An armed, YB-1-dependent oncolytic adenovirus as a candidate for a combinatorial anti-glioma approach of virotherapy, suicide gene therapy and chemotherapeutic treatment

Cancer Gene Ther. 2015 Jan;22(1):30-43. doi: 10.1038/cgt.2014.67. Epub 2014 Dec 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Bystander Effect
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Cytopathogenic Effect, Viral
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Gene Expression
  • Genes, Transgenic, Suicide*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Glioma / genetics*
  • Glioma / mortality
  • Glioma / pathology
  • Glioma / therapy*
  • Humans
  • Oncolytic Virotherapy*
  • Oncolytic Viruses / genetics*
  • Spheroids, Cellular
  • Temozolomide
  • Transduction, Genetic
  • Tumor Cells, Cultured
  • Virus Replication
  • Y-Box-Binding Protein 1 / genetics*


  • Antineoplastic Agents
  • Y-Box-Binding Protein 1
  • YBX1 protein, human
  • Dacarbazine
  • Temozolomide