Puig-Saus C, Laborda E, Rodríguez-García A, Cascalló M, Moreno R, Alemany R
Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain.
1] Translational Research Laboratory, Institut d'Investigació Biomèdica de Bellvitge-Institut Català d'Oncologia (IDIBELL-ICO), Barcelona, Spain [2] Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
Cancer Gene Ther. 2014 Feb;21(2):68-73. doi: 10.1038/cgt.2013.85. Epub 2014 Jan 17.
Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.
腺病毒（Ad）的i-前导蛋白是一种功能未知的小蛋白。i-前导蛋白的C末端截短可增加Ad从感染细胞中的释放及细胞毒性。在本研究中，我们利用i-前导蛋白截短来增强溶瘤腺病毒的效力。在体外，i-前导蛋白截短的溶瘤腺病毒更快释放到感染细胞的上清液中，形成更大的噬斑，并且在人和叙利亚仓鼠细胞系中均具有更强的细胞毒性。在携带人肿瘤异种移植瘤的小鼠中，i-前导蛋白截短增强了溶瘤效力。然而，在具有免疫活性且对人腺病毒敏感性较低的叙利亚仓鼠胰腺肿瘤模型中，仅当i-前导蛋白截短的溶瘤腺病毒而非未截短的溶瘤腺病毒与吉西他滨联合使用时，才观察到抗肿瘤疗效。在叙利亚仓鼠模型中观察到的这种协同效应在体外或在携带相同胰腺仓鼠肿瘤的免疫缺陷小鼠中均未见到，提示免疫系统在这种协同作用中发挥作用。这些结果突出了i-前导蛋白C末端截短的意义，因为它增强了溶瘤腺病毒的抗肿瘤效力，并在免疫活性系统存在的情况下与吉西他滨产生协同效应。
