Vascular targeting effects of ZD6126 in a C3H mouse mammary carcinoma and the enhancement of radiation response

Abstract

Purpose The aim of this study was to investigate the pathophysiologic effects induced by the novel vascular targeting agent ZD6126 in a C3H mouse mammary carcinoma and to evaluate the agent's ability to inhibit tumor growth either when given alone or in combination with radiation. Methods and materials A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was treated when at 200 mm 3 in size. ZD6126 was dissolved in saline and injected intraperitoneally. Blood perfusion was measured using the RbCl extraction procedure, tumor oxygen (pO 2) status was assessed with the Eppendorf electrode, and tumor necrosis was estimated from histologic sections. Radiation (240-kV X-rays) was locally administered to tumors of restrained nonanesthetized mice, and response was assessed using a tumor growth assay. Results ZD6126 induced a significant dose- and time-dependent decrease in tumor perfusion, reaching a maximal 70% reduction around 3 h after injecting 150–300 mg/kg. However, full recovery was seen within 6 h. A 200 mg/kg dose significantly decreased tumor oxygenation status at 3 h (median pO 2 decreased from 7 to 3 mm Hg; % pO 2 values ≤2.5 mm Hg increased from 30% to 55%) and by 24 h had significantly increased necrotic fraction from 14.5% to 25.2%. This ZD6126 dose resulted in a small, yet significant, 1.4 days inhibition of tumor growth when given alone. It also enhanced the tumor response to radiation, giving rise to a significant 1.3-fold increase in the slope of the radiation dose–response curve. Of the normal tissues, only muscle (at 3 h) and spleen (at 6 h) showed any significant reduction in perfusion after injecting 200 mg/kg, but these transient decreases were only 32% and 49%, respectively. Conclusions Our preclinical studies clearly demonstrate a tumor-specific reduction in blood perfusion by ZD6126. Although these changes were transient, they were sufficient to increase tumor necrosis, inhibit tumor growth, and enhance radiation response.