The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice

The aim of this study was to ascertain the potential usefulness of the anti angiogenic compound linomide for treatment of von Hippel-Lindau (VHL)-relat ed tumors. Paraganglioma tissue fragments obtained at surgery from a VHL ty pe 2a patient were transplanted s.c. to male BALB/c nu/nu (nude) mice: (a) 2-3-mm fragments for "prevention" experiments; and (b) 2-3-mm fragments all owed to grow to 1 cm for "intervention" studies. Both groups received eithe r 0.5 mg/ml linomide in drinking water or acidified water and were followed until tumor diameter reached 3 cm or for 4 weeks. In both the prevention a nd intervention experiments, a significant diminution of tumor size and wei ght was observed in the drug-treated animals. In vivo nuclear magnetic reso nance analysis of tumor blood flow in linomide-treated animals showed local ization of blood vessels almost exclusively to the periphery of the poorly vascularized tumors with a significant reduction of both vascular functiona lity and vasodilation. Histological examination of tumors from linomide-tre ated animals revealed marked avascularity, Treated animals also displayed a 2.4-fold reduction of tumor vascular endothelial growth factor mRNA levels , Taken together, our data indicate that in VHL disease, therapy directed a t inhibition of constitutively expressed VEGF induction of angiogenesis by VHL tumors may constitute an effective medical treatment.