title: Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model.
abstract: We have examined whether Ad.sTβRFc and TAd.sTβRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFβRIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and TAd.sTβRFc produced sTGFβRIIFc and viral replication; sTGFβRIIFc caused inhibition of TGF-β-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sTβRFc, an E1(-) adenovirus, produced sTGFβRIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5×10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sTβRFc, TAd.sTβRFc, and Ad(E1-).sTβRFc caused significant inhibition of tumor growth; however, Ad.sTβRFc was the most effective among all the vectors. Only Ad.sTβRFc and TAd.sTβRFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sTβRFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sTβRFc and TAd.sTβRFc can be developed as potential new therapies for prostate cancer bone metastasis.
authors.affiliation: Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, IL 60201, USA.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Hu
authors.forename: Janhavi
authors.initials: J
authors.lastname: Gupta
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Zhang
authors.forename: Helen
authors.initials: H
authors.lastname: Gerseny
authors.forename: Arthur
authors.initials: A
authors.lastname: Berg
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Du
authors.forename: Charles B
authors.initials: CB
authors.lastname: Brendler
authors.forename: Xianghui
authors.initials: X
authors.lastname: Xiao
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Theresa
authors.initials: T
authors.lastname: Guise
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.forename: Paula H
authors.initials: PH
authors.lastname: Stern
authors.forename: Stuart
authors.initials: S
authors.lastname: Stock
authors.forename: Prem
authors.initials: P
authors.lastname: Seth
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta