Development of tumor specific viralvector and application for gene therapy against human pancreatic cancer

肿瘤特异性病毒载体的研制及其在人胰腺癌基因治疗中的应用

• 批准号: 12470232
• 负责人: KATOH Hiroyuki
• 金额: $ 10.43万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470232/
• 关键词: Pancreatic Cancer; genetic analysis; RCAS1; gene therapy; CEAプロモーター

We investigated the correlation between several cancer associated genes and histopathological features in several cancers, and reported that high expression of RCAS1 gene correlated with tumor progression and predicted poor outcome in carcinomas of the gallbladder, the esophagus, the bile duct, and the pancreas. Especially in pancreatic cancer, RCAS1 expression was very frequent. Our data suggested that RCAS1 could be a potential target for gene therapy against pancreatic cancer. We also reported the investigation of gene therapy for pancreatic cancer. As the activation of ras protooncogene was important for progression of pancreatic cancer, we made a replication-deficient recombinant adenovirus expressing a dominant negative ras mutant, which reduced the activation of endogenous ras, driven by the carcinoembryonic antigen promoter (AdCEA-N116Y). We examined the effect of AdCEA-N116Y on the metastatic growth of pancreatic cancer cell line PCI-43 in liver, which was generated by tumor injection into the spleen of nude mice. The results showed that AdCEA-N116Y effectively reduced the number of metastatic colonies without any complication. Thus, N116Y can selectively suppress the metastatic growth of pancreatic tumor cell by using the CEA promoter-driven adenovirus vector indicating that N116Y gene therapy may be potentially useful for the treatment of pancreatic cancer patients with liver micrometastasis

我们研究了几种癌症相关基因与几种癌症的组织病理学特征之间的相关性，并报道了RCAS 1基因的高表达与肿瘤进展相关，并预测胆囊癌、食管癌、胆管癌和胰腺癌的预后不良。尤其在胰腺癌中RCAS 1的表达更为频繁。RCAS 1可能成为胰腺癌基因治疗的潜在靶点。本文还报道了胰腺癌基因治疗的研究进展。由于ras原癌基因的激活对胰腺癌的进展是重要的，我们制作了一个复制缺陷型重组腺病毒，表达一个显性负性ras突变体，它减少了内源性ras的激活，由癌胚抗原启动子驱动（AdCEA-N116 Y）。我们研究了AdCEA-N116 Y对胰腺癌细胞系PCI-43在肝脏中转移生长的影响，该细胞系通过将肿瘤注射到裸鼠脾脏中产生。结果表明，AdCEA-N116 Y能有效地减少转移集落的数量，且无任何并发症。因此，N116 Y可以通过CEA启动子驱动的腺病毒载体选择性地抑制胰腺癌细胞的转移生长，表明N116 Y基因治疗可能用于胰腺癌肝微转移的治疗

项目成果

Hiraoka K: "High expression of tumor associated antigen RCAS1 in pancreatic ductal denocarcinoma is a novel unfavrable prognostic marker"Int J Cancer.. (In press). (2002)

Hiraoka K：“胰腺导管腺癌中肿瘤相关抗原 RCAS1 的高表达是一种新的不良预后标志物”Int J Cancer..（正在出版）。

Takeuchi M: "The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice"Gene Ther.. 7(6). 518-526 (2000)

Takeuchi M：“显性失活 H-ras 突变体 N116Y 可抑制裸鼠肝脏中转移性人胰腺癌细胞的生长”Gene Ther.. 7(6)。

Suzuoki M: "RCASl expression as a prognostic factor after curative surgery for extrahepatic bile ducf carcinoma"Ann Surg Oncol. (In press). (2002)

Suzuoki M：“RCAS1表达作为肝外胆管癌根治性手术后的预后因素”Ann Surg Oncol。

Nakakubo Y: "The prognostic significance of RCASl expression in squamous cell carcinoma of the oesophagus"Cancer Lett. 177(1). 101-105 (2002)

Nakakubo Y：“食管鳞状细胞癌中RCAS1表达的预后意义”Cancer Lett。

Kato K: "Over-expression of caveolin-1 in esophageal squamous cell carcinoma correlates with lymph node metastasis, and pathologic stage"Cancer.. (In press). (2002)

Kato K：“食管鳞状细胞癌中 Caveolin-1 的过度表达与淋巴结转移和病理分期相关”癌症..（正在出版）。