title: Hypoxia imaging using PET and SPECT: the effects of anesthetic and carrier gas on [Cu]-ATSM, [Tc]-HL91 and [F]-FMISO tumor hypoxia accumulation.
abstract: BACKGROUND
  Preclinical imaging requires anaesthesia to reduce motion-related artefacts. For direct translational relevance, anaesthesia must not significantly alter experimental outcome. This study reports on the effects of both anaesthetic and carrier gas upon the uptake of [⁶⁴Cu]-CuATSM, [(⁹⁹m)Tc]-HL91 and [¹⁸F]-FMISO in a preclinical model of tumor hypoxia.
  
  
  RESULTS
  The effect of carrier gas and anaesthetic was studied in 6 groups of CaNT-bearing CBA mice using [⁶⁴Cu]-CuATSM, [(⁹⁹m)Tc]-HL91 or [¹⁸F]-FMISO. Mice were anaesthetised with isoflurane in air, isoflurane in pure oxygen, with ketamine/xylazine or hypnorm/hypnovel whilst breathing air, or in the awake state whilst breathing air or pure oxygen. PET or SPECT imaging was performed after which the mice were killed for organ/tumor tracer quantitation. Tumor hypoxia was confirmed. Arterial blood gas analysis was performed for the different anaesthetic regimes. The results demonstrate marked influences on tumor uptake of both carrier gas and anaesthetic, and show differences between [(99m)Tc]-HL91, [¹⁸F]-FMISO and [⁶⁴Cu]-CuATSM. [(⁹⁹m)Tc]-HL91 tumor uptake was only altered significantly by administration of 100% oxygen. The latter was not the case for [¹⁸F]-FMISO and [⁶⁴Cu]-CuATSM. Tumor-to-muscle ratio (TMR) for both compounds was reduced significantly when either oxygen or anaesthetics (isoflurane in air, ketamine/xylazine or hypnorm/hypnovel) were introduced. For [¹⁸F]-FMISO no further decrease was measured when both isoflurane and oxygen were administered, [⁶⁴Cu]-CuATSM did show an additional significant decrease in TMR. When using the same anaesthetic regimes, the extent of TMR reduction was less pronounced for [⁶⁴Cu]-CuATSM than for [¹⁸F]-FMISO (40-60% versus 70% reduction as compared to awake animals breathing air).
  
  
  CONCLUSIONS
  The use of anaesthesia can have profound effects on the experimental outcome. More importantly, all tested anaesthetics reduced tumor-hypoxia uptake. Anaesthesia cannot be avoided in preclinical studies but great care has to be taken in preclinical models of hypoxia as anaesthesia effects cannot be generalised across applications, nor disease states.
authors.affiliation: Cancer Research United Kingdom/Medical Research Council Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom. Veerle.Kersemans@oncology.ox.ac.uk
authors.forename: Veerle
authors.initials: V
authors.lastname: Kersemans
authors.forename: Bart
authors.initials: B
authors.lastname: Cornelissen
authors.forename: Rebekka
authors.initials: R
authors.lastname: Hueting
authors.forename: Matthew
authors.initials: M
authors.lastname: Tredwell
authors.forename: Kamila
authors.initials: K
authors.lastname: Hussien
authors.forename: Philip D
authors.initials: PD
authors.lastname: Allen
authors.forename: Nadia
authors.initials: N
authors.lastname: Falzone
authors.forename: Sally A
authors.initials: SA
authors.lastname: Hill
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dilworth
authors.forename: Veronique
authors.initials: V
authors.lastname: Gouverneur
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.forename: Sean C
authors.initials: SC
authors.lastname: Smart
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005740:Gases / Q000032:analysis*; D000860:Hypoxia / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D008920:Misonidazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics; D010100:Oxygen / Q000378:metabolism; D049268:Positron-Emission Tomography; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D013882:Thiosemicarbazones / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D056831:Coordination Complexes; D003301:Copper Radioisotopes; D005462:Fluorine Radioisotopes; D005740:Gases; D009942:Organometallic Compounds; D015609:Organotechnetium Compounds; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); C031843:fluoromisonidazole; D008920:Misonidazole; D010100:Oxygen
references.citation: Br J Cancer. 1975 Sep;32(3):380-90
references.pmid: 1233083
references.citation: Radiat Res. 1988 Apr;114(1):64-76
references.pmid: 2895486
references.citation: Appl Radiat Isot. 2010 Sep;68(9):1610-5
references.pmid: 20395152
references.citation: Radiother Oncol. 1991;20 Suppl 1:21-8
references.pmid: 2020765
references.citation: Brain Res. 1994 Nov 14;663(2):191-8
references.pmid: 7874501
references.citation: NMR Biomed. 1999 Apr;12(2):98-106
references.pmid: 10392806
references.citation: Q J Nucl Med Mol Imaging. 2009 Apr;53(2):193-200
references.pmid: 19293767
references.citation: Int J Oncol. 2007 Apr;30(4):873-81
references.pmid: 17332926
references.citation: Magn Reson Med. 1995 May;33(5):610-8
references.pmid: 7596264
references.citation: Int J Radiat Oncol Biol Phys. 1998 Mar 1;40(4):943-51
references.pmid: 9531380
references.citation: Mol Imaging Biol. 2008 Jul-Aug;10(4):192-200
references.pmid: 18516648
references.citation: J Natl Cancer Inst. 2001 Feb 21;93(4):266-76
references.pmid: 11181773
references.citation: Cancer Metastasis Rev. 2007 Jun;26(2):225-39
references.pmid: 17440684
references.citation: J Nucl Med. 2006 Jun;47(6):989-98
references.pmid: 16741309
references.citation: Cancer Res. 1996 Dec 15;56(24):5590-3
references.pmid: 8971160
references.citation: J Nucl Med. 2008 Nov;49(11):1862-8
references.pmid: 18927340
references.citation: Int J Radiat Oncol Biol Phys. 1992;22(3):415-9
references.pmid: 1735671
references.citation: J Nucl Med. 2008 Jun;49 Suppl 2:129S-48S
references.pmid: 18523070
references.citation: Neuropsychopharmacology. 1998 Jan;18(1):18-25
references.pmid: 9408915
references.citation: Radiat Res. 1993 Dec;136(3):422-34
references.pmid: 8278585
references.citation: Radiat Res. 2001 Apr;155(4):515-28
references.pmid: 11260653
references.citation: Cancer Biother Radiopharm. 2010 Jun;25(3):365-74
references.pmid: 20578843
references.citation: Eur Radiol. 2007 Apr;17(4):861-72
references.pmid: 17043737
references.citation: J Appl Physiol (1985). 1997 Jun;82(6):1939-45
references.pmid: 9173962
references.citation: Radiother Oncol. 1991;20 Suppl 1:13-9
references.pmid: 2020762
references.citation: Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1177-86
references.pmid: 19251089
references.citation: Am J Clin Pathol. 1975 Oct;64(4):448-51
references.pmid: 1199969
references.citation: Radiother Oncol. 1991;20 Suppl 1:65-70
references.pmid: 1902320
references.citation: Cancer Res. 1998 Apr 1;58(7):1478-85
references.pmid: 9537251
references.citation: Br J Cancer. 1995 Nov;72(5):1120-4
references.pmid: 7577456
references.citation: Anesthesiology. 1985 Dec;63(6):633-9
references.pmid: 4061918
references.citation: Lab Anim. 2004 Jan;38(1):64-9
references.pmid: 14979990
references.citation: Int J Cancer. 1996 Jul 29;67(3):372-8
references.pmid: 8707411
references.citation: Eur J Nucl Med Mol Imaging. 2009 Oct;36(10):1674-86
references.pmid: 19565239
references.citation: J Nucl Med. 2005 Sep;46(9):1531-6
references.pmid: 16157537
references.citation: J Nucl Med. 2001 Apr;42(4):655-61
references.pmid: 11337556