Cancer Gene Therapy Group, Molecular Cancer Biology Program, Transplantation Laboratory, Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Mol Ther. 2011 Oct;19(10):1858-66. doi: 10.1038/mt.2011.144. Epub 2011 Jul 26.
Oncolytic adenoviruses are an emerging experimental approach for treatment of tumors refractory to available modalities. Although preclinical results have been promising, and clinical safety has been excellent, it is also apparent that tumors can become virus resistant. The resistance mechanisms acquired by advanced tumors against conventional therapies are increasingly well understood, which has allowed development of countermeasures. To study this in the context of oncolytic adenovirus, we developed two in vivo models of acquired resistance, where initially sensitive tumors eventually gain resistance and relapse. These models were used to investigate the phenomenon on RNA and protein levels using two types of analysis of microarray data, quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Interferon (IFN) signaling pathways were found upregulated and Myxovirus resistance protein A (MxA) expression was identified as a marker correlating with resistance, while transplantation experiments suggested a role for tumor stroma in maintaining resistance. Furthermore, pathway analysis suggested potential therapeutic targets in oncolytic adenovirus-resistant cells. Improved understanding of the antiviral phenotype causing tumor recurrence is of key importance in order to improve treatment of advanced tumors with oncolytic adenoviruses. Given the similarities between mechanisms of action, this finding might be relevant for other oncolytic viruses as well.
溶瘤腺病毒是一种新兴的实验方法，可用于治疗对现有治疗方法耐药的肿瘤。虽然临床前研究结果令人鼓舞，临床安全性也很好，但显然肿瘤也会产生抗病毒耐药性。人们越来越了解晚期肿瘤获得的针对传统疗法的耐药机制，这也促使人们开发出了对抗耐药性的对策。为了在溶瘤腺病毒的背景下研究这种情况，我们开发了两种获得性耐药的体内模型，最初敏感的肿瘤最终会产生耐药性并复发。这些模型用于在 RNA 和蛋白质水平上使用两种微阵列数据分析类型（定量逆转录聚合酶链反应和免疫组织化学）进行研究。发现干扰素（IFN）信号通路被上调，并且发现肌氨酸蛋白 A（MxA）表达作为与耐药性相关的标志物。而移植实验表明肿瘤基质在维持耐药性方面起作用。此外，通路分析提示在溶瘤腺病毒耐药细胞中存在潜在的治疗靶点。为了提高溶瘤腺病毒治疗晚期肿瘤的效果，了解导致肿瘤复发的抗病毒表型至关重要。鉴于作用机制之间的相似性，这一发现可能与其他溶瘤病毒也有关。
