Chemoresistance and side effects are considered as the major obstacles in cisplatin-based chemotherapy of various human malignant tumors. Conjugation with cancer-specific apoptotic stimuli TRAIL or typical viro-agent ONYX-015 has been extensively investigated to enhance the antitumor activity of cisplatin. In this study, we presented a novel chemo-gene-virotherapeutic strategy to further improve the toxic effects in cancer cells and reduce the damage in normal cells. Here, an oncolytic adenoviral vector (ZD55), with a deletion of E1B 55-kDa gene, was employed to express the therapeutic TRAIL gene by constructing a recombinant virus ZD55-TRAIL. Exogenous gene delivery efficacy was determined by both in vitro and in vivo experiments and enhanced cytotoxicity of combined treatment of ZD55-TRAIL with cisplatin was evaluated in several cancer cell lines. Moreover, negative effects on normal cells have been tested in both L-02 and MRC-5 cell lines by MTT assay and apoptotic cell staining. According to our observation, combination of ZD55-TRAIL with cisplatin exhibited an apparent synergistic cytotoxicity in cancer cells, yet significantly abolished the negative toxicity in normal cells by reducing the dosage. Thus, a novel chemo-gene-virotherapeutic strategy for cancer therapy was proposed.

译文

:化学抗性和副作用被认为是各种人类恶性肿瘤基于顺铂的化学疗法的主要障碍。与癌症特异性凋亡刺激物TRAIL或典型病毒制剂ONYX-015的结合已被广泛研究以增强顺铂的抗肿瘤活性。在这项研究中,我们提出了一种新的化学基因-病毒治疗策略,以进一步改善癌细胞的毒性作用并减少正常细胞的损伤。在此,通过构建重组病毒ZD55-TRAIL,使用具有E1B 55-kDa基因缺失的溶瘤腺病毒载体(ZD55)来表达治疗性TRAIL基因。通过体外和体内实验确定外源基因的传递功效,并在几种癌细胞系中评估了顺铂联合治疗ZD55-TRAIL的增强的细胞毒性。此外,已经通过MTT测定和凋亡细胞染色在L-02和MRC-5细胞系中测试了对正常细胞的负面影响。根据我们的观察,ZD55-TRAIL与顺铂的组合在癌细胞中表现出明显的协同细胞毒性,但通过减少剂量却显着消除了正常细胞中的阴性毒性。因此,提出了一种用于癌症治疗的新的化学基因-病毒治疗策略。

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