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

胰腺癌是一种预后极差的疾病，而基因治疗作为一种全新的治疗方式，正成为治疗这种难治性疾病的一种潜在治疗方法。本研究尝试利用RNA干扰（RNAi）技术和肿瘤靶向肽载体CRGDCF，开发晚期胰腺癌的非病毒基因治疗（K[H-]KKK）6.一般来说，在长双链RNA（dsRNA）的情况下，序列特异性RNAi效应可以在普通哺乳动物细胞中被掩盖，因为它们对dsRNA有良好的干扰素应答。在人癌细胞系中，甚至通过长dsRNA也观察到RNAi（或RNAi样）效应（Clin ExpPharrnacolPhysiol 30：96，2003），其效力比反义RNA效应高大约两倍。小干扰RNA（siRNA），21 nt RNA与2 nt 3'突出端的双链体，足够短以逃避干扰素应答，但足够长以诱导RNAi效应。用Oligofectamine进行转染，在人白血病细胞系中观察到RNAi效应（Cancer Gene Ther 10：125，2003）。尽管与Oligofectamine相比效率不那么高，但观察到肽载体作为siRNA以及反义寡核苷酸的载体起作用（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。目前正在计划进一步的研究来改进这种肿瘤靶向基因治疗。

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.