Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.
Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.
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DOI：
10.1371/journal.pone.0004545
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Seol, Dai-Wu
中科院分区：
文献类型：
--
作者：
Jeong, Moonsup;Kwon, Yong-Sam;Park, Soon-Hye;Kim, Chae-Young;Jeun, Sin-Soo;Song, Kang-Won;Ko, Yong;Robbins, Paul D.;Billiar, Timothy R.;Kim, Byong-Moon;Seol, Dai-Wu
恶性胶质瘤是最常见的原发性脑肿瘤。尽管有大量的临床研究和许多新的治疗方法，恶性胶质瘤患者的平均生存期仅为1年左右。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）作为一种有前途的肿瘤治疗药物，已显示出强大的肿瘤选择性杀伤活性，并引起了广泛关注，但对递送和毒性的担忧限制了其进展。我们已经开发了一种可分泌的三聚体TRAIL（stTRAIL），并在这里评估了这种基于stTRAIL的基因疗法在脑肿瘤中的治疗潜力。将递送stTRAIL的腺病毒（Ad-stTRAIL）注射到在裸鼠中建立的颅内人神经胶质瘤肿瘤中，并使用磁共振成像（MRI）监测肿瘤生长。Ad-stTRAIL基因治疗显示出有效的肿瘤抑制活性，在治疗有效剂量下无毒副作用。与传统的治疗恶性胶质瘤的药物1，3-二（2-氯乙基）-1-亚硝基脲（BCNU）相比，Ad-stTRAIL更有效地抑制肿瘤生长。与对照小鼠或单独接受Ad-stTRAIL的小鼠相比，Ad-stTRAIL和BCNU的组合显著增加了存活率。我们的数据表明，Ad-stTRAIL，无论是单独或联合BCNU，有希望作为一种新的治疗恶性胶质瘤。
Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL) and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL) delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI). Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.
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