title: Oncolytic adenovirus expressing soluble TGFβ receptor II-Fc-mediated inhibition of established bone metastases: a safe and effective systemic therapeutic approach for breast cancer.
abstract: In recent years, oncolytic adenoviruses have shown some promise as a novel class of antitumor agents. However, their utility in targeting bone metastases is relatively less studied. We have examined whether the systemic therapy of oncolytic adenoviruses expressing the soluble form of transforming growth factor-β (TGFβ) receptor II fused with human immunoglobulin G1 can be developed for the treatment of established breast cancer bone metastases. MDA-MB-231-luc2 human breast cancer cells were injected in the left heart ventricle of nude mice to establish bone metastasis. Mice with hind limb tumors were administered (on days 8 and 11) oncolytic adenoviruses-Ad.sTβRFc or mhTERTAd.sTβRFc. Skeletal tumor growth was monitored weekly by bioluminescence imaging (BLI) and radiography. At the termination time on day 28, hind limb bones were analyzed for tumor burden, synchrotron micro-computed tomography, and osteoclast activation. Intravenous delivery of Ad.sTβRFc and mhTERTAd.sTβRFc induced significant inhibition of tumor growth, reduction of tumor burden, osteoclast activation, and increased animals' survival. Oncolytic adenoviruses were safer than dl309, a wild-type virus. A slight elevation of liver enzyme activity was observed after Ad.sTβRFc administration; this subsided with time. Based on these studies, we believe that Ad.sTβRFc and mhTERTAd.sTβRFc can be developed as a safe and effective approach for the treatment of established bone metastasis.
authors.affiliation: Gene Therapy Program, Department of Medicine, NorthShore Research Institute, University of Chicago, Evanston, Illinois 60201, USA.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Hu
authors.forename: Helen
authors.initials: H
authors.lastname: Gerseny
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Arthur
authors.initials: A
authors.lastname: Berg
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Zhang
authors.forename: Stuart
authors.initials: S
authors.lastname: Stock
authors.forename: Prem
authors.initials: P
authors.lastname: Seth
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D001943:Breast Neoplasms / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D010010:Osteoclasts / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011859:Radiography; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D017356:Synchrotrons / Q000295:instrumentation; D000071681:Tartrate-Resistant Acid Phosphatase; D047368:Tumor Burden; D014779:Virus Replication; D015431:Weight Loss; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D007527:Isoenzymes; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase