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The Antiangiogenic Agent Linomide Inhibits the Growth Rate of von Hippel-Lindau Paraganglioma Xenografts to Mice

Departments of Endocrinology and Metabolism [D. J. G.], Bone Marrow Transplantation and Cancer Immunobiology [I. R., L. W., S. S.], and Department of Molecular Biology [I. S., L. E. B.], Hebrew University-Hadassah Medical Center, Jerusalem, Israel 91120, and Department of Biological Regulation, Weitzmann Institute of Science, Rehovot, Israel 76100 [M. N., R. A.]

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.

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