title: Perfusion MRI for monitoring the effect of sorafenib on experimental prostate carcinoma: a validation study.
abstract: OBJECTIVE
  The purpose of this study was to investigate with immunohistochemical validation whether dynamic contrast-enhanced MRI with small-molecule contrast medium is useful for monitoring the effects of the multikinase inhibitor sorafenib on prostate carcinomas in rats.
  
  
  METHODS
  Copenhagen rats (n = 20) into which prostate carcinoma (MAT-Ly-Lu-B2) had been implanted subcutaneously were imaged on the day of implantation and 7 days later with 3-T dynamic gadobutrol-enhanced MRI. The therapy group (n = 10) received daily administration of 10 mg/kg body weight sorafenib. Quantitative measurements of tumor perfusion, tumor vascularity, and permeability-surface area product were calculated with a two-compartment model. Dynamic contrast-enhanced MRI values were correlated with immunohistochemical results for validation.
  
  
  RESULTS
  Tumor perfusion in sorafenib-treated prostate carcinoma declined significantly from day 0 to day 7 (47.9 ± 36.8 mL/100 mL/min to 24.4 ± 18.6 mL/100 mL/min; p < 0.05). No significant effect on permeability-surface area product was observed in either the therapy or the control group (p > 0.05). Tumor vascularity decreased significantly (p < 0.05) from day 0 to day 7 under sorafenib treatment (15.6% ± 11.4% to 5.4% ± 2.1%). Immunohistochemical analysis revealed significantly lower tumor vascularity in the therapy than in the control group (rat endothelial cell antigen 1, 74.4 ± 16.9 cells vs 197 ± 75.4 cells; p < 0.05). In sorafenib-treated tumors, significantly more apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling, 6923 ± 3761 vs 3167 ± 1500; p < 0.05) and significantly fewer proliferating cells (Ki-67, 10,198 ± 3064 vs 15,003 ± 3674; p < 0.05) were observed than in the control group. Modest but significant correlations were observed between tumor perfusion and immunohistochemical tumor cell apoptosis (r = -0.56; p < 0.05) and between tumor perfusion and immunohistochemical tumor vascularity (r = 0.56; p < 0.05).
  
  
  CONCLUSIONS
  Tumor perfusion quantified with gadobutrol-enhanced dynamic contrast-enhanced MRI can be used as a noninvasive surrogate parameter for monitoring the antiangiogenic, antiproliferative, and proapoptotic effects of sorafenib on prostate carcinoma allografts as validated with immunohistochemical analysis.
authors.affiliation: Department of Clinical Radiology, Center for Experimental Radiology, University Hospitals Munich, Campus Grosshadern, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany. Clemens.Cyran@med.lmu.de
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Paprottka
authors.forename: Bettina
authors.initials: B
authors.lastname: Schwarz
authors.forename: Steven
authors.initials: S
authors.lastname: Sourbron
authors.forename: Michael
authors.initials: M
authors.lastname: Ingrisch
authors.forename: Jobst
authors.initials: J
authors.lastname: von Einem
authors.forename: Hubertus
authors.initials: H
authors.lastname: Pietsch
authors.forename: Olaf
authors.initials: O
authors.lastname: Dietrich
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Christiane J
authors.initials: CJ
authors.lastname: Bruns
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Reiser
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Wintersperger
authors.forename: Konstantin
authors.initials: K
authors.lastname: Nikolaou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D003287:Contrast Media; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives; D009942:Organometallic Compounds; D010671:Phenylurea Compounds; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D003287:Contrast Media; D009942:Organometallic Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; C090600:gadobutrol; D009536:Niacinamide; D000077157:Sorafenib