Doppler ultrasound imaging detects changes in tumor perfusion during antivascular therapy associated with vascular anatomic alterations

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 7; pp. 2974 - 2982
• Main Authors: GEE, Michael S, SAUNDERS, H. Mark, LEE, James C, SANZO, James F, JENKINS, W. Timothy, EVANS, Sydney M, TRINCHIERI, Giorgio, SEHGAL, Chandra M, FELDMAN, Michael D, LEE, William M. F
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-04-2001
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Count; Cell Division - drug effects; Female; Immunotherapy; Interleukin-12 - pharmacology; Medical sciences; Melanoma, Experimental - blood supply; Melanoma, Experimental - diagnostic imaging; Melanoma, Experimental - drug therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Microscopy, Confocal; Monitoring, Physiologic - methods; Neovascularization, Pathologic - diagnostic imaging; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Pharmacology. Drug treatments; Recombinant Proteins - pharmacology; Ultrasonography; Antineoplastic agent; Doppler ultrasound study; Treatment efficiency; Tumoral tissue; Rodentia; Cytokine; Interleukin 12; Confocal microscopy; Malignant tumor; Angiogenesis; Vertebrata; Sensitivity; Mammalia; Treatment; Mouse; Animal; Immunotherapy; Blood vessel; Non invasive method; Medical imagery; Neovascularization; Recombinant protein; Antiangiogenic agent
• ISSN: 0008-5472; 1538-7445

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-gamma-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.