Document Detail


EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate.
MedLine Citation:
PMID:  22692861     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under hypoxic conditions has been reported in vitro. However, the efficacy of 3-bromopyruvate was substantially attenuated in hypoxic tumor regions (pO2<10 mmHg) in vivo using squamous cell carcinoma (SCCVII)-bearing mouse model. Metabolic MRI studies using hyperpolarized 13C-labeled pyruvate showed that monocarboxylate transporter-1 is the major transporter for pyruvate and the analog 3-bromopyruvate in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of monocarboxylate transporter-1 in vivo. Expression of monocarboxylate transporter-1 was enhanced in moderately hypoxic (8-15 mmHg) tumor regions but down regulated in severely hypoxic (<5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia-activated drugs.
Authors:
Shingo Matsumoto; Keita Saito; Hironobu Yasui; H Douglas Morris; Jeeva P Munasinghe; Martin Lizak; Hellmut Merkle; Jan Henrik Ardenkjaer-Larsen; Rajani Choudhuri; Nallathamby Devasahayam; Sankaran Subramanian; Alan P Koretsky; James B Mitchell; Murali C Krishna
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-06-12
Journal Detail:
Title:  Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine     Volume:  69     ISSN:  1522-2594     ISO Abbreviation:  Magn Reson Med     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-18     Completed Date:  2013-11-04     Revised Date:  2014-05-11    
Medline Journal Info:
Nlm Unique ID:  8505245     Medline TA:  Magn Reson Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1443-50     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / therapeutic use
Carbon Radioisotopes / diagnostic use,  pharmacokinetics
Carcinoma, Squamous Cell / diagnosis,  drug therapy*,  metabolism*
Cell Line, Tumor
Electron Spin Resonance Spectroscopy / methods*
Glycolysis / drug effects
Magnetic Resonance Imaging / methods*
Mice
Molecular Imaging / methods
Oxygen / metabolism*
Pyruvates / therapeutic use
Pyruvic Acid / metabolism*
Radiopharmaceuticals / diagnostic use,  pharmacokinetics
Reproducibility of Results
Sensitivity and Specificity
Treatment Outcome
Tumor Markers, Biological / metabolism*
Grant Support
ID/Acronym/Agency:
Z01 BC010476-06/BC/NCI NIH HHS; Z01 BC010477-05/BC/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Carbon Radioisotopes; 0/Pyruvates; 0/Radiopharmaceuticals; 0/Tumor Markers, Biological; 1113-59-3/bromopyruvate; 8558G7RUTR/Pyruvic Acid; S88TT14065/Oxygen
Comments/Corrections

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