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Neoplasia. 2006 May;8(5):394-401.

CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling.

Author information

1
Molecular Oncology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA. xiaolinw@mail.nih.gov

Abstract

Angiogenesis is one of the critical steps in tumor growth and metastasis. The goal of this study was to evaluate whether the antitumor activity of CCI-779 is related to antiangiogenic effects in vivo in tumors of mice bearing human rhabdomyosarcoma (RMS) xenografts. We now demonstrate that CCI-779 rapidly inhibits mTOR activity, as indicated by S6 reduction and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation in two xenograft models of RMS within 24 hours of treatment. Treatment with a single 20-mg/kg dose of CCI-779 suppressed S6 phosphorylation for more than 72 hours and 4E-BP1 phosphorylation for more than 96 hours. Based on these data, an intermittent treatment schedule (every 3 days for 30 days) was chosen and displayed a significant suppression of both tumor growth and mTOR signaling. Western blot analysis and immunohistochemical studies demonstrated that the antitumor activity of CCI-779 was associated with antiangiogenesis, as indicated by impaired levels of hypoxia-inducible factor-1alpha (Hif-1alpha) and vascular endothelial growth factor (VEGF) protein expression and by decreased microvessel density in Rh30 and RD xenografts. Together, these data suggest that CCI-779 inhibits human RMS xenograft growth by an antiangiogenic mechanism associated with the targeting of mTOR/Hif-1alpha/VEGF signaling.

PMID:
16790088
PMCID:
PMC1592447
DOI:
10.1593/neo.05820
[Indexed for MEDLINE]
Free PMC Article

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