Improved glioblastoma treatment with Ad5/35 fiber chimeric conditionally replicating adenoviruses.
Adenovirus type 5 (Ad5)-based vectors have been used in clinical trials for glioblastoma treatment, but the capacity of Ad5 to infect human glioma cells was questioned. Seeking to improve the adenovirus transduction, we tested four Ad5-based vectors differing only in their fiber gene on permanent and short-term cultures of glioblastoma cells. A wild-type fiber Ad5 vector (Ad5.Luc) was compared to an RGD integrin-binding motif-containing fiber adenovirus (AdlucRGD) and the two fiber chimeras Ad5/3 and Ad5/35, with vector binding redirected to the Ad3 or Ad35 receptor, respectively. Compared to Ad5, the transduction of the tested short-term glioblastoma cultures with the vector Ad5/35.Luc, AdlucRGD and Ad5/3.Luc was enhanced by approximately 72%, approximately 13% and approximately 2%, respectively. To limit adenovirus spread, we aimed to develop conditionally replicative Ad5/35 vectors by targeting the expression of the essential E1 and E4 genes; in addition, some vectors had the E1Delta24 deletion. We analyzed eleven promoters for their activity in glioblastoma cells and determined the specificity of eight replicative adenovirus vectors in vitro. We evaluated the most promising vectors with E1/E4 under the control of the GFAP/Ki67 or E2F-1/COX-2 promoters, and the native Ad5 or the chimeric Ad5/35 fiber for their antineoplastic activity in a subcutaneous and intracranial glioblastoma xenograft model. Animals treated with the Ad5/35-based vectors showed significantly smaller tumors and longer survival than those treated with the homologous Ad5 vectors; no significant toxicity was observed in the intracranial model. Our data suggest that Ad5/35-based vectors are promising tools for glioblastoma treatment.
Hoffmann
Dennis
D
Ruhr-University Bochum, Institute of Microbiology and Hygiene, Department of Molecular and Medical Virology, Bldg MA, Rm 6/40, D-44801, Bochum, Germany.
Meyer
Bernhard
B
Wildner
Oliver
O
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017504:Adenovirus E4 Proteins / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D005260:Female; D015316:Genetic Therapy; D005909:Glioblastoma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050504:Oncolytic Viruses / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D017504:Adenovirus E4 Proteins; D014764:Viral Proteins; D008156:Luciferases