Department of Surgery, Institute of DNA Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
Pancreas. 2011 May;40(4):600-7. doi: 10.1097/MPA.0b013e31820b9257.
Paclitaxel (PTX) is a useful treatment for peritoneal dissemination of malignant tumors. However, chemoresistance due to PTX-induced nuclear factor κB (NF-κB) activation is an important cause of suboptimal therapeutic effect. We previously reported nafamostat mesilate (FUT175) inhibits NF-κB activation and promotes apoptosis in pancreatic cancer. We hypothesized that addition of FUT175 to PTX may enhance the antitumor effect in peritoneal dissemination of pancreatic cancer.
In vitro, we assessed NF-κB activity and apoptosis by the combination of FUT175 and PTX using human pancreatic cancer cell line (AsPc-1). In vivo, we established peritoneal dissemination in nude mice by intraperitoneal injection of AsPc-1 cells. The animals were treated with intraperitoneal injection thrice a week of FUT175, once a week of PTX, or a combination of thrice a week of FUT175 and once a week of PTX (combination group).
In the combination groups, PTX-induced NF-κB activation was inhibited, and apoptosis was enhanced in comparison with other groups both in vitro and in vivo. In the combination group, tumor growth, serum tumor marker, and survival rate were significantly better than those in other groups (P < 0.05).
Combination chemotherapy using PTX with FUT175 exerts an antitumor effect for peritoneal dissemination of pancreatic cancer.
紫杉醇（PTX）是治疗恶性肿瘤腹膜转移的有效药物。然而，PTX 诱导核因子 κB（NF-κB）激活导致的化疗耐药是影响治疗效果的重要原因。我们之前的研究表明，那屈肝素钙（FUT175）可抑制 NF-κB 激活并促进胰腺癌凋亡。我们假设在 PTX 中加入 FUT175 可能增强胰腺癌腹膜转移的抗肿瘤作用。
在体外，我们使用人胰腺癌细胞系（AsPc-1）评估 FUT175 与 PTX 联合应用对 NF-κB 活性和凋亡的影响。在体内，我们通过腹腔内注射 AsPc-1 细胞建立腹膜转移模型。动物每周腹腔内注射 FUT175 三次、每周腹腔内注射 PTX 一次或每周腹腔内注射 FUT175 三次联合每周腹腔内注射 PTX 一次（联合组）进行治疗。
与其他组相比，联合组中 PTX 诱导的 NF-κB 激活受到抑制，体外和体内的细胞凋亡均增强。联合组中，肿瘤生长、血清肿瘤标志物和生存率均明显优于其他组（P<0.05）。
PTX 联合 FUT175 的联合化疗对胰腺癌腹膜转移具有抗肿瘤作用。
