沉默Bcl2基因提高溶瘤腺病毒抗肿瘤作用的机制研究

重组人5型腺病毒（H101）注射液已被批准应用于临床。但单独使用H101的临床疗效有限，前期研究中我们利用Bcl2 自身具有的抗凋亡特性及其与p53之间的相互协调关系提出了以Bcl2与P53为双靶点、溶瘤腺病毒与小干扰Bcl2联合，同一载体给药的肿瘤基因治疗模式，明显增强了H101的抗宫颈癌的疗效。本项目拟在前期研究基础上，探讨干扰Bcl2作用后，增强腺病毒抗肿瘤作用的机理，包括促进肿瘤细胞凋亡、荷瘤鼠瘤体缩小、生存期延长等。并分析干扰Bcl2后，肿瘤细胞表面受体CAR变化；腺病毒基因在肿瘤细胞内复制、转录、翻译情况及其对肿瘤细胞的吸附和增殖能力的影响；以及其它一些与腺病毒溶瘤、致死相关基因（如E1A13S、ADP等）的表达变化。该课题有望阐明Bcl2基因被干扰后，腺病毒抗癌疗效提高的内在机理，为将H101等溶瘤腺病毒药物更好地应用于临床提供理论基础。

An oncolytic adenovirus called H101 has been clinically approved for the treatment of several malignancies in China. However, H101 has limited efficacy as a monotherapy in clinical practice. Previous study, the group tested a "double target" approach to antitumor therapy by combining H101 that targets the inactive p53 in tumors, with a small interfering RNA (siBCL2) that targets Bcl2. The combined treatment significantly enhanced the anti-tumor effect of H101 on cervical cancer. On the basis of preliminary studies, the project is planning to inverstigate the mechanism of enhanece the anti-tumor effect of adenovirus after interfering Bcl2, including the promotion of tumor cell apoptosis, tumor growth and survival. And will analysis the changes of tumor cell surface receptor CAR (coxsackievirus-adenovirus receptor) and the expression of some other oncolytic and death related genes (such as E1A13S, ADP). It will also plan to study the replication, transcription and translation of adenovirus in tumor cells and its effect on the adsorption and proliferation of tumor cells. The subject is expected to clarify the internal mechanism of anti-cancer effect of adenovirus when Bcl2 is interfered. It will provide a theoretical basis for oncolytic adenovirus drug better used in clinical.