title: Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry.
abstract: Hypoxia is a critical hallmark of glioma, and significantly compromises treatment efficacy. Unfortunately, techniques for monitoring glioma pO2 to facilitate translational research are lacking. Furthermore, poor prognosis of patients with malignant glioma, in particular glioblastoma multiforme, warrant effective strategies that can inhibit hypoxia and improve treatment outcome. EPR oximetry using implantable resonators was implemented for monitoring pO2 in normal cerebral tissue and U251 glioma in mice. Breathing carbogen (95% O2 + 5% CO2 ) was tested for hyperoxia in the normal brain and glioma xenografts. A new strategy to inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor, was also investigated. The mean pO2 of left and right hemisphere were ∼56-69 mmHg in the normal cerebral tissue of mice. The mean baseline pO2 of U251 glioma on the first and fifth day of measurement was 21.9 ± 3.7 and 14.1 ± 2.4 mmHg, respectively. The mean brain pO2 including glioma increased by at least 100% on carbogen inhalation, although the response varied between the animals over days. Treatment with gemcitabine + MK-8776 significantly increased pO2 and inhibited glioma growth assessed by MRI. In conclusion, EPR oximetry with implantable resonators can be used to monitor the efficacy of carbogen inhalation and chemotherapy on orthotopic glioma in mice. The increase in glioma pO2 of mice breathing carbogen can be used to improve treatment outcome. The treatment with gemcitabine + MK-8776 is a promising strategy that warrants further investigation.
authors.affiliation: EPR Center for the Study of Viable Systems, Department of Radiology, Geisel School of Medicine at Dartmouth, Hanover, NH; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
authors.forename: Huagang
authors.initials: H
authors.lastname: Hou
authors.forename: Venkata
authors.initials: V
authors.lastname: Krishnamurthy Nemani
authors.forename: Gaixin
authors.initials: G
authors.lastname: Du
authors.forename: Ryan
authors.initials: R
authors.lastname: Montano
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.forename: Barjor
authors.initials: B
authors.lastname: Gimi
authors.forename: Harold M
authors.initials: HM
authors.lastname: Swartz
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
authors.forename: Nadeem
authors.initials: N
authors.lastname: Khan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D002245:Carbon Dioxide / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D005910:Glioma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D001239:Inhalation; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D010092:Oximetry; D010100:Oxygen / Q000008:administration & dosage*; D010101:Oxygen Consumption; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C559815:MK-8776; D011720:Pyrazoles; D011743:Pyrimidines; D003841:Deoxycytidine; D002245:Carbon Dioxide; C011700:carbogen; D010100:Oxygen; D000093542:Gemcitabine
keywords: EPR oximetry; carbogen; cell cycle checkpoint; chemotherapy; glioma; pO2
references.citation: Biosens Bioelectron. 2006 Jan 15;21(7):1015-22
references.pmid: 16368480
references.citation: J Clin Oncol. 2001 Feb 1;19(3):792-9
references.pmid: 11157033
references.citation: Cancer Chemother Pharmacol. 2010 Jan;65(2):391-7
references.pmid: 19847425
references.citation: J Neurooncol. 2008 Mar;87(1):79-84
references.pmid: 17987263
references.citation: JAMA. 2013 Nov 6;310(17):1842-50
references.pmid: 24193082
references.citation: J Magn Reson. 2003 Sep;164(1):54-9
references.pmid: 12932455
references.citation: BMC Cancer. 2013 Dec 21;13:604
references.pmid: 24359526
references.citation: Semin Oncol. 1996 Oct;23(5 Suppl 10):3-15
references.pmid: 8893876
references.citation: Mol Cancer Ther. 2011 Apr;10(4):591-602
references.pmid: 21321066
references.citation: Curr Pharm Des. 2012;18(19):2811-29
references.pmid: 22390765
references.citation: Curr Mol Pharmacol. 2009 Nov;2(3):263-84
references.pmid: 20021464
references.citation: J Magn Reson. 2012 Jan;214(1):22-8
references.pmid: 22033225
references.citation: J Clin Oncol. 2012 May 20;30(15):1777-83
references.pmid: 22508814
references.citation: Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):878-85
references.pmid: 19136221
references.citation: Neuroscience. 2008 Oct 28;156(4):932-8
references.pmid: 18786619
references.citation: Br J Neurosurg. 2007 Dec;21(6):550-61
references.pmid: 18071982
references.citation: Front Pharmacol. 2012 May 21;3:94
references.pmid: 22661950
references.citation: Biochim Biophys Acta. 2012 Dec;1826(2):338-49
references.pmid: 22677165
references.citation: Acad Radiol. 2012 Jul;19(7):794-800
references.pmid: 22513110
references.citation: Radiology. 2013 Aug;268(2):532-7
references.pmid: 23564715
references.citation: Radiother Oncol. 2011 Jul;100(1):22-32
references.pmid: 21511351
references.citation: Oncologist. 2008;13 Suppl 3:21-6
references.pmid: 18458121
references.citation: Magn Reson Med. 1993 Aug;30(2):213-20
references.pmid: 8396190
references.citation: Nat Rev Cancer. 2011 Jun;11(6):393-410
references.pmid: 21606941
references.citation: J Magn Reson. 2000 Jan;142(1):159-67
references.pmid: 10617447
references.citation: Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1503-9
references.pmid: 15817356
references.citation: Radiat Res. 2009 Nov;172(5):592-7
references.pmid: 19883227
references.citation: J Magn Reson Imaging. 2002 Nov;16(5):511-21
references.pmid: 12412027
references.citation: J Neurooncol. 2009 May;92(3):317-35
references.pmid: 19357959
references.citation: Ann Oncol. 2009 Jan;20(1):182-7
references.pmid: 18701427
references.citation: Radiat Res. 2013 Mar;179(3):343-51
references.pmid: 23391148
references.citation: Mol Cancer Ther. 2012 Feb;11(2):427-38
references.pmid: 22203733
references.citation: J Clin Oncol. 2007 Sep 10;25(26):4066-74
references.pmid: 17827455