Dynamic contrast-enhanced magnetic resonance imaging rapidly indicates vessel regression in human squamous cell carcinomas grown in nude mice caused by VEGF receptor 2 blockade with DC101.
The purpose of our study was the investigation of early changes in tumor vascularization during antiangiogenic therapy with the vascular endothelial growth factor (VEGF) receptor 2 antibody (DC101) using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). Subcutaneous heterotransplants of human skin squamous cell carcinomas in nude mice were treated with DC101. Animals were examined before and repeatedly during 2 weeks of antiangiogenic treatment using Gd-DTPA-enhanced dynamic T1-weighted MRI. With a two-compartment model, dynamic data were parameterized in "amplitude" (increase of signal intensity relative to precontrast value) and k(ep) (exchange rate constant). Data obtained by MRI were validated by parallel examinations of histological sections immunostained for blood vessels (CD31). Already 2 days after the first DC101 application, a decrease of tumor vascularization was observed, which preceded a reduction of tumor volume. The difference between treated tumors and controls became prominent after 4 days, when amplitudes of treated tumors were decreased by 61% (P =.02). In line with change of microvessel density, the decrease in amplitudes was most pronounced in tumor centers. On day 7, the mean tumor volumes of treated (153 +/- 843 mm(3)) and control animals (596 +/- 384 mm(3)) were significantly different (P =.03). After 14 days, treated tumors showed further growth reduction (83 +/- 93 mm(3)), whereas untreated tumors (1208 +/- 822 mm(3)) continued to increase (P =.02). Our data underline the efficacy of DC101 as antiangiogenic treatment in human squamous cell carcinoma xenografts in nude mice and indicate DCE MRI as a valuable tool for early detection of treatment effects before changes in tumor volume become apparent.
Kiessling
Fabian
F
Division of Medical Physics in Radiology, German Cancer Research Center, INF 280, Heidelberg 96121, Germany. f.kiessling@dkfz.de
Farhan
Nabeel
N
Lichy
Matthias P
MP
Vosseler
Silvia
S
Heilmann
Melanie
M
Krix
Martin
M
Bohlen
Peter
P
Miller
Dan W
DW
Mueller
Margareta M
MM
Semmler
Wolfhard
W
Fusenig
Norbert E
NE
Delorme
Stefan
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D001808:Blood Vessels / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D003287:Contrast Media / Q000008:administration & dosage; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D010477:Perfusion; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D003287:Contrast Media; C511761:DC101 monoclonal antibody; D040301:Vascular Endothelial Growth Factor Receptor-2