利用IETD连接TRAIL和Smac的靶向性双基因溶瘤腺病毒治疗癌症的研究
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摘要
肿瘤的成因往往与细胞的多种基因突变有关,因而对肿瘤有效的基因治疗应是多种外源基因对肿瘤进行多靶点的抑制。理论上双基因治疗策略要远比单基因治疗策略有效和彻底得多,但最关键的问题是缺少一种理想的连接子,使其能够有效地表达双基因。在这方面已做过很多尝试,比较典型的是利用核糖体进入位点(IRES)以及自剪切蛋白FMDV 2A等作为连接工具。IRES自身具有庞大的序列结构以及其上下游基因表达水平不平衡,而自剪切蛋白FMDV 2A自身的剪切效率不高,限制了它们在双基因治疗中的广泛应用。为高效地实现双基因的共表达,本研究采用了一种新的连接子即IETD。
应用分子克隆通过IETD短链将TRAIL和Smac两个基因连接并置于ZD55载体系统上构成靶向性双基因溶瘤腺病毒ZD55-TRAIL-(IETD)-Smac。IETD为凋亡蛋白caspase-8的识别剪切位点,当ZD55-TRAIL-(IETD)-Smac感染肿瘤细胞后,由于腺病毒本身在肿瘤细胞感染复制的过程中,肿瘤细胞产生应激反应而发生凋亡,无活性的caspase-8前体被激活为有活性的caspase-8, caspase-8识别TRAIL-IETD-Smac中的IETD并进行切割,使之成为两个有活性的肿瘤杀伤蛋白TRAIL和Smac,TRAIL同时又可激活caspase-8,使得细胞的凋亡随后被级联放大,之后TRAIL和Smac通过协同互补作用共同抑制肿瘤。
Western blot实验证明,以IETD连接TRAIL和Smac两个基因构建的靶向性双基因溶瘤腺病毒ZD55-TRAIL-(IETD)-Smac,其TRAIL和Smac都得到了很高的表达,与等量单基因病毒相比几乎无明显差别。MTT和结晶紫实验证明了ZD55-TRAIL(-IETD)-Smac的抗癌效果相对于ZD55、ZD55-TRAIL、ZD55-Smac及ZD55-TRAIL+ZD55-Smac联合组来说有显著的优势,同时也证明了其对正常细胞的安全性极高。肺癌H460细胞荷瘤裸鼠动物实验进一步证明ZD55-TRAIL-(IETD)-Smac相比其它病毒组来说能更显著地抑制肿瘤的生长。
本研究证明肿瘤靶向性双基因溶瘤腺病毒ZD55-TRAIL-(IETD)-Smac相对于单基因病毒及单基因病毒联合治疗来说能取得更好的效果,为肿瘤的双基因治疗奠定了坚实的基础。
The causes of cancer are often associated with multiple genes mutation. Effective gene therapy for cancer should be multiple therapeutic genes of multitarget suppression. In theory, a dual genes combination strategy simultaneously targeting multiple defective genes would be more effective and complete than single-gene strategy. But the most critical issue is the lack of an ideal connexon, which can express dual genes effectively. Several strategies have been described to co-express two or more genes by IRES or self-cleaving peptide FMDV 2A. Since the expression level of transgenes often dramatically affects the therapeutic efficacy. The large size and the imbalance expression of IRESes, and the low self-cleave efficiency of FMDV 2A limit their utility in dual genes therapy. So IETD connexon was introduced for an alternative strategy to guarantee a reliable co-expression.
TRAIL and Smac were connected by IETD, and then join in ZD55 system to construct Targeting dual gene-virus ZD55-TRAIL-(IETD)-Smac. When ZD55-TRAIL-(IETD)-Smac infect tumor cells, precursor of caspase-8 can be activated by stress reaction due to duplication of viruses. Activated caspase-8 can recognize and cleave IETD peptide, then generate solitary and competent TRAIL and Smac protein. At the same time, competent TRAIL can further activated caspase-8 precursor, then apoptosis was cascade amplification. TRAIL and Smac have complementary action on co-inhibit tumor cells.
Western blot showed that the expression levels of TRAIL and Smac protein from Targeting dual gene-virus ZD55-TRAIL-(IETD)-Smac were nearly equal to these proteins from single-gene virus. MTT assays and CPE experiments showed that ZD55-TRAIL-(IETD)-Smac exhibited higher antitumor effect than ZD55、ZD55-TRAIL、ZD55-Smac and ZD55-TRAIL plus ZD55-Smac, at the same time, it was proved to be very safe to normal cells. Furthermore, ZD55-TRAIL-(IETD)-Smac can dramatically inhibit the volume of the NCI-H460 lung carcinoma in nude mice compared to other viruses.
Compare to single gene-virotherapy or single gene-virotherapy alliance, Targeting dual gene-virus ZD55-TRAIL-(IETD)-Smac attain better antitumor effect.This study set up a solid foundation for exploring more effective dual gene-virotherapy.
应用分子克隆通过IETD短链将TRAIL和Smac两个基因连接并置于ZD55载体系统上构成靶向性双基因溶瘤腺病毒ZD55-TRAIL-(IETD)-Smac。IETD为凋亡蛋白caspase-8的识别剪切位点,当ZD55-TRAIL-(IETD)-Smac感染肿瘤细胞后,由于腺病毒本身在肿瘤细胞感染复制的过程中,肿瘤细胞产生应激反应而发生凋亡,无活性的caspase-8前体被激活为有活性的caspase-8, caspase-8识别TRAIL-IETD-Smac中的IETD并进行切割,使之成为两个有活性的肿瘤杀伤蛋白TRAIL和Smac,TRAIL同时又可激活caspase-8,使得细胞的凋亡随后被级联放大,之后TRAIL和Smac通过协同互补作用共同抑制肿瘤。
Western blot实验证明,以IETD连接TRAIL和Smac两个基因构建的靶向性双基因溶瘤腺病毒ZD55-TRAIL-(IETD)-Smac,其TRAIL和Smac都得到了很高的表达,与等量单基因病毒相比几乎无明显差别。MTT和结晶紫实验证明了ZD55-TRAIL(-IETD)-Smac的抗癌效果相对于ZD55、ZD55-TRAIL、ZD55-Smac及ZD55-TRAIL+ZD55-Smac联合组来说有显著的优势,同时也证明了其对正常细胞的安全性极高。肺癌H460细胞荷瘤裸鼠动物实验进一步证明ZD55-TRAIL-(IETD)-Smac相比其它病毒组来说能更显著地抑制肿瘤的生长。
本研究证明肿瘤靶向性双基因溶瘤腺病毒ZD55-TRAIL-(IETD)-Smac相对于单基因病毒及单基因病毒联合治疗来说能取得更好的效果,为肿瘤的双基因治疗奠定了坚实的基础。
The causes of cancer are often associated with multiple genes mutation. Effective gene therapy for cancer should be multiple therapeutic genes of multitarget suppression. In theory, a dual genes combination strategy simultaneously targeting multiple defective genes would be more effective and complete than single-gene strategy. But the most critical issue is the lack of an ideal connexon, which can express dual genes effectively. Several strategies have been described to co-express two or more genes by IRES or self-cleaving peptide FMDV 2A. Since the expression level of transgenes often dramatically affects the therapeutic efficacy. The large size and the imbalance expression of IRESes, and the low self-cleave efficiency of FMDV 2A limit their utility in dual genes therapy. So IETD connexon was introduced for an alternative strategy to guarantee a reliable co-expression.
TRAIL and Smac were connected by IETD, and then join in ZD55 system to construct Targeting dual gene-virus ZD55-TRAIL-(IETD)-Smac. When ZD55-TRAIL-(IETD)-Smac infect tumor cells, precursor of caspase-8 can be activated by stress reaction due to duplication of viruses. Activated caspase-8 can recognize and cleave IETD peptide, then generate solitary and competent TRAIL and Smac protein. At the same time, competent TRAIL can further activated caspase-8 precursor, then apoptosis was cascade amplification. TRAIL and Smac have complementary action on co-inhibit tumor cells.
Western blot showed that the expression levels of TRAIL and Smac protein from Targeting dual gene-virus ZD55-TRAIL-(IETD)-Smac were nearly equal to these proteins from single-gene virus. MTT assays and CPE experiments showed that ZD55-TRAIL-(IETD)-Smac exhibited higher antitumor effect than ZD55、ZD55-TRAIL、ZD55-Smac and ZD55-TRAIL plus ZD55-Smac, at the same time, it was proved to be very safe to normal cells. Furthermore, ZD55-TRAIL-(IETD)-Smac can dramatically inhibit the volume of the NCI-H460 lung carcinoma in nude mice compared to other viruses.
Compare to single gene-virotherapy or single gene-virotherapy alliance, Targeting dual gene-virus ZD55-TRAIL-(IETD)-Smac attain better antitumor effect.This study set up a solid foundation for exploring more effective dual gene-virotherapy.
引文
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[2] Larin SS, Georgiev GP, Kiselev SL. Gene transfer approaches in cancer immunotherapy [J].Gene Ther, 2004, 11 Suppl 1: S18-25
[3] Liu M, Acres B, Balloul JM, et al. Gene-based vaccines and immunotherapeutics [J].Proc Natl Acad Sci U S A, 2004, 101 Suppl 2: 14567-71
[4] Roth JA, Grammer SF. Tumor suppressor gene therapy [J].Methods Mol Biol, 2003, 223: 577-98
[5] Kirn D. Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer [J].Oncogene, 2000, 19 (56): 6660-9
[6] Kirn D, Niculescu-Duvaz I, Hallden G, et al. The emerging fields of suicide gene therapy and virotherapy [J].Trends Mol Med, 2002, 8 (4 Suppl): S68-73
[7] Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers [J].Hum Gene Ther, 2005, 16 (9): 1016-27
[8] Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [J].Science, 1996, 274 (5286): 373-6
[9] Liu XY. A new anticancer strategy - Gene-Virotherapy Therapy of cancer [J].Chinese J Cancer Biother, 2001, 8: 1-1
[10] Zhang ZL, Zou WG, Luo CX, et al. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy [J].Cell Res, 2003, 13 (6): 481-9
[11] Liu XY. Targeting gene-virotherapy of cancer and its prosperity [J].Cell Res, 2006, 16 (11): 879-86
[12] Liu XY, Gu JF, Shi WF. Targeting gene-virotherapy for cancer [J].Acta Biochim Biophys Sin (Shanghai), 2005, 37 (9): 581-7
[13] Liu XY, Qiu SB, Zou WG, et al. Effective gene-virotherapy for complete eradication of tumor mediated by the combination of hTRAIL (TNFSF10) and plasminogen k5 [J].Mol Ther, 2005, 11 (4): 531-41
[14] Zhang Y, Gu J, Zhao L, et al. Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy [J].Cancer Res, 2006, 66 (8): 4291-8
[15] Kao CC, Yew PR, Berk AJ. Domains required for in vitro association between the cellular p53 and the adenovirus 2 E1B 55K proteins [J].Virology, 1990, 179 (2): 806-14
[16] Yew PR, Berk AJ. Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein [J].Nature, 1992, 357 (6373): 82-5
[17] Dix BR, Edwards SJ, Braithwaite AW. Does the antitumor adenovirus ONYX-015/dl1520 selectively target cells defective in the p53 pathway? [J].J Virol, 2001, 75 (12): 5443-7
[18] Yang CT, You L, Uematsu K, et al. p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53 [J].Cancer Res, 2001, 61 (16): 5959-63
[19] Geoerger B, Grill J, Opolon P, et al. Oncolytic activity of the E1B-55 kDa-deleted adenovirus ONYX-015 is independent of cellular p53 status in human malignant glioma xenografts [J].Cancer Res, 2002, 62 (3): 764-72
[20] Edwards SJ, Dix BR, Myers CJ, et al. Evidence that replication of the antitumor adenovirus ONYX-015 is not controlled by the p53 and p14(ARF) tumor suppressor genes [J].J Virol, 2002, 76 (24): 12483-90
[21] O'Shea CC, Johnson L, Bagus B, et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity [J].Cancer Cell, 2004, 6 (6): 611-23
[22] Ranieri G, Gasparini G. Angiogenesis and angiogenesis inhibitors: a new potential anticancer therapeuticstrategy [J].Curr Drug Targets Immune Endocr Metabol Disord, 2001, 1 (3): 241-53
[23] Qiu S, Ruan H, Pei Z, et al. Combination of Targeting Gene-ViroTherapy with 5-FU enhances antitumor efficacy in malignant colorectal carcinoma [J].J Interferon Cytokine Res, 2004, 24 (4): 219-30
[24] Pei Z, Chu L, Zou W, et al. An oncolytic adenoviral vector of Smac increases antitumor activity of TRAIL against HCC in human cells and in mice [J].Hepatology, 2004, 39 (5): 1371-81
[25] Zhao L, Gu J, Dong A, et al. Potent antitumor activity of oncolytic adenovirus expressing mda-7/IL-24 for colorectal cancer [J].Hum Gene Ther, 2005, 16 (7): 845-58
[26] Zhao L, Dong A, Gu J, et al. The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer [J].Cancer Gene Ther, 2006, 13 (11): 1011-22
[27] Fanger NA, Maliszewski CR, Schooley K, et al. Human dendritic cells mediate cellular apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [J].J Exp Med, 1999, 190 (8): 1155-64
[28] Gibson SB, Oyer R, Spalding AC, et al. Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL [J].Mol Cell Biol, 2000, 20 (1): 205-12
[29] Gliniak B, Le T. Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11 [J].Cancer Res, 1999, 59 (24): 6153-8
[30] Golstein P. Cell death: TRAIL and its receptors [J].Curr Biol, 1997, 7 (12): R750-3
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