PMID- 17178898
OWN - NLM
STAT- MEDLINE
DCOM- 20070125
LR  - 20181201
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 24
DP  - 2006 Dec 15
TI  - Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model.
PG  - 11991-7
AB  - 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.
FAU - Kang, Seung-Hee
AU  - Kang SH
AD  - Department of Hematology/Oncology,Emory University, School of Medicine, Atlanta, 
      Georgia 30322, USA.
FAU - Cho, Heidi T
AU  - Cho HT
FAU - Devi, Sarojini
AU  - Devi S
FAU - Zhang, Zhaobin
AU  - Zhang Z
FAU - Escuin, Daniel
AU  - Escuin D
FAU - Liang, Zhongxing
AU  - Liang Z
FAU - Mao, Hui
AU  - Mao H
FAU - Brat, Daniel J
AU  - Brat DJ
FAU - Olson, Jeffrey J
AU  - Olson JJ
FAU - Simons, Jonathan W
AU  - Simons JW
FAU - Lavallee, Theresa M
AU  - Lavallee TM
FAU - Giannakakou, Paraskevi
AU  - Giannakakou P
FAU - Van Meir, Erwin G
AU  - Van Meir EG
FAU - Shim, Hyunsuk
AU  - Shim H
LA  - eng
GR  - 1R01CA114335-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Tubulin Modulators)
RN  - 4TI98Z838E (Estradiol)
RN  - 6I2QW73SR5 (2-Methoxyestradiol)
SB  - IM
MH  - 2-Methoxyestradiol
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Brain Neoplasms/*drug therapy/pathology
MH  - Cell Division/drug effects
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Estradiol/*analogs & derivatives/therapeutic use
MH  - Glioma/*drug therapy/pathology
MH  - Magnetic Resonance Imaging
MH  - Rats
MH  - Rats, Inbred F344
MH  - Tubulin Modulators/*therapeutic use
EDAT- 2006/12/21 09:00
MHDA- 2007/01/26 09:00
CRDT- 2006/12/21 09:00
PHST- 2006/12/21 09:00 [pubmed]
PHST- 2007/01/26 09:00 [medline]
PHST- 2006/12/21 09:00 [entrez]
AID - 66/24/11991 [pii]
AID - 10.1158/0008-5472.CAN-06-1320 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Dec 15;66(24):11991-7. doi: 10.1158/0008-5472.CAN-06-1320.