予紫杉醇时联合应用合成丝氨酸蛋白酶抑制剂和 NF-κB 抑制剂法莫替丁（FUT-175）可增强紫杉醇对伴有腹膜扩散的胃癌的抗肿瘤作用。
在体外，我们评估了单独应用 FUT-175、紫杉醇或 FUT-175 与紫杉醇联合应用对人胃癌细胞株（MKN-45）的 NF-κB 活性和凋亡的影响。在体内，我们通过腹腔内注射 MKN-45 细胞建立了腹膜扩散模型。动物接受每周三次腹腔内注射 FUT-175（FUT-175 组）、每周一次腹腔内注射紫杉醇（紫杉醇组）或每周三次和一次腹腔内注射 FUT-175 和紫杉醇（联合组）。
与其他组相比，联合组在体外和体内均抑制了紫杉醇诱导的 NF-κB 激活并增强了凋亡。联合组腹膜结节的数量和重量均显著低于紫杉醇组（p=0.0009 和 p=0.0417）。在生存分析中，联合组的生存状况显著优于紫杉醇组（p=0.0048）。
FUT-175 通过抑制 NF-κB 在小鼠中的激活，增强了腹腔内给予紫杉醇对伴有腹膜扩散的胃癌的抗肿瘤作用。
