肿瘤基因治疗的研究进展
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摘要
基因治疗是指将外源正常基因通过基因转移技术导入靶细胞,纠正或补偿因基因缺陷和异常引起的疾病,以达到治疗目的的一种生物治疗方法。本文从自杀基因、基因沉默、抑癌基因、免疫基因、抑制血管生成基因等几方面综述了近几年肿瘤基因治疗的研究和发展现状。自杀基因治疗系统包括HSV-tk GCV系统、H19 RNA、h TERT等,HSV-tk GCV系统是自杀基因治疗系统研究最多的一种,TK基因是药敏基因,肿瘤细胞转染该基因后,对前体药物丙氧鸟苷(GCV)或无环鸟苷(ACV)变得敏感而能被杀死。RNA干扰是基因沉默治疗的主要方式,通过沉默肿瘤相关基因IDO2、DUSP6、IGF1R、ORAOV1等基因可以明显抑制肿瘤生长。抑癌基因激活或过表达可以抑制肿瘤生长,p53和PTEN是两个最有意义的抑癌基因,重组腺病毒p53和PTEN可以显著抑制肿瘤生长。免疫基因治疗是将细胞因子或共刺激分子基因导入肿瘤细胞或体细胞内,通过激发或调动机体免疫功能来控制或杀伤肿瘤细胞,常用的免疫效应细胞有TIL、CTL、LAK、NK等,可供选择的目的基因有肿瘤坏死因子、白介素、集落刺激因子、干扰素、趋化因子等。抑制血管生成基因可以通过抑制肿瘤新生血管的生成,来阻止肿瘤生长和侵袭,VEGF-Trap、PEDF、ES通过腺病毒导入肿瘤可以显著抑制肿瘤生长。目前肿瘤基因治疗在特异性、安全性和靶向性方面依然存在亟需解决的问题。
Gene therapy is one of biological treatment methods that exogenous normal gene is transferred into target cells by gene transfer technology to correct or compensate for genetic defects or abnormality of diseases in order to achieve the treatment purpose. In this paper,research and development status of tumor gene therapy in recent years were reviewed from suicide gene,gene silencing,tumor suppress gene,immune gene and anti-angiogenesis gene. Suicide gene therapy system include: HSV-tk GCV system,H19 RNA,h TERT,etc. HSV-tk GCV system is one of the most studied suicide gene therapy system. TK gene is drug sensitivity gene and tumor cells will be kill by GCV or ACV after transfect with TK gene.RNA interference is a major mode of gene silencing therapy. The growth of tumor was inhibited obviously when silent tumor related genes( IDO2,DUSP6,IGF1 R,ORAOV1,etc.). Activation or overexpression of tumor suppress genes can also suppress tumor growth,such as p53 and PTEN gene. Cytokines or costimulatory molecules were used to activate immune functions of body to kill tumor cells in immune gene therapy. Common immunologic effector cells were TIL,CTL,LAK,NK,etc. and target genes were TNFIL,CSF,IFN,CF,etc. Anti-angiogenesis gene by suppressing anti-angiogenesis in tumors for stopping tumor growth and metastasis. VEGF-Trap,PEDF,ES can significantly inhibit tumor growth by transfected with adenovirus. The problems such as specificity,safety and targeting still exist in current cancer gene therapy.
Gene therapy is one of biological treatment methods that exogenous normal gene is transferred into target cells by gene transfer technology to correct or compensate for genetic defects or abnormality of diseases in order to achieve the treatment purpose. In this paper,research and development status of tumor gene therapy in recent years were reviewed from suicide gene,gene silencing,tumor suppress gene,immune gene and anti-angiogenesis gene. Suicide gene therapy system include: HSV-tk GCV system,H19 RNA,h TERT,etc. HSV-tk GCV system is one of the most studied suicide gene therapy system. TK gene is drug sensitivity gene and tumor cells will be kill by GCV or ACV after transfect with TK gene.RNA interference is a major mode of gene silencing therapy. The growth of tumor was inhibited obviously when silent tumor related genes( IDO2,DUSP6,IGF1 R,ORAOV1,etc.). Activation or overexpression of tumor suppress genes can also suppress tumor growth,such as p53 and PTEN gene. Cytokines or costimulatory molecules were used to activate immune functions of body to kill tumor cells in immune gene therapy. Common immunologic effector cells were TIL,CTL,LAK,NK,etc. and target genes were TNFIL,CSF,IFN,CF,etc. Anti-angiogenesis gene by suppressing anti-angiogenesis in tumors for stopping tumor growth and metastasis. VEGF-Trap,PEDF,ES can significantly inhibit tumor growth by transfected with adenovirus. The problems such as specificity,safety and targeting still exist in current cancer gene therapy.
引文
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[15]Tabernero J,Shapiro GI,LoRusso PM,et al.First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement[J].Cancer Discov,2013,3(4):406-417.
[16]Li Y,Li B,Li CJ,et al.Key points of basic theories and clinical practice in r Ad-p53(GendicineTM)gene therapy for solid malignant tumors[J].Expert Opin Biol Ther,2015,15(3):437-454.
[17]Tazawa H,Kagawa S,Fujiwara T.Advances in adenovirus-mediated p53 cancer gene therapy[J].Expert Opin Biol Ther,2013,13(11):1569-1583.
[18]周军,张跃伟,赵广生,等.微粒联合重组人p53腺病毒注射液栓塞治疗晚期肝癌疗效观察[J].中华医学杂志,2014,94(9):660-663.
[19]Chen S,Chen J,Xi W,et al.Clinical therapeutic effect and biological monitoring of p53 gene in advanced hepatocellular carcinoma[J].Am J Clin Oncol,2014,37(1):24-29.
[20]徐祯祯,权循凤,蒋俊,等.调强放疗联合p53基因治疗中晚期宫颈癌的临床疗效[J].安徽医学,2015,36(1):19-22.
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[22]Larson C,Oronsky B,Scicinski J,et al.Going viral:a review of replication-selective oncolytic adenoviruses[J].Oncotarget,2015,6(24):19976-19989.
[23]Grandi G,Toss A,Cortesi L,et al.The Association between Endometriomas and Ovarian Cancer:Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life[J].Biomed Res Int,2015,2015:751571.doi:10.1155/2015/751571.
[24]Wu H,Wang K,Liu W,et al.Recombinant adenovirus-mediated overexpression of PTEN and KRT10 improves cisplatin resistance of ovarian cancer in vitro and in vivo[J].Genet Mol Res,2015,14(2):6591-6597.
[25]Zhang H,Zhou X,Xu C,et al.Synergistic tumor suppression by adenovirus-mediated ING4/PTEN double gene therapy for gastric cancer[J].Cancer Gene Ther,2016,23(1):13-23.
[26]Hernandez-Alcoceba R,Poutou J,Ballesteros-Briones MC,et al.Gene therapy approaches against cancer using in vivo and ex vivo gene transfer of interleukin-12[J].Immunotherapy,2016,8(2):179-198.
[27]Liu X,Lu J,He ML,et al.Antitumor effects of interferon-alpha on cell growth and metastasis in human nasopharyngeal carcinoma[J].Current Cancer Drug Targets,2012,12(5):561-570.
[28]Meng FD,Wang S,Jiang YH,et al.Antitumor effect of dendritic cells transfected with prostate-specific membrane antigen recombinant adenovirus on prostate cancer:An in vitro study[J].Mol Med Rep,2016,13(3):2124-2134.
[29]Strauss J,Madan RA,Figg WD.Evaluating immune responses after sipuleucel-T therapy[J].Cancer Biol Ther,2015,16(8):1119-1121.
[30]Voena C,Chiarle R.Advances in Cancer Immunology and Cancer Immunotherapy[J].Discov Med,2016,21(114):125-133.
[31]Priceman SJ,Forman SJ,Brown CE.Smart CARs engineered for cancer immunotherapy[J].Curr Opin Onco,2015,27(6):466-474.
[32]Bonini C,Mondino A.Adoptive T-cell therapy for cancer:The era of engineered T cells[J].Eur J Immunol,2015,45(9):2457-2469.
[33]Lu L,Luo ST,Shi HS,et al.AAV2-mediated gene transfer of VEGFTrap with potent suppression of primary breast tumor growth and spontaneous pulmonary metastases by long-term expression[J].Oncol Rep,2012,28(4):1332-1338.
[34]He SS,Shi HS,Yin T,et al.AAV-mediated gene transfer of human pigment epithelium-derived factor inhibits Lewis lung carcinoma growth in mice[J].Oncol Rep,2012,27(4):1142-1148.
[35]Ye W,Liu R,Pan C,et al.Multicenter randomized phase 2 clinical trial of a recombinant human endostatin adenovirus in patients with advanced head and neck carcinoma[J].Mol Ther,2014,22(6):1221-1229.
[36]邓洪新,魏于全.肿瘤基因治疗的研究现状和展望[J].中国肿瘤生物治疗杂志,2015,22(2):170-176.
[37]Chira S,Jackson CS,Oprea I,et al.Progresses towards safe and efficient gene therapy vectors[J].Oncotarget,2015,6(31):30675-30703.
[2]Amer MH.Gene therapy for cancer:present status and future perspective[J].Mol Cell Ther,2014,2:27.
[3]Zeng ZJ,Xiang SG,Xue WW,et al.The cell death and DNA damages caused by the Tet-On regulating HSV-tk/GCV suicide gene system in MCF-7 cells[J].Biomed Pharmacother,2014,68(7):887-892.
[4]Abdelaziz M,Sherif L,El Khiary M,et al.Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for In Vivo Gene Therapy of Uterine Leiomyoma[J].Reprod Sci,2016,23(4):464-474.
[5]Jiang X,Yan Y,Hu M,et al.Increased level of H19 long noncoding RNA promotes invasion,angiogenesis,and stemness of glioblastoma cells[J].J Neurosurg,2016,124(1):129-136.
[6]Matouk I,Raveh E,Ohana P,et al.The increasing complexity of the oncofetal h19 gene locus:functional dissection and therapeutic intervention[J].Int J Mol Sci,2013,14(2):4298-4316.
[7]Wang L,Cai Y,Zhao X,et al.Down-regulated long non-coding RNA H19 inhibits carcinogenesis of renal cell carcinoma[J].Neoplasma,2015,62(3):412-418.
[8]Hashimoto Y,Tazawa H,Teraishi F,et al.The h TERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment[J].PLo S One,2012,7(6):e39292.
[9]Pan J,Wang H,Liu X,et al.Tumor Restrictive Suicide Gene Therapy for Glioma Controlled by the FOS Promoter[J].PLo S One,2015,10(11):e0143112.
[10]Ji N,Weng D,Liu C,et al.Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma[J].Oncotarget,2016,7(4):4369-4378.
[11]Liu Y,Zhang Y,Zheng X,et al.Gene silencing of indoleamine 2,3-dioxygenase 2 in melanoma cells induces apoptosis through the suppression of NAD+and inhibits in vivo tumor growth[J].Oncotarget,2016,7(22):32329-32340.
[12]Song H,Wu C,Wei C,et al.Silencing of DUSP6 gene by RNAi-mediation inhibits proliferation and growth in MDA-MB-231 breast cancer cells:an in vitro study[J].Int J Clin Exp Med,2015,8(7):10481-10490.
[13]Song H,Wu C,Wei C,et al.Silencing of DUSP6 gene by RNAi-mediation inhibits proliferation and growth in MDA-MB-231 breast cancer cells:an in vitro study[J].Int J Clin Exp Med,2015,8(7):10481-10490.
[14]Zuckerman JE,Gritli I,Tolcher A,et al.Correlating animal and human phase Ia/Ib clinical data with CALAA-01,a targeted,polymerbased nanoparticle containing siRNA[J].Proc Natl Acad Sci USA,2014,111(31):11449-11454.
[15]Tabernero J,Shapiro GI,LoRusso PM,et al.First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement[J].Cancer Discov,2013,3(4):406-417.
[16]Li Y,Li B,Li CJ,et al.Key points of basic theories and clinical practice in r Ad-p53(GendicineTM)gene therapy for solid malignant tumors[J].Expert Opin Biol Ther,2015,15(3):437-454.
[17]Tazawa H,Kagawa S,Fujiwara T.Advances in adenovirus-mediated p53 cancer gene therapy[J].Expert Opin Biol Ther,2013,13(11):1569-1583.
[18]周军,张跃伟,赵广生,等.微粒联合重组人p53腺病毒注射液栓塞治疗晚期肝癌疗效观察[J].中华医学杂志,2014,94(9):660-663.
[19]Chen S,Chen J,Xi W,et al.Clinical therapeutic effect and biological monitoring of p53 gene in advanced hepatocellular carcinoma[J].Am J Clin Oncol,2014,37(1):24-29.
[20]徐祯祯,权循凤,蒋俊,等.调强放疗联合p53基因治疗中晚期宫颈癌的临床疗效[J].安徽医学,2015,36(1):19-22.
[21]Ferguson PJ,Sykelyk A,Figueredo R,et al.Synergistic cytotoxicity against human tumor cell lines by oncolytic adenovirus dl1520(ONYX-015)and melphalan[J].Tumori,2016,102(1):31-39.
[22]Larson C,Oronsky B,Scicinski J,et al.Going viral:a review of replication-selective oncolytic adenoviruses[J].Oncotarget,2015,6(24):19976-19989.
[23]Grandi G,Toss A,Cortesi L,et al.The Association between Endometriomas and Ovarian Cancer:Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life[J].Biomed Res Int,2015,2015:751571.doi:10.1155/2015/751571.
[24]Wu H,Wang K,Liu W,et al.Recombinant adenovirus-mediated overexpression of PTEN and KRT10 improves cisplatin resistance of ovarian cancer in vitro and in vivo[J].Genet Mol Res,2015,14(2):6591-6597.
[25]Zhang H,Zhou X,Xu C,et al.Synergistic tumor suppression by adenovirus-mediated ING4/PTEN double gene therapy for gastric cancer[J].Cancer Gene Ther,2016,23(1):13-23.
[26]Hernandez-Alcoceba R,Poutou J,Ballesteros-Briones MC,et al.Gene therapy approaches against cancer using in vivo and ex vivo gene transfer of interleukin-12[J].Immunotherapy,2016,8(2):179-198.
[27]Liu X,Lu J,He ML,et al.Antitumor effects of interferon-alpha on cell growth and metastasis in human nasopharyngeal carcinoma[J].Current Cancer Drug Targets,2012,12(5):561-570.
[28]Meng FD,Wang S,Jiang YH,et al.Antitumor effect of dendritic cells transfected with prostate-specific membrane antigen recombinant adenovirus on prostate cancer:An in vitro study[J].Mol Med Rep,2016,13(3):2124-2134.
[29]Strauss J,Madan RA,Figg WD.Evaluating immune responses after sipuleucel-T therapy[J].Cancer Biol Ther,2015,16(8):1119-1121.
[30]Voena C,Chiarle R.Advances in Cancer Immunology and Cancer Immunotherapy[J].Discov Med,2016,21(114):125-133.
[31]Priceman SJ,Forman SJ,Brown CE.Smart CARs engineered for cancer immunotherapy[J].Curr Opin Onco,2015,27(6):466-474.
[32]Bonini C,Mondino A.Adoptive T-cell therapy for cancer:The era of engineered T cells[J].Eur J Immunol,2015,45(9):2457-2469.
[33]Lu L,Luo ST,Shi HS,et al.AAV2-mediated gene transfer of VEGFTrap with potent suppression of primary breast tumor growth and spontaneous pulmonary metastases by long-term expression[J].Oncol Rep,2012,28(4):1332-1338.
[34]He SS,Shi HS,Yin T,et al.AAV-mediated gene transfer of human pigment epithelium-derived factor inhibits Lewis lung carcinoma growth in mice[J].Oncol Rep,2012,27(4):1142-1148.
[35]Ye W,Liu R,Pan C,et al.Multicenter randomized phase 2 clinical trial of a recombinant human endostatin adenovirus in patients with advanced head and neck carcinoma[J].Mol Ther,2014,22(6):1221-1229.
[36]邓洪新,魏于全.肿瘤基因治疗的研究现状和展望[J].中国肿瘤生物治疗杂志,2015,22(2):170-176.
[37]Chira S,Jackson CS,Oprea I,et al.Progresses towards safe and efficient gene therapy vectors[J].Oncotarget,2015,6(31):30675-30703.