4.5 Article

A chimeric adenovirus with an Ad 3 fiber knob modification augments glioma virotherapy

期刊

JOURNAL OF GENE MEDICINE
卷 11, 期 11, 页码 1005-1011

出版社

WILEY
DOI: 10.1002/jgm.1385

关键词

adenovirus; brain tumor; glioma; survivin; virotherapy

资金

  1. National Cancer Institute [R01-CA122930]
  2. National Institute of Neurological Disorders and Stroke [K08-NS046430]
  3. Alliance for Cancer Gene Therapy Young Investigator Award
  4. American Cancer Society [RSG-07-276-01-MGO]

向作者/读者索取更多资源

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 cyrotoxicity 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 (C) 2009 John Wiley & Sons, Ltd.

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