title: DCE-MRI biomarkers for monitoring an anti-angiogenic triple combination therapy in experimental hypopharynx carcinoma xenografts with immunohistochemical validation.
abstract: BACKGROUND
  Novel anti-angiogenic treatments are increasingly complementing established cancer therapy strategies in head and neck tumors. Contrast-enhanced magnetic resonance imaging (MRI) can be applied for early and non-invasive therapy monitoring by non-invasive quantitative assessment of tumor microcirculation as in vivo imaging biomarkers of therapy response.
  
  
  OBJECTIVE
  To monitor the anti-angiogenic effects of a novel combination therapy on experimental head and neck squamous cell carcinomas (HNSCC) with dynamic contrast-enhanced (DCE)-MRI.
  
  
  METHODS
  Athymic rats (n = 18) with subcutaneous HNSCC xenografts were investigated by DCE-MRI before and after 7 days of a daily triple therapy regimen combining the COX-II-inhibitor celecoxib, the matrix-metalloproteinase-inhibitor GM6001, and the uPA-inhibitor upamostat. Quantitative measurements of tumor blood flow (tBF), tumor blood volume (tBV), and permeability-surface area product (PS) were calculated and validated by immunohistochemistry.
  
  
  RESULTS
  Mean tBF and tBV in triple-therapy animals decreased significantly from day 0 to day 7 (tBF, 41.0 ± 14.2 to 20.4 ± 5.7 mL/100 mL/min; P < 0.01; tBV, 17.7 ± 3.9 to 7.5 ± 3.3%; P < 0.01). No significant effects on PS were observed in either group (P > 0.05). Immunohistochemical analysis showed a significantly lower tumor vascularity in the therapy group than in the control group (CD31), significantly fewer Ki-67+ proliferating tumor cells and significantly more Capase-3+ apoptotic tumor cells (P < 0.05). Significant (P < 0.05) correlations were observed between tBF/tBV and CD31 (tBF, r = 0.84; tBV, r = 0.70), tBV and Ki-67 (r = 0.62), as well as tBF and caspase-3 (r = -0.64).
  
  
  CONCLUSIONS
  DCE-MRI may be a suitable tool for the non-invasive monitoring of the anti-vascular effects of this innovative triple therapy regimen with potential for clinical translation.
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sterzik
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Paprottka
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Zengel
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Hirner
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Roßpunt
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Eschbach
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Moser
authors.affiliation: Josef Lissner Laboratory for Biomedical Imaging, Department of Clinical Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Havla
authors.affiliation: Josef Lissner Laboratory for Biomedical Imaging, Department of Clinical Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ingrisch
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Mack
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Reiser
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Nikolaou
authors.affiliation: Department of Clinical Radiology, Laboratory of Experimental Radiology, University of Munich Hospitals, Ludwig-Maximilians-University Munich, Munich, Germany Clemens.Cyran@med.lmu.de.
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000188:drug therapy*; D000068579:Celecoxib; D003131:Combined Modality Therapy; D003287:Contrast Media; D004151:Dipeptides / Q000627:therapeutic use; D004195:Disease Models, Animal; D007012:Hypopharyngeal Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D007089:Image Enhancement / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D010091:Oximes; D010879:Piperazines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D011923:Rats, Nude; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D003287:Contrast Media; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010091:Oximes; D010879:Piperazines; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; C580590:upamostat
keywords: Dynamic; GM6001; celecoxic; contrast-enhanced MRI; hypopharyngeal squamous cell carcinoma; therapy monitoring; upamostat