title: Potentiation of tumor radiotherapy by a radiation-inducible oncolytic and oncoapoptotic adenovirus in cervical cancer xenografts.
abstract: The p53 tumor suppressor pathway is impaired in more than 90% of cervical cancers and cancer-derived cell lines as a result of infection by human papillomavirus (HPV). The HPV E6 oncoprotein forms complexes with p53 and promotes its degradation via ubiquitin-dependent mechanism. In our study, we attempted to improve the clinical outcomes of this combined therapy by modifying the p53-targeted adenovirus to become radiation-responsive. The antitumor adenovirus was constructed by inserting a radiation-responsive expression cassette composed of the promoter of early growth response-1 (Egr-1) and the proapoptotic protein TRAIL. We showed that the addition of adenovirus containing Egr-1/TRAIL significantly increased cell death and apoptosis caused by radiotherapy. In mice bearing xenograft tumors, intratumoral administration of the Egr-1/TRAIL adenovirus followed by radiation significantly reduced tumor growth and enhanced tumor survival. Our Egr-1/TRAIL adenoviral gene product may offer a novel "one-two punch" tumor therapy for cervical cancers not only by potentiating radiation treatment but also by preserving p53 defect-specific tumor killing of the oncolytic adenovirus.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, Peoples Republic of China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Song
authors.forename: He
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Shen
authors.forename: Yixiong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xianqun
authors.initials: X
authors.lastname: Fan
authors.forename: Liyan
authors.initials: L
authors.lastname: Dai
authors.forename: Guanxiang
authors.initials: G
authors.lastname: Qian
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hoffman
authors.forename: Ji-Fan
authors.initials: JF
authors.lastname: Hu
authors.forename: Shengfang
authors.initials: S
authors.lastname: Ge
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D003131:Combined Modality Therapy; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D011401:Promoter Regions, Genetic / Q000528:radiation effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D014775:Virus Activation / Q000528:radiation effects; D014779:Virus Replication
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53