携带IL-24基因的E1区双调控溶瘤腺病毒治疗肿瘤的研究
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摘要
目前恶性肿瘤已经超越心血管疾病,成为危害人类健康和生命的头号杀手。在世界范围内每年肿瘤患者的发病率和死亡率都急剧增加,而且50年来大部分肿瘤患者的5年生存率并没有发生变化。传统的手术、放疗和化疗对恶性肿瘤的治疗无济于事,肿瘤的复发率和致死率仍然居高不下。由此可见,肿瘤的传统疗法的发展已经举步维艰,人类迫切需要寻找更加有效安全的治疗理念和方法来破除癌症无法治疗的“魔咒”。
随着肿瘤的基因治疗和病毒治疗的日益发展,目前以肿瘤特异性增殖腺病毒(即溶瘤腺病毒)为代表的生物疗法已经成为癌症治疗领域的研究热点。此后刘新垣院士融合了基因治疗和病毒治疗的优势提出了一种新型的肿瘤治疗策略:靶向基因-病毒治疗策略,通过溶瘤病毒载体携带一个或多个肿瘤治疗基因来实现对肿瘤细胞的有效杀伤,从而为肿瘤治疗的前景带来了新的曙光与希望。
溶瘤腺病毒的改造位点通常选在对病毒复制有重要调控作用的E1区,如通过删除E1B 55kD区域或者E1A CR2区的24bp碱基来分别靶向不同的信号通路。还可以利用肿瘤或组织特异性启动子替代E1A或E1B野生型启动子来限制溶瘤腺病毒在特定的肿瘤或组织中复制增殖。Mda-7/IL-24(melanoma differentiation associated gene-7/interleukin-24)是一种新型的广谱抗肿瘤的多功能细胞因子,能选择性地促进肿瘤细胞凋亡而对正常细胞没有毒害,并具有潜在的“旁观者效应”,而且还能诱导免疫调节反应和抑制肿瘤血管生成。实验室目前已经完成了ZD55-IL-24(E1B 55kD删除)和Ad.sp- E1A_((△24))-IL-24(E1A 24bp删除)两种E1区单调控溶瘤腺病毒的体内与体外实验,结果两者都显示了非常好的肿瘤杀伤与抑制效果。
我们将IL-24基因插入到E1A和E1B双调控的溶瘤腺病毒载体Ad·sp·E1A_((△24))·E1B_((△55))中,构建出重组基因病毒Ad·sp·E1A_((△24))·E1B_((△55))·IL-24。体外实验表明Ad·sp·E1A_((△24))·E1B_((△55))·IL-24能诱导多种肿瘤细胞的死亡如肺癌、鼻咽癌、肝癌、结肠癌、宫颈癌等肿瘤细胞,而且肺癌NCI-H460荷瘤裸鼠实验也证明Ad·sp·E1A_((△24))·E1B_((△55))·IL-24能够有效地抑制肿瘤的疯狂增长。本实验首次利用E1A和E1B双调控的溶瘤腺病毒载体携带肿瘤治疗基因IL-24在体外和体内实验中都实现了对肿瘤良好的抑制作用,从而为肿瘤靶向性治疗的研究提供了一个实验参考。
Currently malignant tumors have taken over the cardiovascular and cerebrovascular diseases and become the first-leading lethiferous disease. In the worldwide, the morbidity and mortality of tumor patients have increased dramatically each year, and the 5-year survival rates of the majority of cancer patients have not been improved. Traditional therapies such as surgery, radiotherapy and chemotherapy were found to no avail and tumor recurrent rates and mortality rates remain very high, which indicate that the development of traditional therapies has been trapped. Therefore, it is imperative to develop more effective and secure therapeutic programs to break the“curse”that cancer cannot be cured.
As gene therapy and viroherapy for cancer treatment have well developed in these days, the biological therapy such as the conditionally replicating adenoviruses (oncolytic adenoviruses) has become a hot research. Prof. Liu then combines the advantages of gene therapy and viroherapy and proposes a novel strategy for cancer treatment named“Cancer Targeting Gene-Virotherapy”. The strategy is to incorporate one or more therapeutic genes into oncolytic viral vector, which has brought new light and hope for cancer treatment.
Since the E1A and E1B play critical roles in regulating adenoviral replication, modifications were usually located in E1 region of adenoviral DNA. We can target diverse abnormal signal pathways in tumor cells by deleting E1B-55kD or E1A-24bp of adenoviral genome. Besides, we can use the cancer or tissue specific promoters to replace the E1A or E1B wild-type promoter. Mda-7/IL-24(melanoma differentiation associated gene-7/interleukin-24)is a new multifunctional cytokine with the ability of suppressing many tumor types. IL-24 can selectively induce apoptosis of tumor cells and leave normal cells unaffected, and it also can induce immune response and suppress tumor angiogenesis. Our lab has successfully constructed two E1 single-restricted oncolytic adenovirus, ZD55-IL-24(deletion of E1B 55kD)and Ad.sp- E1A(△24)-IL-24(deletion of E1A 24bp). Results showed that both could effectively suppress tumors in vitro and in vivo experiments.
We introduced IL-24 into the E1A, E1B double-restricted oncolytic adenovirus and constructed the Ad·sp·E1A_((△24))·E1B_((△55))·IL-24. Data showed that Ad·sp·E1A_((△24))·E1B_((△55))·IL-24 had excellent antitumor effect in vitro for human lung, nasopharyngeal, liver, colorectal, cervical carcinoma cell lines. Furthermore, Ad·sp·E1A_((△24))·E1B_((△55))·IL-24 could also effectively inhibit the progression of the xenograft NCI-H460 carcinoma in nude mice. This study firstly used the E1A and E1B double-restricted oncolytic adenovirus vector carrying IL-24 to treat tumors and attained efficient anti-tumor effect, which provides an experimental foundation for cancer therapy.
随着肿瘤的基因治疗和病毒治疗的日益发展,目前以肿瘤特异性增殖腺病毒(即溶瘤腺病毒)为代表的生物疗法已经成为癌症治疗领域的研究热点。此后刘新垣院士融合了基因治疗和病毒治疗的优势提出了一种新型的肿瘤治疗策略:靶向基因-病毒治疗策略,通过溶瘤病毒载体携带一个或多个肿瘤治疗基因来实现对肿瘤细胞的有效杀伤,从而为肿瘤治疗的前景带来了新的曙光与希望。
溶瘤腺病毒的改造位点通常选在对病毒复制有重要调控作用的E1区,如通过删除E1B 55kD区域或者E1A CR2区的24bp碱基来分别靶向不同的信号通路。还可以利用肿瘤或组织特异性启动子替代E1A或E1B野生型启动子来限制溶瘤腺病毒在特定的肿瘤或组织中复制增殖。Mda-7/IL-24(melanoma differentiation associated gene-7/interleukin-24)是一种新型的广谱抗肿瘤的多功能细胞因子,能选择性地促进肿瘤细胞凋亡而对正常细胞没有毒害,并具有潜在的“旁观者效应”,而且还能诱导免疫调节反应和抑制肿瘤血管生成。实验室目前已经完成了ZD55-IL-24(E1B 55kD删除)和Ad.sp- E1A_((△24))-IL-24(E1A 24bp删除)两种E1区单调控溶瘤腺病毒的体内与体外实验,结果两者都显示了非常好的肿瘤杀伤与抑制效果。
我们将IL-24基因插入到E1A和E1B双调控的溶瘤腺病毒载体Ad·sp·E1A_((△24))·E1B_((△55))中,构建出重组基因病毒Ad·sp·E1A_((△24))·E1B_((△55))·IL-24。体外实验表明Ad·sp·E1A_((△24))·E1B_((△55))·IL-24能诱导多种肿瘤细胞的死亡如肺癌、鼻咽癌、肝癌、结肠癌、宫颈癌等肿瘤细胞,而且肺癌NCI-H460荷瘤裸鼠实验也证明Ad·sp·E1A_((△24))·E1B_((△55))·IL-24能够有效地抑制肿瘤的疯狂增长。本实验首次利用E1A和E1B双调控的溶瘤腺病毒载体携带肿瘤治疗基因IL-24在体外和体内实验中都实现了对肿瘤良好的抑制作用,从而为肿瘤靶向性治疗的研究提供了一个实验参考。
Currently malignant tumors have taken over the cardiovascular and cerebrovascular diseases and become the first-leading lethiferous disease. In the worldwide, the morbidity and mortality of tumor patients have increased dramatically each year, and the 5-year survival rates of the majority of cancer patients have not been improved. Traditional therapies such as surgery, radiotherapy and chemotherapy were found to no avail and tumor recurrent rates and mortality rates remain very high, which indicate that the development of traditional therapies has been trapped. Therefore, it is imperative to develop more effective and secure therapeutic programs to break the“curse”that cancer cannot be cured.
As gene therapy and viroherapy for cancer treatment have well developed in these days, the biological therapy such as the conditionally replicating adenoviruses (oncolytic adenoviruses) has become a hot research. Prof. Liu then combines the advantages of gene therapy and viroherapy and proposes a novel strategy for cancer treatment named“Cancer Targeting Gene-Virotherapy”. The strategy is to incorporate one or more therapeutic genes into oncolytic viral vector, which has brought new light and hope for cancer treatment.
Since the E1A and E1B play critical roles in regulating adenoviral replication, modifications were usually located in E1 region of adenoviral DNA. We can target diverse abnormal signal pathways in tumor cells by deleting E1B-55kD or E1A-24bp of adenoviral genome. Besides, we can use the cancer or tissue specific promoters to replace the E1A or E1B wild-type promoter. Mda-7/IL-24(melanoma differentiation associated gene-7/interleukin-24)is a new multifunctional cytokine with the ability of suppressing many tumor types. IL-24 can selectively induce apoptosis of tumor cells and leave normal cells unaffected, and it also can induce immune response and suppress tumor angiogenesis. Our lab has successfully constructed two E1 single-restricted oncolytic adenovirus, ZD55-IL-24(deletion of E1B 55kD)and Ad.sp- E1A(△24)-IL-24(deletion of E1A 24bp). Results showed that both could effectively suppress tumors in vitro and in vivo experiments.
We introduced IL-24 into the E1A, E1B double-restricted oncolytic adenovirus and constructed the Ad·sp·E1A_((△24))·E1B_((△55))·IL-24. Data showed that Ad·sp·E1A_((△24))·E1B_((△55))·IL-24 had excellent antitumor effect in vitro for human lung, nasopharyngeal, liver, colorectal, cervical carcinoma cell lines. Furthermore, Ad·sp·E1A_((△24))·E1B_((△55))·IL-24 could also effectively inhibit the progression of the xenograft NCI-H460 carcinoma in nude mice. This study firstly used the E1A and E1B double-restricted oncolytic adenovirus vector carrying IL-24 to treat tumors and attained efficient anti-tumor effect, which provides an experimental foundation for cancer therapy.
引文
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[2] Kirn D. Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned? [J]. Gene therapy 2001;8:89-98.
[3] Khuri FR, Nemunaitis J, Ganly I, et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer [J]. Nature medicine 2000;6:879-885.
[4] Ganly I, Kirn D, Eckhardt G, et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer [J]. Clin Cancer Res 2000;6:798-806.
[5] Lamont JP, Nemunaitis J, Kuhn JA, Landers SA, McCarty TM. A prospective phase II trial of ONYX-015 adenovirus and chemotherapy in recurrent squamous cell carcinoma of the head and neck (the Baylor experience) [J]. Annals of surgical oncology 2000;7:588-592.
[6] Liu XY. Targeting gene-virotherapy of cancer and its prosperity [J]. Cell research 2006;16:879-886.
[7] Liu XY, Gu JF, Shi WF. Targeting gene-virotherapy for cancer [J]. Acta biochimica et biophysica Sinica 2005;37:581-587.
[8] 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;39:1371-1381.
[9] Zhang ZL, Zou WG, Luo CX, et al. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy [J]. Cell research 2003;13:481-489.
[10] Zhang Z, Zou W, Wang J, et al. Suppression of tumor growth by oncolytic adenovirus-mediated delivery of an antiangiogenic gene, soluble Flt-1 [J]. Mol Ther 2005;11:553-562.
[11] 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 research 2006;66:4291-4298.
[12] 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 therapy 2006;13:1011-1022.
[13] Barnett BG, Crews CJ, Douglas JT. Targeted adenoviral vectors [J]. Biochimica et biophysica acta 2002;1575:1-14.
[14] Douglas JT. Adenoviral vectors for gene therapy [J]. Molecular biotechnology 2007;36:71-80.
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