title: Permeability to macromolecular contrast media quantified by dynamic MRI correlates with tumor tissue assays of vascular endothelial growth factor (VEGF).
abstract: OBJECTIVE
  To correlate dynamic MRI assays of macromolecular endothelial permeability with microscopic area-density measurements of vascular endothelial growth factor (VEGF) in tumors.
  
  
  METHODS
  This study compared tumor xenografts from two different human cancer cell lines, MDA-MB-231 tumors (n=5), and MDA-MB-435 (n=8), reported to express respectively higher and lower levels of VEGF. Dynamic MRI was enhanced by a prototype macromolecular contrast medium (MMCM), albumin-(Gd-DTPA)35. Quantitative estimates of tumor microvascular permeability (K(PS); μl/min × 100 cm(3)), obtained using a two-compartment kinetic model, were correlated with immunohistochemical measurements of VEGF in each tumor.
  
  
  RESULTS
  Mean K(PS) was 2.4 times greater in MDA-MB-231 tumors (K(PS)=58 ± 30.9 μl/min × 100 cm(3)) than in MDA-MB-435 tumors (K(PS)=24 ± 8.4 μl/min × 100 cm(3)) (p<0.05). Correspondingly, the area-density of VEGF in MDA-MB-231 tumors was 2.6 times greater (27.3 ± 2.2%, p<0.05) than in MDA-MB-435 cancers (10.5 ± 0.5%, p<0.05). Considering all tumors without regard to cell type, a significant positive correlation (r=0.67, p<0.05) was observed between MRI-estimated endothelial permeability and VEGF immunoreactivity.
  
  
  CONCLUSIONS
  Correlation of MRI assays of endothelial permeability to a MMCM and VEGF immunoreactivity of tumors support the hypothesis that VEGF is a major contributor to increased macromolecular permeability in cancers. When applied clinically, the MMCM-enhanced MRI approach could help to optimize the appropriate application of VEGF-inhibiting therapy on an individual patient basis.
authors: Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, Box 0628, 505 Parnassus Ave, San Francisco, CA 94143-0628, United States. Clemens.Cyran@med.lmu.de
authors: Clemens C
authors: CC
authors: Cyran
authors: Barbara
authors: B
authors: Sennino
authors: Yanjun
authors: Y
authors: Fu
authors: Victor
authors: V
authors: Rogut
authors: David M
authors: DM
authors: Shames
authors: Bundit
authors: B
authors: Chaopathomkul
authors: Michael F
authors: MF
authors: Wendland
authors: Donald M
authors: DM
authors: McDonald
authors: Robert C
authors: RC
authors: Brasch
authors: Hans-Juergen
authors: HJ
authors: Raatschen
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics; D005260:Female; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D006801:Humans; D046911:Macromolecular Substances / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009363:Neoplasm Proteins / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011923:Rats, Nude; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D019786:Gadolinium DTPA