生物化学与生物物理进展
生物化學與生物物理進展
생물화학여생물물리진전
PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS
2005年
12期
1156-1164
,共9页
叶迅%陆琴%赵毅%任臻%孟夏%葛盛芳%邱祺宏%童涌%LIEBER ANDRE%梁旻%胡放%陈红专
葉迅%陸琴%趙毅%任臻%孟夏%葛盛芳%邱祺宏%童湧%LIEBER ANDRE%樑旻%鬍放%陳紅專
협신%륙금%조의%임진%맹하%갈성방%구기굉%동용%LIEBER ANDRE%량민%호방%진홍전
腺病毒%转导调节%溶瘤
腺病毒%轉導調節%溶瘤
선병독%전도조절%용류
adenovirus%transductional control%oncolytic
ONYX-015和H101为可复制E1B 55-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-adenovirus receptor,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和H101為可複製E1B 55-kDa蛋白缺陷的C族腺病毒,它們正作為抗癌藥物進行臨床研究.然而它們在癌癥基因治療中的應用卻受到瞭C族腺病毒天然特性的製約,部分原因是由于在噁性腫瘤中C族腺病毒受體(coxsackievirus-adenovirus receptor,CAR)的錶達量較低.構建瞭一箇以H101為骨架的含有編碼35型腺病毒鞭毛區域的基因,替代5型腺病毒鞭毛基因的嵌閤型腺病毒載體.這一改動使得腺病毒載體可以通過一種在腫瘤中高錶達的膜蛋白CD46感染腫瘤細胞.應用RT-PCR方法檢測不同腫瘤細胞株中CAR和CD46錶達量的區彆.在CAR受體低錶達的細胞株中(MDA-MB-435和MCF-7),H101-F35錶現齣比H101和ONYX-015更彊的細胞殺傷效果;在CAR受體高錶達的細胞株中(A549,NCI-H446,Hep3B,LNCaP,ZR-75-30和Bcap-37),H101-F35、H101和ONYX-015的細胞殺傷效果則相似.在荷MDA-MB-435腫瘤的裸鼠模型中,註射H101-F35的抑瘤效果比註射H101的抑瘤效果更明顯.這些結果錶明嵌閤型溶瘤腺病毒載體H101-F35在腫瘤基因治療中將有很好的應用前景.
ONYX-015화H101위가복제E1B 55-kDa단백결함적C족선병독,타문정작위항암약물진행림상연구.연이타문재암증기인치료중적응용각수도료C족선병독천연특성적제약,부분원인시유우재악성종류중C족선병독수체(coxsackievirus-adenovirus receptor,CAR)적표체량교저.구건료일개이H101위골가적함유편마35형선병독편모구역적기인,체대5형선병독편모기인적감합형선병독재체.저일개동사득선병독재체가이통과일충재종류중고표체적막단백CD46감염종류세포.응용RT-PCR방법검측불동종류세포주중CAR화CD46표체량적구별.재CAR수체저표체적세포주중(MDA-MB-435화MCF-7),H101-F35표현출비H101화ONYX-015경강적세포살상효과;재CAR수체고표체적세포주중(A549,NCI-H446,Hep3B,LNCaP,ZR-75-30화Bcap-37),H101-F35、H101화ONYX-015적세포살상효과칙상사.재하MDA-MB-435종류적라서모형중,주사H101-F35적억류효과비주사H101적억류효과경명현.저사결과표명감합형용류선병독재체H101-F35재종류기인치료중장유흔호적응용전경.
ONYX-015 and H101 are E1B 55-kDa protein-deficient replicating C group adenoviruses that are currently in clinical trials as antitumor agents. However, their application in cancer gene therapy is limited by the native tropism of C group adenoviruses. This is in part due to low expression of the C group adenovirus receptor (coxsackievirus-adenovirus receptor, CAR) on malignant tumors. An H101-based chimeric virus vector containing sequences encoding the Ad35 fiber domain instead of the Ad5 fiber (H101-F35) was constructed. This modification allowed infection of tumor cells through CD46, a membrane protein over-expressed on tumors. The CAR and CD46 RNA expression was evaluated by RT-PCR method. H101-F35 conferred a stronger cytocidal effect than H101 and ONYX-015 in tumor cell lines that lacked CAR expression (MDA-MB-435 and MCF-7), while the cytocidal effect of H101-35, H101 and ONYX-015 was similar in high-level CAR expressing cancer cell lines (A549, NCI-H446, Hep3B, LNCaP, ZR-75-30 and Bcap-37). In an MDA-MB-435 xenograft mouse tumor model, tumor growth in mice receiving H101-F35 was significantly inhibited compared with mice injected with H101. These results suggest that the chimeric oncolytic adenovirus H101-F35 vector might be a useful candidate for gene therapy of cancer.
