Tumor endothelial cells as a potential target of metronomic chemotherapy

Drug resistance and toxic side effects are major therapeutic hurdles affecting cancer patients receiving conventional chemotherapy based on the maximum tolerated dose. Metronomic chemotherapy (MCT), a new therapeutic approach developed to avoid these problems generally, consists of the continuous administration of low-dose cytotoxic agents without extended intervals. This therapy targets the tumor microenvironment, rather than exerting a direct effect on tumor cells. As a result, the MCT regimen functionally impairs tumor endothelial cells and circulating endothelial progenitor cells, leading to tumor dormancy via anti-angiogenesis. Over the past 10 years, several studies have highlighted the impact of MCT on the tumor microenvironment and angiogenesis and demonstrated its potential as a switch from the pro-angiogenic to the anti-angiogenic state. However, the mechanisms of action are still obscure. Here, we systematically review the evidence regarding the anti-angiogenic potential of MCT as a crucial determinant of tumor dormancy and cancer treatment.