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Experimental Therapeutics |
Biomedical Graduate Program [M. S. G.], Section of Radiology [H. M. S., S. M. E.], School of Veterinary Medicine, Departments of Medicine [J. C. L., W. M. F. L.], Radiation Oncology [W. T. J., S. M. E.], Radiology [C. M. S.], and Pathology and Laboratory Medicine [J. F. S., M. D. F.], School of Medicine, and the Cancer Center [W. M. F. L.], University of Pennsylvania, Philadelphia, Pennsylvania 19104; and Schering-Plough Laboratory for Immunological Research, 69571 Lyons, France [G. T.].
Noninvasive monitoring of antiangiogenic therapy was performed by serial power Doppler ultrasound imaging of murine tumors treated with recombinant interleukin 12, the results of which were correlated with assessments of tumor vascularity by microscopy. Growth of established K1735 tumors, but not of IFN-
-unresponsive K1735.N23 variants, was suppressed by treatment. Serial Doppler imaging of K1735 tumor vascularity during treatment revealed a progressive change from a diffuse perfusion pattern to a more punctate distribution. Quantitative analysis of the images revealed that color-weighted fractional average, representing overall tumor perfusion, consistently decreased in these tumors, primarily because of a decrease in fractional tumor cross-sectional area carrying blood flow. In contrast, these parameters increased in nonresponsive tumors during treatment. Confocal microscopy of thick tumor sections revealed a reduction in the density and arborization of vessels labeled in vivo by fluorochrome-conjugated lectin with effective treatment. Immunohistological examination of thin tumor sections confirmed the preferential loss of small vessels with successful therapy. Similar changes in tumor vascular anatomy and perfusion were also observed during recombinant interleukin 12 treatment of two other responsive murine tumor types. These results indicate that power Doppler ultrasound is a sensitive, noninvasive method for reporting functional consequences of therapy-induced vascular anatomical changes that can be used to serially monitor tumor perfusion and efficacy of antivascular therapy in clinical trials.
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