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Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model.

Authors
Kang, SH; Cho, HT; Devi, S; Zhang, Z; Escuin, D; Liang, Z; Mao, H; Brat, DJ; Olson, JJ; Simons, JW; Lavallee, TM; Giannakakou, P; Van Meir, EG; Shim, H
Citation
Cancer research, 66(24):11991-11997, 2006
Journal Title
Cancer research
ISSN
0008-54721538-7445
Abstract
Grade 4 malignant glioma (GBM) is a fatal disease despite aggressive surgical and adjuvant therapies. The hallmark of GBM tumors is the presence of pseudopalisading necrosis and microvascular proliferation. These tumor cells are hypoxic and express hypoxia-inducible factor-1 (HIF-1), a prosurvival transcription factor that promotes formation of neovasculature through activation of target genes, such as vascular endothelial growth factor. Here, we evaluated whether 2-methoxyestradiol, a microtubule and HIF-1 inhibitor, would have therapeutic potential for this disease in a 9L rat orthotopic gliosarcoma model using a combination of noninvasive imaging methods: magnetic resonance imaging to measure the tumor volume and bioluminescence imaging for HIF-1 activity. After imaging, histologic data were subsequently evaluated to elucidate the drug action mechanism in vivo. Treatment with 2-methoxyestradiol (60-600 mg/kg/d) resulted in a dose-dependent inhibition of tumor growth. This effect was also associated with improved tumor oxygenation as assessed by pimonidazole staining, decreased HIF-1alpha protein levels, and microtubule destabilization as assessed by deacetylation. Our results indicate that 2-methoxyestradiol may be a promising chemotherapeutic agent for the treatment of malignant gliomas, with significant growth inhibition. Further studies are needed to assess the effect of low or intermediate doses of 2-methoxyestradiol in combination with chemotherapeutic agents in clinical studies focused on malignant gliomas. In addition to showing tumor growth inhibition, we identified three potential surrogate biomarkers to determine the efficacy of 2-methoxyestradiol therapy: decreased HIF-1alpha levels, alpha-tubulin acetylation, and degree of hypoxia as determined by pimonidazole staining.
MeSH terms
AnimalsAntineoplastic Agents/therapeutic use*Brain Neoplasms/drug therapy*Brain Neoplasms/pathologyCell Division/drug effectsCell Line, TumorDisease Models, AnimalEstradiol/analogs & derivatives*Estradiol/therapeutic useGlioma/drug therapy*Glioma/pathologyMagnetic Resonance ImagingRatsRats, Inbred F344Tubulin Modulators/therapeutic use*
DOI
10.1158/0008-5472.CAN-06-1320
PMID
17178898
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Radiation Oncology
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