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JN : Invest Radiol. 2008 May;43(5):298-305.
TI : Magnetic resonance imaging assays for dimethyl sulfoxide effect on cancer vasculature.
AU : Cyran CC, Sennino B, Chaopathomkul B, Fu Y, Rogut V, Shames DM, Wendland MF, McDonald DM, Brasch RC.
EN-AB: OBJECTIVES: 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. MATERIAL AND 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. CONCLUSION: 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. (NO 18424950)
JN : J Magn Reson Imaging. 2008 Mar;27(3):581-9.
TI : New macromolecular polymeric MRI contrast agents for application in the differentiation of cancer from benign soft tissues.
AU : Cyran CC, Fu Y, Raatschen HJ, Rogut V, Chaopathomkul B, Shames DM, Wendland MF, Yeh BM, Brasch RC.
EN-AB: PURPOSE: To compare three new macromolecular polyethylene glycol (PEG) -core dendrimeric gadolinium(Gd)-based MRI contrast agents for their applicability in quantitative assays of endothelial leakiness and tissue vascular density for the differentiation of cancer from normal soft tissues. MATERIALS AND METHODS: Thirty-two athymic rats with human breast cancer xenografts (MDA-MB-435) were imaged by dynamic MRI following enhancement with one of three new (Gd-DOTA)-conjugated PEG-core dendrimer contrast agents (effective molecular weights 161 to 323 kDa). Results were compared with a prototype macromolecular contrast agent, albumin (Gd-DTPA). Assays of permeabilities (K(PS); microL/min . 100 cm(3)) and tumor fractional plasma volumes (%) based on a two-compartment kinetic model were performed for skeletal muscle and tumors. RESULTS: The largest PEG-core contrast agent, PEG(20,000)-Gen4-(Gd-DOTA), leaked in breast tumors (K(PS) = 50 +/- 23 microL/min . 100 cm(3)), while exhibiting no measurable transendothelial leak (K(PS) = 0 microL/min . 100 cm(3)) in normal soft tissue microvessels allowing successful differentiation (P < 0.05) of cancers from normal muscle. PEG(12,000)-Gen4-(Gd-DOTA) leaked in tumors and in normal muscle (K(PS) = 51 +/- 26 and K(PS) = 21 +/- 18 microL/min . 100 cm(3), respectively). The smallest agent, PEG(12,000)-Gen3-(Gd-DOTA) also showed a measurable leak in both normal and malignant microvessels. CONCLUSION: MRI assays of vascular endothelial leakiness using new PEG-core, (Gd-DOTA)-conjugated macromolecular contrast agents proved applicable for the differentiation of human breast cancer from normal soft tissue. The apparent threshold in effective molecular weight for a clear differentiation of cancer from normal muscle with no measurable leak in the muscle is between 194 and 323 kDa. (NO 18219614)
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