LINOMIDE BLOCKS ANGIOGENESIS BY BREAST-CARCINOMA VASCULAR ENDOTHELIALGROWTH-FACTOR TRANSFECTANTS

The blocking of angiogenesis provides a novel therapeutic target to in hibit tumour spreading. In this study, we investigated the effect of l inomide on angiogenesis induced in vivo by highly angiogenic breast ca rcinoma cells. The rabbit cornea was used to assess neovascular growth in the absence of a tumour mass. MCF-7 cells stably transfected with the cDNA encoding for vascular endothelial growth factor 121 (VEGF(121 )) (V12 clone) were used to elicit a potent VEGF-dependent corneal ang iogenesis. After tumour cell implant, albino rabbits received 100 mg k g(-1) day(-1) linomide for 5 consecutive days. Daily observation of ne ovascular progression indicated that linomide blocked angiogenesis. Th e antiangiogenic effect of linomide was apparent within 48 h from the beginning of the treatment and was both angiosuppressive and angiostat ic. The block of neovascular growth lasted over 10 days from treatment suspension, and preformed vessels, which had regressed, remained dorm ant, suggesting the persistence of unfavourable conditions for capilla ry progression. Linomide (50-200 mu g ml(-1)) was not cytotoxic in vit ro on resting capillary endothelial cells but blocked endothelial cell replication induced by VEGF. Our data indicate that linomide can effi ciently and persistently block VEGF-dependent angiogenesis in vivo in the absence of a growing tumour mass. These data suggest that linomide could be a chemopreventive drug in breast cancer patients and a valua ble tool in clinical settings in which metastatic spreading occurs in the absence of a detectable tumour mass.