title: An armed, YB-1-dependent oncolytic adenovirus as a candidate for a combinatorial anti-glioma approach of virotherapy, suicide gene therapy and chemotherapeutic treatment.
abstract: We investigated the novel recombinant oncolytic adenovirus Ad-delo-sr39TK-RGD, armed with a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39TK) as a suicide gene, and explored its antitumor efficacy in combination with HSV1-sr39TK/ganciclovir (GCV) gene therapy and temozolomide (TMZ). Ad-delo-sr39TK-RGD is an E1-mutated conditionally replicating adenovirus dependent on the human Y-box binding protein 1 (YB-1). Thus, we utilized the YB-1 dependency of the vector to target human glioma cells in vitro, using two-dimensional cell culture and three-dimensional multicellular spheroids, and demonstrated the strong replication competence and oncolytic potential of the virus. The cytotoxicity mediated by HSV1-sr39TK and its prodrug GCV enhanced the oncolytic effect even at <0.1 μg ml(-1) GCV and induced cell killing of > 95% after adding GCV 0-1 days following infection. An increased bystander effect of viral replication and GCV in co-cultured infected and uninfected cells was observed. Co-administrating Ad-delo-sr39TK-RGD with TMZ and GCV, spheroid growth was reduced drastically. Gamma counting of infected spheroids demonstrated successful accumulation of the radiotracer (18)F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine mediated by HSV1-sr39TK. Hence, our results show that the combination of YB-1-dependent virotherapy with suicide genes and TMZ effectively induces glioma cell killing and may allow for in vivo non-invasive imaging within a limited time frame.
authors.affiliation: Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Kostova
authors.affiliation: Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Mantwill
authors.affiliation: Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: P S
authors.initials: PS
authors.lastname: Holm
authors.affiliation: Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Anton
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D024201:Bystander Effect; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D003588:Cytopathogenic Effect, Viral; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression; D041722:Genes, Transgenic, Suicide; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D018874:Spheroids, Cellular; D000077204:Temozolomide; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D051840:Y-Box-Binding Protein 1 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D003606:Dacarbazine; D000077204:Temozolomide