title: Potent antitumoral effects of targeted promoter-driven oncolytic adenovirus armed with Dm-dNK for breast cancer in vitro and in vivo.
abstract: Currently, no curative treatments are available for late-stage metastatic or recurrent breast cancer, because the cancer tolerates both chemotherapy and endocrine therapy. In this study, we investigated the feasibility of a dual-regulated oncolytic adenoviral vector with a novel suicide gene to treat breast cancer. Following targeted gene virotherapy of conditionally replicating adenoviruses (CRAds), the novel suicide gene of multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-DNK) was inserted into the double-regulated oncolytic adenovirus SG500 to ensure more safety and enhanced antitumor activity against breast cancer both in vitro and in vivo. Selective replication, cell-killing efficacy, and cytotoxicity, combined with chemotherapeutics were investigated in several breast cell lines (MDA-MB-231 and MCF-7), normal cells (WI-38 and MRC-5), and human (MDA-MB-231) tumor models in vivo. The double-regulated SG500-dNK had high cell-killing activity in breast cancer. Replication was similar to wild-type in breast cells and was attenuated in normal cells. SG500-dNK combined with the chemotherapeutics (E)-5-(2-bromovinyl)-2'-deoxyuridine (Bvdu) and 2',2'-difluoro-deoxycytidine (dFdC) resulted in synergistically enhanced cell killing and greatly improved antitumor efficacy in vitro or in breast xenografts in vivo. These data suggest that the novel oncolytic variant SG500-dNK is a promising candidate for targeting breast tumors specifically when combined with chemotherapeutics.
authors.affiliation: Department of Surgical Oncology, First Affiliated Hospital, China Medical University, Shenyang, China.
authors.forename: Xiaoshen
authors.initials: X
authors.lastname: Dong
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Qu
authors.forename: Shuai
authors.initials: S
authors.lastname: Ma
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhu
authors.forename: Caiwei
authors.initials: C
authors.lastname: Zheng
authors.forename: Anning
authors.initials: A
authors.lastname: He
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor); D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D029721:Drosophila Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C020018:deoxyribonucleoside kinases