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

Kostova, Y; Mantwill, K; Holm, P S; Anton, M

doi:10.1038/cgt.2014.67

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Document type:: Journal Article; Research Support, Non-U.S. Gov't
Author(s):: Kostova, Y; Mantwill, K; Holm, P S; Anton, M
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 ?g 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.
Journal title abbreviation:: Cancer Gene Ther
Year:: 2015
Journal volume:: 22
Journal issue:: 1
Pages contribution:: 30-43
Language:: eng
Fulltext / DOI:: doi:10.1038/cgt.2014.67
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/25501992
Print-ISSN:: 0929-1903
TUM Institution:: Institut für Experimentelle Onkologie und Therapieforschung
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