¹Department of Hematology, Oncology and Clinical Immunology, University of Düsseldorf, Düsseldorf, Germany

²A3D GmbH, Antisense Design and Drug Development, Heidelberg, Germany

³Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

Correspondence to: Dr Ralf Kronenwett, Klinik für Haematologie, Onkologie und Klinische Immunologie, Universitaet Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany. E-mail: kronenwett@med.uni-duesseldorf.de

The integrin v3 plays a central role in angiogenesis. In this study, we used antisense oligodeoxyribonucleotides (ONs) directed against the v subunit of v3 to inhibit integrin expression. Ten ON sequences, which were selected by systematic alignment of computer-predicted secondary structures of v mRNA, were transfected into human umbilical vein endothelial cells (HUVECs). Following stimulation by PMA, five antisense ONs significantly inhibited v mRNA and protein expression in activated HUVEC at a concentration of 0.05 M with complete prevention of PMA-induced v up-regulation by the most potent antisense ON. Inhibition of v expression was associated with significant inhibition of migration of HUVEC by 28% and had no effect on proliferation and apoptosis. Moreover, transfection of antisense ON inhibited the formation of tube-like structures of HUVEC in Matrigel by 44%. In a cell culture model of angiogenesis consisting of a co-culture of endothelial cells with fibroblasts, transfection of antisense ONs resulted in an inhibition of tube formation of 61%. In conclusion, v antisense ONs are potent inhibitors of angiogenesis in vitro. They might, therefore, be a therapeutic alternative to antagonists, which directly bind to v integrins, and might be useful for the treatment of malignant tumors and hematological malignancies. Cancer Gene Therapy (2002) 9, 587-596 doi:10.1038/sj.cgt.7700474

alpha V integrin; angiogenesis; antagonist; antisense oligonucleotides