title: Retargeted adenoviruses for radiation-guided gene delivery.
abstract: The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment.
authors: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.|Biologic Therapeutics Center, Washington University School of Medicine, St Louis, MO, USA.
authors: S A
authors: SA
authors: Kaliberov
authors: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.|Biologic Therapeutics Center, Washington University School of Medicine, St Louis, MO, USA.
authors: L N
authors: LN
authors: Kaliberova
authors: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.|Biologic Therapeutics Center, Washington University School of Medicine, St Louis, MO, USA.
authors: H
authors: H
authors: Yan
authors: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors: V
authors: V
authors: Kapoor
authors: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.|Biologic Therapeutics Center, Washington University School of Medicine, St Louis, MO, USA.|Siteman Cancer Center, St Louis, MO, USA.
authors: D E
authors: DE
authors: Hallahan
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005910:Glioma / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D011839:Radiation, Ionizing; D019030:Receptors, Vitronectin / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D036022:Capsid Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; C018315:hexon capsid protein, Adenovirus; C064660:integrin alphaVbeta5