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Preclinical Experimental Therapeutics |
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
2 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{at}mdanderson.org).
Abstract
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 1
in
the intracerebral compartment. These findings demonstrate that the complex
operational mechanisms of rapamy-cin 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.
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