title: Significant impact of different oxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging using [¹⁸F]-fluoro-azomycinarabino-furanoside ([¹⁸F]FAZA).
abstract: BACKGROUND
  [18F]FAZA is a PET biomarker with great potential for imaging tumor hypoxia. Aim of our study was to compare [18F]FAZA uptake in mice with subcutaneous exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas and to analyze the influence of different breathing protocols in CT26 colon carcinomas as well as the reversibility or irreversibility of [18F]FAZA uptake.
  
  
  METHODS
  We injected subcutaneous CT26 colon carcinoma or polyomavirus middle-T (PyV-mT) mammary carcinoma-bearing mice intravenously with18F-FAZA and performed PET scans 1-3 h post injection (p.i.). To analyze the impact of oxygen supply in CT26 carcinomas we used three different breathing protocols: (P0) air; (P1) 100% oxygen 1 h prior injection until 3 h p.i.; (P2) 100% oxygen breathing starting 2 min prior tracer injection until 1 h p.i. and during the PET scans; mice were breathing air between the 2 h and 3 h 10 min static scans. Normalized PET images were analyzed by using defined regions of interest. Finally, some mice were dissected for pimonidazole immunohistochemistry.
  
  
  RESULTS
  There was no difference in18F-FAZA uptake 1-3 h p.i. between the two carcinoma types (CT26: 1.58 ± 0.45%ID/cc; PyV-mT: 1.47 ± 0.89%ID/cc, 1 h p.i., tumor size < 0.5 cm3). We measured a significant tracer clearance, which was more pronounced in muscle tissue (P0). The [18F]FAZA tumor-to-muscle-ratios in CT26 colon carcinoma-bearing mice 2 h and 3 h, but not 1 h p.i. were significantly higher when the mice breathed air (P0: 3.56 ± 0.55, 3 h) compared to the oxygen breathing protocols (P1: 2.45 ± 0.58; P2: 2.77 ± 0.42, 3 h). Surprisingly, the breathing protocols P1 and P2 showed no significant differences in T/M ratios, thus indicating that the crucial [18F]FAZA uptake phase is during the first hour after [18F]FAZA injection. Importantly, the muscle clearance was not affected by the different oxygen breathing conditions while the tumor clearance was lower when mice were breathing air.
  
  
  CONCLUSIONS
  Exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas showed no differences in [18F]FAZA uptake 1-3 h p.i. Our analysis using various breathing protocols with air (P0) and with pure oxygen (P1, P2) clearly indicate that [18F]FAZA is an appropriate PET biomarker for in vivo analysis of hypoxia revealing an enhanced tracer uptake in tumors with reduced oxygen supply. [18F]FAZA uptake was independent of tumor-type.
authors: Department of Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, University of Tübingen, Germany.
authors: Florian C
authors: FC
authors: Maier
authors: Manfred
authors: M
authors: Kneilling
authors: Gerald
authors: G
authors: Reischl
authors: Funda
authors: F
authors: Cay
authors: Daniel
authors: D
authors: Bukala
authors: Andreas
authors: A
authors: Schmid
authors: Martin S
authors: MS
authors: Judenhofer
authors: Martin
authors: M
authors: Röcken
authors: Hans-Jürgen
authors: HJ
authors: Machulla
authors: Bernd J
authors: BJ
authors: Pichler
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D003952:Diagnostic Imaging / Q000379:methods*; D005462:Fluorine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D000860:Hypoxia / Q000000981:diagnostic imaging; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging*; D009593:Nitroimidazoles / Q000378:metabolism / Q000493:pharmacokinetics; D010100:Oxygen; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics; D012119:Respiration; D012266:Ribose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; C498052:fluoroazomycin arabinoside; D012266:Ribose; D010100:Oxygen