Journal
CANCER GENE THERAPY
Volume 14, Issue 7, Pages 627-639Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cgt.7701055
Keywords
glioblastoma multiforme; conditionally replicative fiber chimeric Ad5/35 adenoviral vector; engineered oncolytic herpes simplex type 1; measles virus fusogenic membrane proteins; chemotherapy
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In this study we compared side-by-side the anti-neoplastic activity of the oncolytic herpes simplex virus-1 (HSV-1) vector G47 Delta 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 similar to 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 G47 Delta 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 antineoplastic 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.
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