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Mechanisms of action of rapamycin in
gliomas
Amy B. Heimberger,
Enze Wang, Eric C. McGary, Kenneth R. Hess, Verlene K. Henry, Tadahisa
Shono, Zvi Cohen, Joy Gumin, Raymond Sawaya, Charles A. Conrad, and Frederick
F. Lang
Brain Tumor Center and
Departments of Neurosurgery (A.B.H., E.W., V.K.H., T.S., Z.C., J.G.,
R.S., F.F.L.), Biostatistics (K.R.H.), and Neuro-Oncology (C.A.C.),
The University of Texas M.D. Anderson Cancer Center, Houston, TX
77030; Hilton Head Regional Medical Center, Hilton Head, SC 29926
(E.C.M.); USA. Address
correspondence to Amy B. Heimberger, Department of Neurosurgery, The
University of Texas M.D. Anderson Cancer Center, Unit 442, 1515
Holcombe Boulevard, Houston, TX 77030-4009, USA
(aheimber@mdanderson.org).
Rapamycin has previously been shown to
be efficacious against intracerebral glioma xenografts and to act in a
cytostatic manner against gliomas.
However, very little is known about the mechanism of action of
rapamycin.
The purpose of our study was to further investigate the in vitro and
in vivo mechanisms of action of rapamycin, to elucidate molecular end
points that may be applicable for investigation in a clinical trial,
and to examine potential mechanisms of treatment failure.
In the phosphatase and tensin homolog deleted from chromosome 10
(PTEN)-null glioma cell lines U-87 and D-54, but not the
oligodendroglioma cell line HOG (PTEN null), doses of rapamycin at the
IC50 resulted in accumulation of cells in G1,
with a corresponding decrease in the fraction of cells traversing the
S phase as early as 24 h after dosing.
All glioma cell lines tested had markedly diminished production of
vascular endothelial growth factor (VEGF) when cultured with
rapamycin, even at doses below the IC50.
After 48 h of exposure to rapamycin, the glioma cell lines (but not
HOG cells) showed downregulation of the membrane type-1 matrix
metalloproteinase (MMP) invasion molecule.
In U-87 cells, MMP-2 was downregulated, and in D-54 cells, both MMP-2
and MMP-9 were downregulated after treatment with rapamycin.
Treatment of established subcutaneous U-87 xenografts in vivo resulted
in marked tumor regression (P < 0.05).
Immunohistochemical studies of subcutaneous U-87 tumors demonstrated
diminished production of VEGF in mice treated with rapamycin.
Gelatin zymography showed marked reduction of MMP-2 in the mice with
subcutaneous U-87 xenografts that were treated with rapamycin as
compared with controls treated with phosphatebuffered saline.
In contrast, treatment of established intracerebral U-87 xenografts
did not result in increased median survival despite inhibition of the
Akt pathway within the tumors.
Also, in contrast with our findings for subcutaneous tumors,
immunohistochemistry and quantitative Western blot analysis results
for intracerebral U-87 xenografts indicated that there is not
significant VEGF production, which suggests possible deferential
regulation of the hypoxia-inducible factor 1α in the
intracerebral compartment.
These findings demonstrate that the complex operational mechanisms of
rapamycin against gliomas include cytostasis, anti-VEGF, and
anti-invasion activity, but these are dependent on the in vivo
location of the tumor and have implications for the design of a
clinical trial.
© 2005 Duke University Press
Source: http://taddeo.ingentaselect.com/vl=2268510/cl=18/nw=1/rpsv/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v7n1/s1/p1&user_id=undefined
DOI:
http://dx.doi.org/10.1215/S1152851704000420
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