title: Magnetic resonance imaging assays for dimethyl sulfoxide effect on cancer vasculature.
abstract: OBJECTIVE
  To evaluate the potential of quantitative assays of vascular characteristics based on dynamic contrast-enhanced magnetic resonance imaging (MRI) using a macromolecular contrast medium (MMCM) to search for and measure effects of dimethyl sulfoxide (DMSO) on cancer vasculature with microscopic correlations.
  
  
  METHODS
  Saline-treated control (n = 8) and DMSO-treated (n = 7) human breast cancer xenografts (MDA-MB-435) in rats were imaged dynamically by MMCM-enhanced MRI using albumin-(Gd-DTPA)27-(biotin)11 (molecular weight approximately 90 kDa), before and after a 1-week, 3-dose treatment course. After the posttreatment MRI examinations, tumors were perfused with lectin and fixative and subsequently stained with RECA-1 and streptavidin for quantitative fluorescent microscopy. Quantitative MRI estimates of cancer microvessel permeability (KPS; microL/min.100 cm3) and fractional plasma volume (fPV; %) were based on a 2-compartment kinetic model. Fluorescent microscopy yielded estimates of MMCM extravasation and vascular density that were compared to the MRI results.
  
  
  RESULTS
  DMSO decreased cancer vascular endothelial permeability significantly (P < 0.05) from tumor KPSday0 = 19.3 +/- 8.8 microL/min.100 cm3 to KPSday7 = 0 microL/min.100 cm3). K values in the saline-treated tumors did not change significantly. The amount of extravasated albumin-Gd-(DTPA)27-(biotin)11, as assayed by a fluorescently labeled streptavidin stain that strongly binds to the biotin tag on the MMCM, was significantly (P < 0.05) lower in the DMSO-treated cancers than in the control cancers (57.7% +/- 5.5% vs. 34.2% +/- 4.9%). Tumor vascular richness as reflected by the MRI-assayed fPV and by the RECA-1 and lectin-stained microscopy did not change significantly with DMSO or saline treatment.
  
  
  CONCLUSIONS
  Reductions in cancer microvascular leakiness induced by a 7-day course of DMSO could be detected and measured by dynamic MMCM-enhanced MRI and were confirmed by microscopic measurements of the leaked macromolecular agents in the same cancers. Results support the robustness of an MMCM-enhanced MRI approach to the characterization of cancers and providing first evidence for an in vivo effect of DMSO on cancer blood vessels.
authors.affiliation: Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, CA 94143-0628, USA.
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
authors.forename: Barbara
authors.initials: B
authors.lastname: Sennino
authors.forename: Bundit
authors.initials: B
authors.lastname: Chaopathomkul
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Fu
authors.forename: Victor
authors.initials: V
authors.lastname: Rogut
authors.forename: David M
authors.initials: DM
authors.lastname: Shames
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wendland
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
authors.forename: Robert C
authors.initials: RC
authors.lastname: Brasch
mesh_terms: D000818:Animals; D001710:Biotin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D003287:Contrast Media / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use*; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D007091:Image Processing, Computer-Assisted / Q000379:methods; D021621:Imaging, Three-Dimensional / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000188:drug therapy; D051381:Rats; D011923:Rats, Nude; D012965:Sodium Chloride / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D003287:Contrast Media; D016166:Free Radical Scavengers; D012965:Sodium Chloride; D001710:Biotin; D019786:Gadolinium DTPA; D004121:Dimethyl Sulfoxide