Development of antisense therapy for pancreatic cancer or hepatoma : potential of the tumor targeting.

胰腺癌或肝癌反义疗法的发展：肿瘤靶向的潜力。

• 批准号: 11670489
• 负责人: AOKI Yuji
• 金额: $ 2.3万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670489/
• 关键词: pancreatic cancer; hepatoma; antisense theraphy; peptide vector; RGD motif; tumor targeting; K-ras

I have sought the potential of the tumor targeting to achieve successful gene the rapy for pancreatic cancer or hepatoma including antisense therapy.1. Studies concerning K-ras, DPC4, p53 and cyclin A in pancreatic cancer and the inhibitory effect of caffein on hepatocarcinogenesis have been performed, and the results have been published or are in press. It seems to be worthy to design a strategy of gene therapy for pancreatic cancer or hepatoma by targeting the ras signalling pathway.2. A novel tumor-targeting peptide vector (cRGD-hK) has been developed, that is intended to be systemically and repeatedly administered to patients with advanced solid tumors (the patent application has been done). The peptide vector of 36 1-amino acid residues, CRGDCF (K[H-]KKK) 6, has three elements : (i) a tumor-homing RGD motif to target tumor tissues, (ii) cationic oligolysine to form complexes with plasmid DNA or oligonucleotides, and (iii) histidyl residues to facilitate the escape from the acidic endosomes. Using CMV-driven luciferase expression plasmids as a reporter in pancreatic cancer and hepatoma celllines, the potential usefulness as a tumor-targeting vector was demonstrated in vitro and in vivo. The results were presented at the 3rd Conference of American Society of Gene Theraphy and at the 9th International Conference of Cancer Gene Therapy. Even if the targeting of cancer cells is successful, it seems to be unrealistic to expect a transduction of the majority of cells. In addition to repetitive antisense theraphy, we propose a potential non-viral gene theraphy for advanced pancreatic cancer or hepatoma through use of the tumor-targeting peptide vector and the concept of RNA interference.

本课题的研究目的是探索肿瘤靶向治疗胰腺癌或肝癌的可能性，包括反义治疗.关于胰腺癌中K-ras、DPC 4、p53和cyclin A的研究以及咖啡因对肝癌发生的抑制作用，已发表或正在出版。以ras信号通路为靶点设计胰腺癌或肝癌的基因治疗策略具有重要意义.已经开发了一种新型的肿瘤靶向肽载体（cRGD-hK），旨在全身重复给药于晚期实体瘤患者（专利申请已完成）。36个1-氨基酸残基的肽载体CRGDCF（K[H-]KKK）6具有三个元件：（i）靶向肿瘤组织的肿瘤归巢RGD基序，（ii）与质粒DNA或寡核苷酸形成复合物的阳离子寡聚赖氨酸，和（iii）促进从酸性内体逃逸的组氨酰残基。使用CMV驱动的荧光素酶表达质粒作为胰腺癌和肝癌细胞系中的报告基因，在体外和体内证明了作为肿瘤靶向载体的潜在有用性。研究结果在第三届美国基因治疗学会会议和第九届国际癌症基因治疗会议上发表。即使靶向癌细胞是成功的，期望转导大多数细胞似乎是不现实的。除了重复的反义治疗外，我们提出了一种潜在的非病毒基因治疗晚期胰腺癌或肝癌，通过使用肿瘤靶向肽载体和RNA干扰的概念。

项目成果

Aoki Y.: "Potential non-viral gene theraphy of pancreatic cancer targeting the ras signalling pathway"in Research Advances in Cancer. (in press).

Aoki Y.：“针对 ras 信号通路的胰腺癌潜在非病毒基因治疗”，《癌症研究进展》。

Mukawa K,Kawa S.,Aoki Y,Zhai Y,Nikaido T: "Reduced expression of p53 and cyclin A in intraductal mucin-hyperseoreting neoplasm of the pancreas compared with usual pancreatic ductal adenocareinoma"Am J Gastroenterol. 94. 2262-2267 (1999)

Mukawa K、Kawa S.、Aoki Y、Zhai Y、Nikaido T：“与普通胰腺导管腺癌相比，胰腺导管内粘蛋白过度肿瘤中 p53 和细胞周期蛋白 A 的表达减少”Am J Gastroenterol。

Aoki Y.: "Potential non-viral gene therapy of pancreatic cancer targeting the ras signaling pathway."Research Advances in Cancer. (in press).

Aoki Y.：“针对 ras 信号通路的胰腺癌潜在非病毒基因疗法。”癌症研究进展。

Aoki Y,Hosaka S,Tachibana N,Karasawa Y,Kawa S,Kiyosawa K.: "Reassessment of k-1 as mutations at codon 12 by direct PCR and sequencing from tissue microdissestion in human pancreatic adenocarcinomas"Pancreas. 21. 152-157 (2000)

Aoki Y、Hosaka S、Tachibana N、Karasawa Y、Kawa S、Kiyosawa K.：“通过直接 PCR 和人胰腺腺癌组织微解剖测序重新评估 k-1 作为密码子 12 的突变”。

Hosaka S,Kawa S,Aoki Y,Tamaka E,Yoshizawa K,Karasawa Y,Hosuka N,Kiyotawa K: "Hepatocarcinogenesis inhibition by cattein in ACI rats treated with 2-acetylamino fluorene."Food Chem Toxicol. (in press).

Hosaka S、Kawa S、Aoki Y、Tamaka E、Yoshizawa K、Karasawa Y、Hosuka N、Kiyotawa K：“用 2-乙酰氨基芴处理的 ACI 大鼠中 cattein 抑制肝癌发生。”食品化学毒理学。