Specific Gene Therapy for Pancreatic Cancer

在胰腺癌中，c-K-ras基因突变是肿瘤生长和转移的关键事件。我们以前已经证明了N116 Y对胰腺癌细胞生长的显性负效应。为了评价N116 Y抑制胰腺癌细胞转移生长的潜力，我们制备了由癌胚抗原（CEA）启动子驱动的复制缺陷型重组N116 Y腺病毒（Ad CEA-N116 Y）。我们证明，N116 Y的表达，生长抑制和凋亡诱导都是特异性的胰腺癌细胞系（PCI-35和PCI-43）的启动子阳性，而没有观察到生长迟缓后，在人胚胰腺衍生的细胞系1C 3D 3的Ad CEA-N116 Y感染。我们检测了Ad CEA-N116 Y对PCI-43集落在肝脏中转移生长的影响，所述集落通过将肿瘤注射到裸鼠脾脏中产生。结果表明，Ad CEA-N116 Y在肿瘤细胞接种后5天通过脾内注射有效地减少了转移集落的数量，而没有任何并发症。因此，N116 Y基因能够选择性地抑制胰腺癌细胞的转移生长，提示N116 Y基因治疗胰腺癌肝微转移具有潜在的应用价值。

In pancreatic cancer, the mutation of c-K-ras is a critical event of tumor growth and meastasis. We have previously demonstrated a dominant negative effect of N116Y on the growth of pancreatic cancer cells. To evaluate the potential of N116Y for suppressing the metastatic growth of pancreatic tumor cells, we made a replication-deficient recombinant N116Y adenovirus driven by the carcinoembryonic antigen (CEA) promoter (Ad CEA-N116Y). We demonstrated that the expression of N116Y, growth inhibition, and apoptotic death induction were all specific to pancreatic cancer cell lines (PCI-35 and PCI-43) that were promoter positive, whereas no growth retardation was observed in human embrynic pancreas-derived cell line 1C3D3 after Ad CEA-N116Y infection. We examined the effect of Ad CEA-N116Y on the metastatic growth of PCI-43 colonies in liver, which were generated by tumor injection into the spleen of nude mice. The results showed that Ad CEA-N116Y effectively reduced the number of metastatic colonies without any complication by injecting intrasplenically five days after tumor cell inoculation. Thus N116Y can selectively suppress the metastatic growth of pancreatic tumor cell by using the CEA promoter driven adenovirus vector indicating the N116Y gene therapy may be potentially useful for the treatment of pancreatic cancer patients with liver micrometastasis.