Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation
Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation
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DOI：
10.1016/j.ymthe.2004.03.014
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发表时间：
2004-06-01
影响因子：
12.4
通讯作者：
Meyn, RE
中科院分区：
文献类型：
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作者：
Nishikawa, T;Ramesh, R;Meyn, RE
黑色素瘤分化相关基因-7（mda-7），最近被分类为白细胞介素-24（批准的基因符号IL 24），被认为是一种肿瘤抑制基因，基于其在许多不同类型的癌症中的表达缺失。通过腺病毒介导的mda-7（Ad-mda 7）基因转移的基因治疗已被证明在体外和体内抑制几种不同的肿瘤细胞系的生长。我们以前证明，Ad-mda 7放射增敏的非小细胞肺癌（NSCLC）细胞株，通过增强细胞凋亡途径，通过激活的INK和c-Jun。在本研究中，我们研究了肿瘤内给药的Ad-mda 7联合电离辐射治疗裸鼠A549异种移植瘤的疗效。在联合治疗后，肿瘤生长的实质性和持久抑制是明显的。组织学检查显示，与单独使用Ad-mda 7或单独使用放射治疗的肿瘤相比，联合治疗的肿瘤中血管生成因子（bFGF，VEGF）和微血管密度显着降低，细胞凋亡增强。为了证实分泌的MDA-7蛋白的放射增敏作用，我们进行了克隆形成的生存试验，使用人脐静脉内皮细胞（HUVECs），A549细胞，和正常的人肺成纤维细胞，CCD 16细胞，预处理的条件培养基从293细胞已稳定转染MDA-7或对照载体。结果表明，MDA-7蛋白对HUVECs有辐射增敏作用，而对A549细胞和CCD 16细胞无辐射增敏作用。我们的研究结果表明，Ad-mda 7与辐射结合增强肿瘤细胞凋亡，分泌的MDA-7蛋白通过使内皮细胞对电离辐射敏感而不影响其他正常细胞来抑制血管生成。因此，mda-7基因治疗与放疗联合应用可能是治疗非小细胞肺癌的一种可行而有效的策略。
Melanoma differentiation-associated gene-7 (mda-7), recently classified as interleukin-24 (approved gene symbol IL24), is thought to be a tumor suppressor gene based on the loss of its expression in many different types of cancer. Gene therapy by adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to inhibit the growth of several different tumor cell lines, in vitro and in vivo. We previously demonstrated that Ad-mda7 radiosensitized non-small-cell lung cancer (NSCLC) cell lines by enhancing an apoptosis pathway through the activation of INK and c-Jun. In the present study, we investigated the efficacy of intratumoral administration of Ad-mda7 combined with ionizing radiation for treating A549 xenograft tumors in nude mice. Substantial and long-lasting inhibition of tumor growth was evident following the combined treatment. Histological examination revealed marked reduction of angiogenic factors (bFGF, VEGF) and microvessel density and enhanced apoptosis in the tumors treated with the combination therapy compared to those treated with Ad-mda7 alone or radiation alone. To confirm the radiosensitizing effect of secreted MDA-7 protein, we performed clonogenic survival assays using human umbilical vein endothelial cells (HUVECs), A549 cells, and normal human lung fibroblasts, CCD16 cells, pretreated with the conditioned medium from 293 cells that had been stably transfected with mda-7 or a control vector. The results showed that MDA-7 protein sensitized HUVECs to ionizing radiation but not A549 cells or CCD16 cells. Our results suggest that Ad-mda7 in combination with radiation enhances apoptosis in the tumors and that secreted MDA-7 protein inhibits angiogenesis by sensitizing endothelial cells to ionizing radiation without affecting other normal cells. We conclude that the combination of mda-7 gene therapy and radiotherapy may be a feasible and effective strategy for treatment of NSCLC.