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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。

基本信息

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

项目摘要

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.

我一直在寻找肿瘤靶向的潜力，以实现胰腺癌或肝癌的成功基因治疗，包括反义治疗。 1．关于K-ras、DPC4、p53和cyclin A在胰腺癌中的作用以及咖啡因对肝癌发生的抑制作用的研究已经进行，结果已发表或正在出版。设计针对ras信号通路的胰腺癌或肝癌基因治疗策略似乎是值得的。2．开发出一种新型肿瘤靶向肽载体（cRGD-hK），旨在对晚期实体瘤患者进行系统、重复给药（已申请专利）。 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) 阳离子寡聚赖氨酸，与质粒 DNA 或寡核苷酸形成复合物，以及 (iii) 组氨酰残基，以促进从酸性内涵体中逃逸。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用途。研究结果发表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。即使成功靶向癌细胞，期望转导大多数细胞似乎也是不现实的。除了重复反义疗法之外，我们还提出了一种通过使用肿瘤靶向肽载体和RNA干扰概念来治疗晚期胰腺癌或肝癌的潜在非病毒基因疗法。