The rationale behind the frequent administration of chemotherapeutic drugs at low doses — high-time or metronomic dosing — is to prevent time for repair of damage to the tumour vasculature, thereby deriving increased therapeutic benefit. Logically, haematopoietic cells and gut epithelial tissues should also sustain more damage because of the lack of recovery time between cycles of chemotherapy, but, interestingly, such side effects, at least in the short term, seem to be much less severe. Bocci and colleagues provide an explanation for this as they show, in Cancer Research, that cycling endothelial cells are inherently more sensitive than other cells to continuous low-dose therapy, and suggest that this might therefore be an optimal way of delivering certain types of anti-angiogenic therapies, especially those using conventional chemotherapeutic drugs.

Bocci et al. exposed human tumour cells, fibroblasts and endothelial cells to daily low concentrations of chemotherapeutic drugs for up to 6 days — analogous to the protracted metronomic protocols used in patients. They observed specific inhibition of endothelial-cell proliferation with taxanes and cyclophosphamide after 6 days, but not after 24 hours, using concentrations of 10–100 pM and 1–100 nM, respectively. By contrast, normal fibroblasts and breast cancer cell lines were not affected. Not all drugs showed this differential effect — doxorubicin had similar antiproliferative activity against both endothelial cells and breast cancer cells. In addition, the authors observed that treated endothelial cells had a higher level of apoptosis than the cancer cell lines or fibroblasts.

So, prolonged exposure times, once an effective dose of drug has been reached, are crucial for cell kill in high-time chemotherapy regimens and might be selective for endothelial cells. This type of schedule might create an anti-angiogenic therapeutic window, and could be used to treat tumours that are resistant to the very drugs that are used for low-dose chemotherapy or to decrease host toxicity without reducing efficacy. It remains to be seen whether other types of normal cells are also highly sensitive to metronomic dosing.