TY - JOUR
T1 - Magnetic resonance imaging monitors physiological changes with antihedgehog therapy in pancreatic adenocarcinoma xenograft model
AU - Guimaraes, Alexander R.
AU - Rakhlin, Elena
AU - Weissleder, Ralph
AU - Thayer, Sarah P.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2008/11
Y1 - 2008/11
N2 - OBJECTIVES:: The sonic hedgehog (Shh) pathway has an established role in pancreatic cancer (pancreatic adenocarcinoma [PDAC]). We tested whether magnetic resonance imaging measures of vascular volume fraction (VVF) using magnetic iron oxide nanoparticles are sensitive to the antiangiogenic effect of targeted Shh therapies in a PDAC xenograft model. METHODS:: Pancreatic adenocarcinoma xenograft lines were subcutaneously implanted into nude mice (n = 19 samples within 4 groups). Therapies were targeted to 3 loci of the Shh signaling pathway (anti-Shh antibody, cyclopamine, or forskolin). Magnetic resonance imaging (4.7-T Bruker Pharmascan) was performed (after 1 week of intraperitoneal therapy) before and after intravenous injection of MION-47. Vascular volume fraction was quantified as ΔR2 (from multicontrast T2 sequences) and normalized to an assumed VVF in muscle of 3%. Linear regression compared VVF to histological indices including microvessel density (MVD), viable gland density (VGD), and proliferative index (PI). RESULTS:: In response to anti-Hh treatment, tumors showed a decrease in VGD, PI, MVD, and VVF compared with controls (P < 0.001). Vascular volume fraction was compared with histological indicators of response: PI (R = 0.88; P < 0.05), VGD (R = 0.87; P< 0.05), and MVD (R = 0.85; P < 0.05). CONCLUSIONS:: Magnetic resonance imaging VVF using magnetic iron oxide nanoparticles may serve as a noninvasive measure of biological response to Shh PDAC therapy with easy translation to the clinic.
AB - OBJECTIVES:: The sonic hedgehog (Shh) pathway has an established role in pancreatic cancer (pancreatic adenocarcinoma [PDAC]). We tested whether magnetic resonance imaging measures of vascular volume fraction (VVF) using magnetic iron oxide nanoparticles are sensitive to the antiangiogenic effect of targeted Shh therapies in a PDAC xenograft model. METHODS:: Pancreatic adenocarcinoma xenograft lines were subcutaneously implanted into nude mice (n = 19 samples within 4 groups). Therapies were targeted to 3 loci of the Shh signaling pathway (anti-Shh antibody, cyclopamine, or forskolin). Magnetic resonance imaging (4.7-T Bruker Pharmascan) was performed (after 1 week of intraperitoneal therapy) before and after intravenous injection of MION-47. Vascular volume fraction was quantified as ΔR2 (from multicontrast T2 sequences) and normalized to an assumed VVF in muscle of 3%. Linear regression compared VVF to histological indices including microvessel density (MVD), viable gland density (VGD), and proliferative index (PI). RESULTS:: In response to anti-Hh treatment, tumors showed a decrease in VGD, PI, MVD, and VVF compared with controls (P < 0.001). Vascular volume fraction was compared with histological indicators of response: PI (R = 0.88; P < 0.05), VGD (R = 0.87; P< 0.05), and MVD (R = 0.85; P < 0.05). CONCLUSIONS:: Magnetic resonance imaging VVF using magnetic iron oxide nanoparticles may serve as a noninvasive measure of biological response to Shh PDAC therapy with easy translation to the clinic.
KW - Angiogenesis
KW - Magnetic resonance imaging
KW - Nanoparticle
KW - Pancreatic cancer
KW - Sonic hedgehog
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U2 - 10.1097/MPA.0b013e31817c5113
DO - 10.1097/MPA.0b013e31817c5113
M3 - Article
C2 - 18953259
AN - SCOPUS:58149175893
VL - 37
SP - 440
EP - 444
JO - Pancreas
JF - Pancreas
SN - 0885-3177
IS - 4
ER -