Anti-oncogene hammerhead ribozymes (RNA enzymes) specifically inhibit oncogens in a mice model system.

抗癌基因锤头核酶（RNA 酶）可特异性抑制小鼠模型系统中的致癌基因。

• 批准号: 09670239
• 负责人: KIJIMA Hiroshi
• 金额: $ 2.05万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670239/
• 关键词: ribozyme; RNA enzyme; gene modulation; pancreatic cancer; ras oncogene; mice model

Pancreatic cancer is one on lethal human cancers, and development of its new therapeutic strategy is eagerly required today. Point mutation in the K-ras gene is observed at a high incidence in human pancreatic carcinomas. These alterations can be used as potential targets for specific ribozyme-mediated reversal of the malignant phenotype. We have demonstrated the efficacy of a hammerhead ribozyme directed against codon 12 of the activated K-ras gene in a Capan-1 human pancreatic carcinoma cell line. To develop this strategy into a therapeutic application, we designed a recombinant adenovirus encoding a gene cassette for the anti-K-ras ribozyme. By using this recombinant adenovirus in a mice model system, it was possible to accomplish efficient reversion of the malignant phenotype in human pancreatic tumors with K- ras gene mutation. The high efficiency adenoviral-mediated delivery of anti-oncogene ribozyme could emerge as a significant gene therapy strategy against human malignancies.

胰腺癌是人类致命的癌症之一，当今迫切需要开发其新的治疗策略。在人类胰腺癌中观察到 K-ras 基因点突变的发生率很高。这些改变可用作特定核酶介导的恶性表型逆转的潜在靶标。我们已经在 Capan-1 人胰腺癌细胞系中证明了锤头核酶针对激活的 K-ras 基因密码子 12 的功效。为了将该策略开发为治疗应用，我们设计了一种编码抗 K-ras 核酶基因盒的重组腺病毒。通过在小鼠模型系统中使用这种重组腺病毒，可以有效逆转具有 K-ras 基因突变的人胰腺肿瘤的恶性表型。高效腺病毒介导的抗癌基因核酶递送可能成为针对人类恶性肿瘤的重要基因治疗策略。

项目成果

Hitoshi Yamazaki: "Inhibition of tumor growth by ribozyme-mediated suppression of aberrant epidermal growth factor receptor gene expression." Journal of National Cancer Institute. 90. 581-587 (1998)

Hitoshi Yamazaki：“通过核酶介导的异常表皮生长因子受体基因表达抑制来抑制肿瘤生长。”

Hiroshi Kijima: "Hammerhead ribozymes against γ-glutamylcysteine synthetase mRNA down-regulate intracellular glutathione concentration of mouse islet cells." Biochemical and Biophysical Research Communications. 247. 697-703 (1998)

Hiroshi Kijima：“针对 γ-谷氨酰半胱氨酸合成酶 mRNA 的锤头核酶下调小鼠胰岛细胞的细胞内谷胱甘肽浓度。” 生物化学和生物物理研究通讯。

Hiroshi Kijima: "Ribozymes as a novel approach for the treatment of human pancreatic carcinoma." Methods in Molecular Medicine. 11. 193-208 (1998)

Hiroshi Kijima：“核酶作为治疗人类胰腺癌的新方法。”

Takamiya,Y.: "Murine P-Glycoprotein on Stromal Vessels Mediates Multidrug Resistance in Intracerebral Human Glioma Xenografts" British Journal of Cancer. 76. 445-450 (1997)

Takamiya,Y.：“基质血管上的鼠 P-糖蛋白介导人脑胶质瘤异种移植物的多药耐药性”英国癌症杂志。

Hitoshi Yamazaki, Hiroshi Kijima, Yasuyuki Ohnishi Y,Yoshiyuki Abe, Yoshiro Oshika, Takashi Tsuchida, Tetsuji Tokunaga, Atsush Tsugu, Yoshito Ueyama Norikazu Tamaoki, Masato Nakamura.: "Inhibition of tumor growth by ribozyme-mediated suppression of aberra

Hitoshi Yamazaki、Hiroshi Kijima、Yasuyuki Ohnishi Y、Yoshiyuki Abe、Yoshiro Oshika、Takashi Tsuchida、Tetsuji Tokunaga、Atsush Tsugu、Yoshito Ueyama Norikazu Tamaoki、Masato Nakamura。：“通过核酶介导的 aberra 抑制来抑制肿瘤生长