Ketola Anna, Hinkkanen Ari, Yongabi Felicitas, Furu Petra, Määttä Ann-Marie, Liimatainen Timo, Pirinen Risto, Björn Marko, Hakkarainen Tanja, Mäkinen Kimmo, Wahlfors Jarmo, Pellinen Riikka
Department of Biotechnology and Molecular Medicine, AI Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
Cancer Res. 2008 Oct 15;68(20):8342-50. doi: 10.1158/0008-5472.CAN-08-0251.
Oncolytic viruses are a promising tool for treatment of cancer. We studied an oncolytic Semliki Forest virus (SFV) vector, VA7, carrying the enhanced green fluorescent protein gene (EGFP), as a novel virotherapy candidate against unresectable osteosarcoma. The efficiency and characteristics of the VA7-EGFP treatment were compared with a widely studied oncolytic adenovirus, Ad5Delta24, both in vitro and in vivo. VA7-EGFP resulted in more rapid oncolysis and was more efficient at low multiplicities of infection (MOI) when compared with Ad5Delta24 in vitro. Yet, in MG-63 cells, a subpopulation resistant to the VA7-EGFP vector emerged. In subcutaneous human osteosarcoma xenografts in nude mice treatment with either vector reduced tumor size, whereas tumors in control mice expanded quickly. The VA7-EGFP-treated tumors were either completely abolished or regressed to pinpoint size. The efficacy of VA7-EGFP vector was studied also in an orthotopic osteosarcoma nude mouse model characterized by highly aggressive tumor growth. Treatment with oncolytic SFV extended survival of the animals significantly (P < 0.01), yet none of the animals were finally cured. Sera from SFV-treated mice contained neutralizing antibodies, and as nude mice are not able to establish IgG response, the result points out the role of IgM class antibodies in clearance of virus from peripheral tumors. Furthermore, biodistribution analysis at the survival end point verified the presence of virus in some of the brain samples, which is in line with previous studies demonstrating that IgG is required for clearance of SFV from central nervous system.
溶瘤病毒是一种很有前景的癌症治疗工具。我们研究了一种携带增强型绿色荧光蛋白基因（EGFP）的溶瘤塞姆利基森林病毒（SFV）载体VA7，作为一种针对不可切除骨肉瘤的新型病毒疗法候选物。在体外和体内，将VA7-EGFP治疗的效率和特性与广泛研究的溶瘤腺病毒Ad5Delta24进行了比较。与体外的Ad5Delta24相比，VA7-EGFP导致更快的溶瘤作用，并且在低感染复数（MOI）时更有效。然而，在MG-63细胞中，出现了对VA7-EGFP载体耐药的亚群。在用任何一种载体治疗的裸鼠皮下人骨肉瘤异种移植模型中，肿瘤大小均减小，而对照小鼠中的肿瘤迅速扩大。经VA7-EGFP治疗的肿瘤要么完全消失，要么缩小到针尖大小。还在以高度侵袭性肿瘤生长为特征的原位骨肉瘤裸鼠模型中研究了VA7-EGFP载体的疗效。溶瘤SFV治疗显著延长了动物的生存期（P <0.01），但最终没有一只动物被治愈。来自SFV治疗小鼠的血清含有中和抗体，由于裸鼠无法建立IgG反应，结果指出了IgM类抗体在从外周肿瘤清除病毒中的作用。此外，在生存终点的生物分布分析证实了在一些脑样本中存在病毒，这与先前的研究一致，即IgG是从中枢神经系统清除SFV所必需的。
