Metronomic treatment of temozolomide increases anti-angiogenicity accompanied by down-regulated O6-methylguanine-DNA methyltransferase expression in endothelial cells

Metronomic chemotherapy is a continuous low-dose administration of chemotherapeutic agents to minimize toxicity and target tumor-associated endothelial cells. This therapy is beneficial to anti-angiogenic efficacy which is linked to the inhibition of tumor growth. In the present study, we compared the anti-angiogenicity of temozolomide in human umbilical vein endothelial cells (HUVECs) between conventional and metronomic treatment. Metronomic treatment of temozolomide (TMZ) (6.25 and 12.5 mu M) showed increased inhibition of the proliferation of HUVECs compared to an equivalent conventional treatment of TMZ. The differential effects between conventional and metronomic treatment of TMZ were also noted in cell migration and angiogenic tube formation. Notably, the expression level of O-6-methylguanine-DNA methyltransferase (MGMT) was markedly reduced in the HUVECs treated with metronomic TMZ (12.5 and 25 mu M) compared to cells treated with conventional treatment of TMZ. Accordingly, HUVECs treated with metronomic treatment of TMZ were more sensitive to TMZ treatment. Taken together, metronomic chemotherapy with TMZ enhances the inhibition of angiogenesis accompanied by the down-regulation of MGMT expression in endothelial cells when compared to conventional chemotherapy.