title: Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model.
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.
authors.affiliation: Department of Hematology/Oncology,Emory University, School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Kang
authors.forename: Heidi T
authors.initials: HT
authors.lastname: Cho
authors.forename: Sarojini
authors.initials: S
authors.lastname: Devi
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Escuin
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Simons
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Lavallee
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051381:Rats; D011916:Rats, Inbred F344; D050257:Tubulin Modulators / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol