Candesartan induces tumor vascular normalization to improve the efficacy of radiotherapy in the therapeutic window

Abstract

Background: This study sought to examine whether candesartan induces tumor vascular normalization in a narrow therapeutic window to increase perfusion and oxygen content, and thus enhance the effect of radiotherapy (RT). Methods: Candesartan was administered to tumor-bearing mice to induce the normalization of tumor vessels, and the time window for normalization was determined. Then, tumor vascular density, perfusion, pericyte coverage, hypoxia of tumor-bearing mice was detected at 3, 6, 9, 12 days, respectively. In the treatment window, RT was administered to enhance the anti-tumor effect, which was evaluated based on relevant anti-tumor indicators. The tumor volume and tumor weight were recorded. Next, tumor growth inhibition rate was calculated according to the tumor weight. The Tunnel and Ki-67 expression of the tumor tissues of every group was measured to evaluate the effects on tumor proliferation and apoptosis. Results: Based on tumor vascular density, perfusion, pericyte coverage, hypoxia, and other indicators, the tumor vascular normalization window occurred 9 days after the administration of candesartan. The anti-tumor results showed that administering RT during the therapeutic window enhanced anti-tumor efficacy, with a tumor growth inhibition rate of 66.67%. The results of Tunnel and Ki-67 expression showed that window-period RT significantly promoted tumor cell apoptosis and limited proliferation compared to the control group (P<0.05 in Tunnel expression and P<0.01 in Ki-67 expression). Conclusions: Candesartan regulates the normalization of tumor vessels and increases the sensitivity of RT in the therapeutic window.