Premium
Evaluation of E1A double mutant oncolytic adenovectors in anti‐glioma gene therapy
Author(s) -
Ulasov Ilya V.,
Tyler Matthew A.,
Rivera Angel A.,
Nettlebeck Dirk M.,
Douglas Joanne T.,
Lesniak Maciej S.
Publication year - 2008
Publication title -
journal of medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.782
H-Index - 121
eISSN - 1096-9071
pISSN - 0146-6615
DOI - 10.1002/jmv.21264
Subject(s) - oncolytic virus , glioma , cancer research , biology , cytolysis , genetic enhancement , virology , cytotoxicity , cell culture , flow cytometry , cytopathic effect , mutant , western blot , microbiology and biotechnology , in vitro , gene , virus , genetics , biochemistry
Malignant glioma, in particular glioblastoma multiforme (GBM), represents one of the most devastating cancers currently known and existing treatment regimens do little to change patient prognosis. Conditionally replicating adenoviral vectors (CRAds) represent attractive experimental anti‐cancer agents with potential for clinical application. However, early protein products of the wild type adenovirus backbone—such as E1A—limit CRAds' replicative specificity. In this study, we evaluated the oncolytic potency and specificity of CRAds in which p300/CPB and/or pRb binding capacities of E1A were ablated to reduce non‐specific replicative cytolysis. In vitro cytopathic assays, quantitative PCR analysis, Western blot, and flow cytometry studies demonstrate the superior anti‐glioma efficacy of a double‐mutated CRAd, Ad2/24CMV, which harbors mutations that reduce E1A binding to p300/CPB and pRb. When compared to its single‐mutated and wild type counterparts, Ad2/24CMV demonstrated attenuated replication and cytotoxicity in representative normal human brain while displaying enhanced replicative cytotoxicity in malignant glioma. These results have implications for the development of double‐mutated CRAd vectors for enhanced GBM therapy. J. Med. Virol. 80:1595–1603, 2008. © 2008 Wiley‐Liss, Inc.