Department of Surgery and Oncology, Kyushu University, Fukuoka 812-8582, Japan.
Anticancer Res. 2011 Apr;31(4):1279-87.
Although gemcitabine is the standard treatment for pancreatic cancer, this particular type of cancer develops rapidly and has intrinsic chemoresistance. Chemoresistance plays a critical role in tumor progression, invasion and migration. Nevertheless, the effect of adenoviral therapy on chemoresistant cancer cells has not been studied. In this study, we compared the efficacy of adenoviral therapy in parental and chemoresistant pancreatic cancer cells.
To establish gemcitabine-resistant cells, pancreatic cancer SUIT2 cells were exposed to increasing concentrations of gemcitabine. Both parental and chemoresistant cells were infected with adenoviruses expressing either green fluorescent protein (Ad-GFP) or the hepatocyte growth factor antagonist, NK4 (Ad-NK4). To investigate the transduction efficacy, GFP expression and NK4 concentrations were measured and an invasion assay was used to investigate the efficacy of the adenoviral therapy.
The 50% inhibitory concentration of gemcitabine was <10 nM in the parental SUIT-2 cells, while it was >1 μM in gemcitabine-resistant cells. A large number of gemcitabine-resistant cells were GFP-positive compared with only a small number of parental cells (p<0.05). The NK4 expression level was significantly higher in gemcitabine-resistant cells than in parental cells (p<0.05). The supernatant from Ad-NK4-infected gemcitabine-resistant cells significantly inhibited the invasion of cancer cells compared with that from Ad-NK4-infected parental cells (p<0.05).
Both the efficiency of transduction and the therapeutic efficacy of adenoviral therapy were higher in gemcitabine-resistant cells than in parental cells, suggesting that adenoviral gene therapy is more effective in patients with gemcitabine-resistant pancreatic cancer.
吉西他滨是胰腺癌的标准治疗药物，但这种特殊类型的癌症发展迅速，具有内在的化疗耐药性。化疗耐药性在肿瘤的进展、侵袭和迁移中起着关键作用。然而，尚未研究腺病毒治疗对耐药性癌细胞的影响。在本研究中，我们比较了腺病毒治疗对亲本和耐药性胰腺癌细胞的疗效。
为了建立吉西他滨耐药细胞，将胰腺癌细胞 SUIT2 暴露于逐渐增加的吉西他滨浓度下。用表达绿色荧光蛋白（Ad-GFP）或肝细胞生长因子拮抗剂 NK4（Ad-NK4）的腺病毒分别感染亲本和耐药细胞。为了研究转导效率，测量 GFP 表达和 NK4 浓度，并进行侵袭实验以研究腺病毒治疗的效果。
亲本 SUIT-2 细胞的吉西他滨 50%抑制浓度<10 nM，而耐药细胞的吉西他滨 50%抑制浓度>1 μM。与少量亲本细胞相比，大量耐药细胞呈 GFP 阳性（p<0.05）。耐药细胞中 NK4 的表达水平明显高于亲本细胞（p<0.05）。与 Ad-NK4 感染的亲本细胞相比，Ad-NK4 感染的耐药细胞的上清液显著抑制了癌细胞的侵袭（p<0.05）。
与亲本细胞相比，吉西他滨耐药细胞中的转导效率和腺病毒治疗的疗效都更高，这表明腺病毒基因治疗在吉西他滨耐药胰腺癌患者中更有效。
