Production by Iron Chelators Up-Regulation of Vascular Endothelial Growth Factor

Agents that modulate cellular iron availability have been studied for their antitumor activity. Based on encouraging in vitro studies, the iron chelator deferoxamine (DFO) has been used in clinical studies to treat cancer patients. The observation that DFO induced macular edema in several cancer patients led to the present investigation of vascular endothelial growth factor (VEGF) as a possible mediator of the encountered side effects. Both normal and malignant cell lines were incubated with DFO and a variety of other iron chelators. DFO, at concentrations achiev able in humans, induced a 3—5-foldincrease in VEGF niKNA expression in all cell lines studied. This increased VEGF inUNA expression was dose and time dependent. A panel of structurally different iron chelators induced an even more potent increase in VEGF mRNA expression. The DFO-induced increase in VEGF mRNA expression translated into 6and 4-fold increases in VEGF protein secretion in conditioned media of retinal pigment epithelial and C6 glioblastoma cells, respectively. These findings suggest that VEGF may act as a mediator of the side effects induced by iron chelation therapy. In addition, because VEGF is an important regu lator of angiogenesis, iron chelators should be given with caution to cancer patients.