title: Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD.
abstract: Retargeting oncolytic adenoviruses from their systemic preeminent liver tropism to disseminated tumor foci would highly improve the efficacy of these agents at eradicating tumors. We have replaced the KKTK fiber shaft heparan sulfate glycosaminoglycan-binding domain with an RGDK motif in order to achieve simultaneously liver detargeting and tumor targeting. When inserted into a wild-type backbone, this mutation palliated liver transaminase elevation and hematological alterations in mice. Importantly, when tested in a backbone that redirects E1A transcription towards pRB pathway deregulation, RGD at this novel shaft location also improved significantly systemic antitumor therapy compared with the broadly used RGD location at the HI-loop of the fiber knob domain.
authors.affiliation: Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Rojas
authors.forename: M
authors.initials: M
authors.lastname: Gimenez-Alejandre
authors.forename: R
authors.initials: R
authors.lastname: Gil-Hoyos
authors.forename: M
authors.initials: M
authors.lastname: Cascallo
authors.forename: R
authors.initials: R
authors.lastname: Alemany
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006497:Heparan Sulfate / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy*; D009842:Oligopeptides; D050130:Oncolytic Virotherapy / Q000379:methods*; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D006497:Heparan Sulfate; D009842:Oligopeptides; D011956:Receptors, Cell Surface; C086020:glycosaminoglycan receptor; C047981:arginyl-glycyl-aspartic acid