Comparison of herpes simplex virus- and conditionally replicative adenovirus-based vectors for glioblastoma treatment.
In this study we compared side-by-side the anti-neoplastic activity of the oncolytic herpes simplex virus-1 (HSV-1) vector G47Delta with that of a conditionally replicative adenoviral vector for the treatment of glioblastoma. We analyzed the transduction efficiency of permanent glioblastoma cell lines and short-term cultures of glioblastoma cells with HSV.Luc and four adenovirus type 5 (Ad5)-based vectors that differed only in their fiber gene (Ad5.Luc, AdlucRGD, and the fiber chimeric vectors Ad5/3.Luc and Ad5/35.Luc). In the tested short-term cultures of glioblastoma cells the vectors Ad5/35.Luc and HSV.Luc had an equal transduction efficiency which was approximately 70% higher than that of Ad5.Luc. In a subcutaneous xenograft glioblastoma model in nude mice we observed a significantly higher local tumor control with the G47Delta vector compared to the conditionally replicative Ad5/35 adenovirus. We confirmed in glioblastoma that the intratumoral expression of measles virus fusogenic membrane glycoproteins (FMG) encoded by replication-defective Ad5/35 or HSV-1 amplicon vectors synergistically enhances chemotherapy with temozolomide. The anti-neoplastic effect was superior when the replication-defective FMG encoding vectors were trans-complemented for replication with the respective oncolytic vector. This approach was necessary due to packaging constraints of adenovirus. At day 100, of 6 treated animals 1 was alive that received the Ad5/35- and 3 that received the HSV-1-based triple therapy. In an intracranial glioblastoma xenograft model we demonstrated the applicability of this strategy. Due to the higher oncolytic efficacy and packaging capacity of the HSV-1 vectors compared to adenovirus, these vectors are promising for the treatment of glioblastoma.
Hoffmann
D
D
Institute of Microbiology and Hygiene, Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, NRW, Germany.
Wildner
O
O
D000256:Adenoviridae / Q000235:genetics*; D001932:Brain Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D015316:Genetic Therapy; D005822:Genetic Vectors; D005909:Glioblastoma / Q000473:pathology / Q000601:surgery / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms; D016133:Polymerase Chain Reaction; D053586:Virus Internalization