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具有复制能力的塞姆利基森林病毒可延长实验性肺癌模型的生存期。

Replication competent Semliki Forest virus prolongs survival in experimental lung cancer.

作者信息

Määttä Ann-Marie, Mäkinen Kimmo, Ketola Anna, Liimatainen Timo, Yongabi Felicitas Newu, Vähä-Koskela Markus, Pirinen Risto, Rautsi Outi, Pellinen Riikka, Hinkkanen Ari, Wahlfors Jarmo

机构信息

A. I. Virtanen Institute, Department of Biotechnology and Molecular Medicine, University of Kuopio, Kuopio, Finland.

出版信息

Int J Cancer. 2008 Oct 1;123(7):1704-11. doi: 10.1002/ijc.23646.

Abstract

We evaluated the therapeutic potential of the replication competent vector VA7-EGFP, which is based on the avirulent Semliki Forest virus (SFV) strain A7 (74) carrying the EGFP marker gene in an orthotopic lung cancer tumor model in nude mice. We have previously shown that this oncolytic vector destroys tumor cells efficiently in vitro and in vivo (in subcutaneous tumor model). Tumor growth in animals with orthotopically implanted adenocarcinoma cells (A549) were monitored during the study with small animal CT. We show that locally administered virotherapy with VA7-EGFP increased survival rate in experimental lung cancer significantly (p < 0.001) comparable to results obtained with the second generation conditionally replicating adenoviral vector Ad5-Delta24TK-GFP, used for comparison. The limited efficacy in systemically administered oncolytic viruses is the essential problem in oncolytic virotherapy and also in this study we were not able to elicit significant response with systemic administration route. Despite the fact that tumor microenvironment in orthotopic lung cancer is more optimal, viruses failed to home to the tumors and were unable to initiate efficient intratumoral replication. Clearly, the efficacy of virotherapy is influenced by many factors such as the route of virus administration, immunological and physiological barriers and cancer cell-specific features (IFN-responsiveness).

摘要

我们在裸鼠原位肺癌肿瘤模型中评估了具有复制能力的载体VA7-EGFP的治疗潜力,该载体基于携带EGFP标记基因的无毒塞姆利基森林病毒(SFV)A7株(74)。我们之前已经表明,这种溶瘤载体在体外和体内(皮下肿瘤模型)均能有效破坏肿瘤细胞。在研究过程中,使用小动物CT监测原位植入腺癌细胞(A549)的动物的肿瘤生长情况。我们发现,与用于比较的第二代条件性复制腺病毒载体Ad5-Delta24TK-GFP相比,局部给予VA7-EGFP进行病毒疗法可显著提高实验性肺癌的生存率(p < 0.001)。全身给药的溶瘤病毒疗效有限是溶瘤病毒疗法中的关键问题,在本研究中,我们也无法通过全身给药途径引发显著反应。尽管原位肺癌的肿瘤微环境更为理想,但病毒未能归巢至肿瘤部位,也无法启动有效的肿瘤内复制。显然,病毒疗法的疗效受多种因素影响,如病毒给药途径、免疫和生理屏障以及癌细胞特异性特征(IFN反应性)。

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