The aim of this study was to ascertain the potential usefulness of the antiangiogenic compound
linomide for treatment of von Hippel-Lindau (VHL)-related
tumors.
Paraganglioma tissue fragments obtained at surgery from a VHL type 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 allowed to grow to 1 cm for "intervention" studies. Both groups received either 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 and intervention experiments, a significant diminution of
tumor size and weight was observed in the
drug-treated animals. In vivo nuclear magnetic resonance analysis of
tumor blood flow in
linomide-treated animals showed localization of blood vessels almost exclusively to the periphery of the poorly vascularized
tumors with a significant reduction of both vascular functionality and vasodilation. Histological examination of
tumors from
linomide-treated 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 at inhibition of constitutively expressed
VEGF induction of angiogenesis by VHL
tumors may constitute an effective medical treatment.