Metronomic chemotherapy and anti-angiogenesis: can upgraded pre-clinical assays improve clinical trials aimed at controlling tumor growth?

Metronomic chemotherapy, which is continuously administered systemically at close to non-toxic doses, targets the endothelial cells (ECs) that are proliferating during tumor angiogenesis. This leads to harmful effects of an even greatly increased number contiguous tumor cells. Although pre-clinical studies of angiogenesis-related EC features in vitro and of the anti-angiogenic and anti-tumor effects in vivo of metronomic chemotherapy have provided valuable insights, clinical trials with this type of therapy have been less successful in inhibiting tumor growth. One possible reason for the apparent disconnect between the pre-clinical and clinical outcomes is that most of the currently used experimental angiogenesis assays and tumor models are incapable of yielding data that can be translated readily into the clinical setting. Many of the assays used suffer from unintentional artifactual effects, e.g., oxidative stress in vitro, and inflammation in vivo, which reduces the sensitivity and discriminatory power of the assays. Co-treatment with an antioxidant or the inclusion of antioxidants in the vehicle often significantly affects the angiogenesis-modulating outcome of metronomic mono-chemotherapy in vivo. This 'metronomic chemotherapy vehicle factor' merits further study, as do the observations of antagonistic effects following metronomic treatment with a combination of standard chemotherapeutic drugs in vivo.