载体介导RNA干扰技术在肿瘤治疗中的应用进展(2)
RNAi作为一项基因沉默技术，在诱导细胞凋亡、增加药物敏感性、抑制突变基因和血管生成等方面将可能成为新的肿瘤治疗方法[15]。近期研究发现Raf-1因子可能在一些血管生成因子的调控激活中起决定作用。Meng等[16]通过沉默胃癌肿瘤细胞的Rcf-1基因发现，可以抑制胃癌裸鼠移植瘤的生长和降低血管生成，因而认为Rcf-1有可能成为肿瘤治疗和血管生成抑制剂的新靶点。Guo等[17]通过沉默结肠癌细胞SW480的CTNNB1基因发现，结肠癌细胞的增殖下降、细胞出现死亡，与此同时，c-Myc和cyclinD1的表达水平也得到了相应的下调。密歇根大学在研究中发现，EZH2蛋白的增高与乳腺癌、前列腺癌、胰腺癌等的发生有关。Chen等[18]通过沉默EZH2基因发现，胰腺癌细胞在体外的生长受到抑制，并且在体内的成瘤率显著降低，证明了EZH2在胰腺癌的肿瘤生长和肝转移的过程中起着关键作用。AURKB和EGFR同属于酪氨酸蛋白激酶家族成员，在激素难治性前列腺细胞癌等上皮细胞癌中过度表达。Addepalli等[19]通过分别沉默了前列腺细胞癌的AURKB和EGFR基因，使其在裸鼠体内的生长得到了抑制。将两个基因联合敲除后，裸鼠体内的肿瘤出现消退，约40%的治疗后裸鼠体内未检测出肿瘤，因而认为联合敲除有望成为治疗肿瘤的新方法。
, 百拇医药
3展望
RNAi技术已经引起了实验生物学的巨大变革，在肿瘤治疗中，它可以单独应用，也可以与药物等其它治疗手段联合应用。虽然目前质粒和慢病毒载体介导的RNAi技术用于肿瘤的基因治疗已取得了一些进展，但临床应用尚早，还需要深入研究和探讨其转染细胞的机制，需要构建更加高效、安全、且可调控的肿瘤靶向性的载体。相信，随着人们对RNAi研究的不断深入，它必将从实验研究走向临床应用?
参考文献
[1]Timmons L,Fire A.Specific interference by ingested dsRNA.Nature,1998,395(45):854.
[2]Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature,2001,411(12):494-498.
, 百拇医药
[3]Dong L,Xu H,Liu YB, et al.M-PEIs nanogels: potential nonviral vector for systemic plasmid delivery to tumor cells.Cancer Gene Ther,2009,16(7):561-566.
[4]Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo.Science,1990,247(4949):1465-1468.
[5]Durcan N, Murphy C, Cryan SA. Inhalable siRNA: potential as a therapeutic agent in the lungs. Mol Pharm,2008,5(4):559-566.
, http://www.100md.com
[6]Gao JQ, Zhao QQ, Lv TF, et al. Gene-carried chitosan-linked-PEI induced high gene transfection efficiency with low toxicity and significant tumor-suppressive activity.Int J Pharm,2010,387(1-2):286-294.
[7]Koppu S, Oh YJ,Edrada-Ebel R, et al.Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA.J Control Release,2010,143(2):215-221.
[8]Naldini L, Blomer U, Gallay P, et al . In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science,1996,272:263.
, 百拇医药
[9]Nishitsuji H, Ikeda T, Miyoshi H, et al. Expression of small hairpin RNA by lentivirus-based vector confers efficient and stable gene-suppression of HIV-1 on human cells including primary non-dividing cells.Microbes Infect,2004,6(1):76-85.
[10]Li M, Rossi JJ. Lentiviral vector delivery of siRNA and shRNA encoding genes into cultured and primary hematopoietic cells. Methods Mol Biol,2005,30(9):261-272.
[11]Tsai BY, Uen JL, Chiang BL.Lentiviral-mediated Foxp3 RNAi suppresses tumor growth of regulatory T cell-like leukemia in a murine tumor model.Gene Ther, 2010,17(8):972-979.
, 百拇医药
[12]Matsui K, Sasaki Y, Komatsu T, et al. RNAi gene silencing using cerasome as a viral-size siRNA-carrier free from fusion and cross-linking. Bioorg Med Chem Lett,2007,17(14):3935-3938.
[13]Tian W, Liou HC.RNAi-mediated c-Rel silencing leads to apoptosis of B cell tumor cells and suppresses antigenic immune response in vivo.Plos One,2009,4(4):5028.
[14]Lin W, Zhang J, Liu X,et al. RNAi-mediated inhibition of MSP58 decreases tumour growth, migration and invasion in a human glioma cell line.J Cell Mol Med,2009,13(11-12):4608-4622.
, http://www.100md.com
[15]Bessard A, Fremin C, Ezan F, et al. RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo.Oncogene,2008,27(40):5315-5325.
[16]Meng F,Dong B, Li H, et al.RNAi-mediated inhibition of Raf-1 leads to decreased angiogenesis and tumor growth in gastric cancer.Cancer Biol Ther, 2009,8(2):174-179.
[17]Guo H,Zhang J, Inal C. Targeting tumor gene by shRNA-expressing Salmonella-mediated RNAi.Gene Ther,2011,18(1):95-105.
, http://www.100md.com
[18]Chen Y, Xie D, Yin Li W, et al. RNAi targeting EZH2 inhibits tumor growth and liver metastasis of pancreatic cancer in vivo.Cancer Lett,2010,297(1):109-116.
[19]Addepalli MK, Ray KB, Kumar B, et al. RNAi-mediated knockdown of AURKB and EGFR shows enhanced therapeutic efficacy in prostate tumor regression.Gene Ther,2010,17(3):352-359.
【收稿日期】2011-03-21
(本文编辑:郎威), http://www.100md.com(林洪坦 蔡建春)
, 百拇医药
3展望
RNAi技术已经引起了实验生物学的巨大变革，在肿瘤治疗中，它可以单独应用，也可以与药物等其它治疗手段联合应用。虽然目前质粒和慢病毒载体介导的RNAi技术用于肿瘤的基因治疗已取得了一些进展，但临床应用尚早，还需要深入研究和探讨其转染细胞的机制，需要构建更加高效、安全、且可调控的肿瘤靶向性的载体。相信，随着人们对RNAi研究的不断深入，它必将从实验研究走向临床应用?
参考文献
[1]Timmons L,Fire A.Specific interference by ingested dsRNA.Nature,1998,395(45):854.
[2]Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature,2001,411(12):494-498.
, 百拇医药
[3]Dong L,Xu H,Liu YB, et al.M-PEIs nanogels: potential nonviral vector for systemic plasmid delivery to tumor cells.Cancer Gene Ther,2009,16(7):561-566.
[4]Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo.Science,1990,247(4949):1465-1468.
[5]Durcan N, Murphy C, Cryan SA. Inhalable siRNA: potential as a therapeutic agent in the lungs. Mol Pharm,2008,5(4):559-566.
, http://www.100md.com
[6]Gao JQ, Zhao QQ, Lv TF, et al. Gene-carried chitosan-linked-PEI induced high gene transfection efficiency with low toxicity and significant tumor-suppressive activity.Int J Pharm,2010,387(1-2):286-294.
[7]Koppu S, Oh YJ,Edrada-Ebel R, et al.Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA.J Control Release,2010,143(2):215-221.
[8]Naldini L, Blomer U, Gallay P, et al . In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science,1996,272:263.
, 百拇医药
[9]Nishitsuji H, Ikeda T, Miyoshi H, et al. Expression of small hairpin RNA by lentivirus-based vector confers efficient and stable gene-suppression of HIV-1 on human cells including primary non-dividing cells.Microbes Infect,2004,6(1):76-85.
[10]Li M, Rossi JJ. Lentiviral vector delivery of siRNA and shRNA encoding genes into cultured and primary hematopoietic cells. Methods Mol Biol,2005,30(9):261-272.
[11]Tsai BY, Uen JL, Chiang BL.Lentiviral-mediated Foxp3 RNAi suppresses tumor growth of regulatory T cell-like leukemia in a murine tumor model.Gene Ther, 2010,17(8):972-979.
, 百拇医药
[12]Matsui K, Sasaki Y, Komatsu T, et al. RNAi gene silencing using cerasome as a viral-size siRNA-carrier free from fusion and cross-linking. Bioorg Med Chem Lett,2007,17(14):3935-3938.
[13]Tian W, Liou HC.RNAi-mediated c-Rel silencing leads to apoptosis of B cell tumor cells and suppresses antigenic immune response in vivo.Plos One,2009,4(4):5028.
[14]Lin W, Zhang J, Liu X,et al. RNAi-mediated inhibition of MSP58 decreases tumour growth, migration and invasion in a human glioma cell line.J Cell Mol Med,2009,13(11-12):4608-4622.
, http://www.100md.com
[15]Bessard A, Fremin C, Ezan F, et al. RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo.Oncogene,2008,27(40):5315-5325.
[16]Meng F,Dong B, Li H, et al.RNAi-mediated inhibition of Raf-1 leads to decreased angiogenesis and tumor growth in gastric cancer.Cancer Biol Ther, 2009,8(2):174-179.
[17]Guo H,Zhang J, Inal C. Targeting tumor gene by shRNA-expressing Salmonella-mediated RNAi.Gene Ther,2011,18(1):95-105.
, http://www.100md.com
[18]Chen Y, Xie D, Yin Li W, et al. RNAi targeting EZH2 inhibits tumor growth and liver metastasis of pancreatic cancer in vivo.Cancer Lett,2010,297(1):109-116.
[19]Addepalli MK, Ray KB, Kumar B, et al. RNAi-mediated knockdown of AURKB and EGFR shows enhanced therapeutic efficacy in prostate tumor regression.Gene Ther,2010,17(3):352-359.
【收稿日期】2011-03-21
(本文编辑:郎威), http://www.100md.com(林洪坦 蔡建春)