Quantitative assessment of tumor blood flow in mice after treatment with different doses of an antiangiogenic agent with contrast-enhanced destruction-replenishment US

Abstract

Purpose: To quantify tumor blood flow by using contrast material-enhanced destruction-replenishment ultrasonography (US) to evaluate tumor response to different doses of an agent for antiangiogenic treatment in hepatoma-bearing mice, with histologic measurements of microvascular density (MVD) as the reference standard.

Materials and methods: Experiments were approved by the regional animal care committee. Mice bearing subcutaneous H22 hepatoma were treated with different doses of thalidomide, 100 mg/kg in group B and 200 mg/kg in group C. Group A (control group) was treated with 0.5% carboxylmethylcellulose. Treatment groups and the control group included 10 mice each. Contrast-enhanced US was used to evaluate the percentage of nonenhanced area, and contrast-enhanced destruction-replenishment US was used to evaluate tumor blood flow. Tumor blood flow was compared with measurements of MVD. Comparisons were made by using one-way analysis of variance and the post hoc least significant difference test for multiple comparisons.

Results: Contrast-enhanced gray-scale US showed significant increases in the percentage of nonenhanced area in group C (mean, 10.56% ± 7.25 [standard deviation]), as compared with groups A (mean, 2.40% ± 3.12; P = .004) and B (mean, 3.75% ± 5.55; P = .012). Contrast-enhanced destruction-replenishment US showed significant decreases of tumor blood flow in groups B and C, as compared with group A (P = .003 and P < .001, respectively), and the blood flow in group C was significantly lower than that of group B (P = .01). Immunohistochemical analysis revealed significant decreases of MVD in groups B and C, as compared with MVD in group A (P = .002 and P < .001, respectively); however, there was no significant difference in MVD between groups B and C (P = .21).

Conclusion: Quantification of tumor blood flow by using contrast-enhanced destruction-replenishment US shows the potential to guide drug dosage during antiangiogenic therapy.