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ONYX-015和H101为可复制E1B55-kDa蛋白缺陷的C族腺病毒,它们正作为抗癌药物进行临床研究.然而它们在癌症基因治疗中的应用却受到了C族腺病毒天然特性的制约,部分原因是由于在恶性肿瘤中C族腺病毒受体(coxsackievirus-adenovirusreceptor,CAR)的表达量较低.构建了一个以H101为骨架的含有编码35型腺病毒鞭毛区域的基因,替代5型腺病毒鞭毛基因的嵌合型腺病毒载体.这一改动使得腺病毒载体可以通过一种在肿瘤中高表达的膜蛋白CD46感染肿瘤细胞.应用RT-PCR方法检测不同肿瘤细胞株中CAR和CD46表达量的区别.在CAR受体低表达的细胞株中(MDA-MB-435和MCF-7),H101-F35表现出比H101和ONYX-015更强的细胞杀伤效果;在CAR受体高表达的细胞株中(A549,NCI-H446,Hep3B,LNCaP,ZR-75-30和Bcap-37),H101-F35、H101和ONYX-015的细胞杀伤效果则相似.在荷MDA-MB-435肿瘤的裸鼠模型中,注射H101-F35的抑瘤效果比注射H101的抑瘤效果更明显.这些结果表明嵌合型溶瘤腺病毒载体H101-F35在肿瘤基因治疗中将有很好的应用前景.
ONYX-015 and H101 are group C adenoviruses that are deficient in E1B55-kDa protein replication and are being investigated as anticancer drugs, however, their use in cancer gene therapy is restricted by the natural characteristics of C-type adenovirus, Part of the reason is due to the low expression of Cxsackievirus-adenovirus receptor (CAR) in malignant tumors, a H101-containing gene encoding the flagellar region encoding adenovirus type 35 was constructed to replace type 5 gland Virus flagellar gene chimeric adenovirus vector.This change makes the adenovirus vector through a high expression in tumor membrane protein CD46 infection of tumor cells.RT-PCR method was used to detect the expression of CAR and CD46 in different tumor cell lines H101-F35 showed a stronger cell killing effect than H101 and ONYX-015 in cell lines with low expression of CAR receptor (MDA-MB-435 and MCF-7) The cytotoxicity was similar in cell lines (A549, NCI-H446, Hep3B, LNCaP, ZR-75-30 and Bcap-37), H101- F35, H101 and ONYX- In the nude mouse model, the anti-tumor effect of injection of H101-F35 was better than that of injection of H101 More obvious. These results indicate that chimeric oncolytic adenovirus H101-F35 has good application prospect in the tumor gene therapy.