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A chimeric adenovirus with an Ad 3 fiber knob modification augments glioma virotherapy
Author(s) -
Nandi Suvobroto,
Ulasov Ilya V.,
Rolle Cleo E.,
Han Yu,
Lesniak Maciej S.
Publication year - 2009
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1385
Subject(s) - oncolytic virus , glioma , survivin , virotherapy , oncolytic adenovirus , adenoviridae , cancer research , cytotoxicity , virology , biology , genetic enhancement , cell culture , virus , in vitro , biochemistry , genetics , gene
Background Malignant gliomas remain refractory to treatment despite advances in chemotherapy and surgical techniques. Viral vectors developed to treat gliomas have had low transduction capabilities, limiting their use. Gliomas over‐express CD46, CD80, and CD86, all of which bind adenovirus serotype 3. Methods To increase the infectivity and replication of oncolytic vectors in malignant brain tumors, we created a conditionally replicating adenovirus, CRAd‐Survivin‐5/3, which contains a survivin promoter‐driving E1A and a chimeric fiber consisting of adenovirus serotype 3 knob. Results In vitro, this modified CRAd showed ten‐ to 100‐fold increased cytotoxicity against glioma cells. Ex vivo analysis of primary glioblastoma multiforme samples infected with CRAd‐Survivin‐5/3 showed an increase in cytotoxicity of 20–30% compared to adenovirus wild‐type (AdWT). In normal human astrocytes and normal brain tissues, CRAd‐Survivin‐5/3 exhibited 30–40% and 10–15% lower cytotoxicity than AdWT, respectively. In an intracranial xenograft model of glioma, this oncolytic virus increased tumor‐free survival and overall lifespan by 50% compared to controls ( p < 0.05). Conclusions CRAd‐Survivin‐5/3 represents an attractive alternative to existing vectors and should be tested further in the pre‐clinical setting. Copyright © 2009 John Wiley & Sons, Ltd.