An attempt to develop non-viral gene therapy for advanced pancreatic cancer.

尝试开发针对晚期胰腺癌的非病毒基因疗法。

• 批准号: 13670503
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670503/
• 关键词: pancreatic cancer; gene therapy; tumor-targeting vector; RNA interference; 非ウイルスベクター; RNA interfereuce; ペプチドベクター; 腫瘍標的; c-raf

Pancreatic cancer is adisease with an extremely poor prognosis, but gene therapy, a totally novel treatment modality, is emerging as a potential treatment for curing such an intractable disese. In this study, an attempt is made to develop non-viral gene therapy for advanced pancreatic cancer through use of RNA interference (RNAi) and a tumor-targeting peptide vector, CRGDCF(K[H-]KKK)6.In general, the sequence-specific RNAi effect in the case of long double-stranded RNAs (dsRNAs) can be masked in commom mammalian cells because of their well-developed interferon response to dsRNAs, In human cancer cell lines, the RNAi (or RNAi-like) effect was observed even by long dsRNAs (Clin ExpPharrnacolPhysiol30: 96, 2003), being approximately two-fold more potent than the antisense RNA effect. Small interfering RNAs (siRNAs), duplexes of 21 nt RNA with 2 nt 3' overhangs, are short enough for evading the interferon response but long enough for inducing the RNAi effect. With Oligofectamine for transfection, the RNAi effect was observed in human leukemia cell lines (Cancer Gene Ther 10: 125, 2003). Although the efficiency was not so high compared with that with Oligofectamine, the peptide vector was observed to function as a carrier for siRNAs as wellas antisense oligonucleotides (Clin Exp Pharmacol Physiol 30: 96, 2003). The peptide vector and siRNA is supposed to electrostatically form a complex in a 1 to 1 molar ratio. Further studies are being planned to improve such a tumor-targeting gene therapy.

胰腺癌是一种预后极差的疾病，但基因治疗这种全新的治疗方式正在成为治愈这种难治性疾病的潜在治疗方法。在本研究中，尝试通过使用 RNA 干扰 (RNAi) 和肿瘤靶向肽载体 CRGDCF(K[H-]KKK)6 开发晚期胰腺癌的非病毒基因疗法。一般来说，长双链 RNA (dsRNA) 的序列特异性 RNAi 效应可能在普通哺乳动物细胞中被掩盖，因为它们的 对 dsRNA 的良好干扰素反应，在人类癌细胞系中，甚至在长 dsRNA 中也观察到了 RNAi（或 RNAi 样）效应（Clin ExpPharrnacolPhysiol30：96，2003），其效力大约是反义 RNA 效应的两倍。小干扰 RNA (siRNA) 是 21 nt RNA 与 2 nt 3' 突出端的双链体，其长度足够短，足以逃避干扰素反应，但又足够长，足以诱导 RNAi 效应。使用 Oligofectamine 进行转染，在人白血病细胞系中观察到 RNAi 效果（Cancer Gene Ther 10：125，2003）。虽然与 Oligofectamine 相比效率不高，但观察到肽载体可作为 siRNA 以及反义寡核苷酸的载体 (Clin Exp Pharmacol Physiol 30: 96, 2003)。肽载体和 siRNA 应该以 1:1 的摩尔比静电形成复合物。正在计划进一步的研究来改进这种肿瘤靶向基因疗法。

项目成果

Aoki Y., et al.: "RNA interference may be more potent than antisense RNA in human cancer cell lines"Clin Exp Pharmacol Physiol. 30. 96-102 (2003)

Aoki Y. 等人：“在人类癌细胞系中，RNA 干扰可能比反义 RNA 更有效”Clin Exp Pharmacol Physiol。

Aoki Y, Otuki T: "Ligand-directed tumor targeting in cancer gene therapy"Curr Top Pharmacol. (in press).

Aoki Y，Otuki T：“癌症基因治疗中的配体定向肿瘤靶向”Curr Top Pharmacol。

Cioca DP, Aoki Y, et al.: "RNA interference is a functional pathway with therapeutic potential in human myeloid leukemia cell lines"Cancer Gene Ther. 10. 125-133 (2003)

Cioca DP、Aoki Y 等人：“RNA 干扰是人髓系白血病细胞系中具有治疗潜力的功能途径”Cancer Gene Ther。

Aoki Y., Otsuki T.: "Ligand-directed tumor targeting in cancer gene therapy"Curr Top Pharmacol. (in press)

Aoki Y.，Otsuki T.：“癌症基因治疗中的配体定向肿瘤靶向”Curr Top Pharmacol。

Aoki Y, et al.: "RNA interference may be more potent than antisense RNA in human cancer cell lines"Clin Exp Pharmacol Physiol. 30. 96-102 (2003)

Aoki Y 等人：“在人类癌细胞系中，RNA 干扰可能比反义 RNA 更有效”Clin Exp Pharmacol Physiol。