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，但基因治疗是一种全新的治疗方式，正在成为治愈这种顽固性疾病的潜在治疗方法。在这项研究中，试图通过RNA干扰(RNAi)和肿瘤靶向多肽载体CRGDCF(K[H-]KKK)6来发展晚期胰腺癌的非病毒基因治疗。一般来说，在普通哺乳动物细胞中，由于长双链RNA(DsRNAs)对dsRNAs发育良好的干扰素反应，序列特异性RNAi效应可以被掩盖，在人类癌细胞系中，RNAi(或RNAi样)效应甚至被长dsRNAs(Clin ExpPharrnacolPhysiol30：96,2003)观察到，其效力大约是反义RNA的两倍。小干扰RNAs(SiRNAs)是由21ntRNA和2个nt3‘端突出物组成的双链，其长度足以避开干扰素反应，但足以诱导RNAi效应。以低聚氨基甲胺为转染剂，在人白血病细胞系中观察到RNAi效应(癌症基因Ther 10：125,2003)。虽然效率不如低聚链霉胺那样高，但可以观察到该多肽载体可以作为siRNA和反义寡核苷酸的载体(Clin Exp Pharmacol Physiol 30：96,2003)。多肽载体和siRNA被认为以1：1的摩尔比静电形成复合体。进一步的研究正在计划中，以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。