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Preclinical Experimental Therapeutics |
Brain Tumor Research Laboratories, Division of Neurosurgery, Department of Surgery (E.K.H., J.M.M., C.P.L., S.B., G.Y.G.), and Division of Clinical Virology, Department of Pediatrics (J.N.P., R.J.W.), University of Alabama School of Medicine, Birmingham AL 35294, USA; Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, Chicago, IL 60637, USA (B.H., B.R.); University of Illinois, Chicago, IL 60612, USA (B.H.); Laboratoire d'Oncologie Virale et Moléculaire, Institut Curie, 91405 Orsay, France (B.P.)
2 Address correspondence to G. Yancey Gillespie, Division of Neurosurgery, 1032 THT, University of Alabama at Birmingham, 1530 3rd Avenue, South, Birmingham, AL 35294-0006, USA (yancey{at}uab.edu).
Abstract
Long-term survivors of glioblastoma multiforme, the most common form of
primary intracranial malignancy in adults, are extremely rare. Experimental
animal models that more closely resemble human disease are essential for the
identification of effective novel therapies. We report here an extensive
analysis of the 4C8 glioma model to assess its suitability for evaluating
novel type 1 herpes simplex virus (HSV-1) therapies of malignant glioma. We
first determined that expression of major histocompatibility complex I and II
and of 
vß3 in the 4C8 model was comparable
to that seen in human glioma cells. Next, using a panel of
134.5 HSVs, we demonstrated that, in vitro,
4C8 cells were as sensitive as human glioma cells to both infection and lysis
and that the 4C8 cells supported the production of foreign gene products.
Replication competence of HSV was demonstrated in vitro. Finally, 4C8
intracranial gliomas were established in immunologically competent syngeneic
B6D2F1 mice, treated by intratumoral injection of selected
engineered HSVs, including the interleukin-12-expressing virus, M002. Survival
data from these studies demonstrated that 4C8 cells in vivo are sensitive to
both direct oncolysis and HSV-mediated interleukin-12 expression.
Fluorescence-activated cell sorting analyses of immune-related infiltrating
cells supported the concept that survival was prolonged in part because of
antitumor actions of these cells. We conclude that the 4C8/B6D2F1
syngeneic glioma model is suitable for preclinical evaluation of HSV-based
therapies and that M002 is a superior virus for the treatment of murine glioma
in this model.
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