Inhibition of basement membrane biosynthesis prevents angiogenesis.

GPA1734, an inhibitor of BM collagen biosynthesis, was investigated in the CAM model system for its effect on angiogenesis. Evaluation of angiogenesis was performed by placing a thin plastic coverslip inscribed with concentric circles on the CAM and counting the number of vessels intercepting the circles. The rate of BM collagen biosynthesis was monitored using [U-14C] proline incorporation into CAM proteins and determining the collagenase-digestible protein fraction. A marked depression in the vascular density was observed in the CAM area under a plastic disc containing GPA1734 as compared to control discs placed on the CAM about 1 cm apart from days 9 to 12 of incubation. A concomitant decrease in collagenous protein biosynthesis was observed in the area under the discs containing GPA1734 and [U-14C]proline as compared to control discs containing only the radiolabeled proline. The forementioned effects of GPA1734 on CAM were specific because no similar effects were observed with a closely related compound, 9,10-dihydroxy-7-methyl-benzo[b]quinolizinium bromide or with GPA1734 plus Fe++, which did not affect the rate of BM collagen biosynthesis. These results suggest that inhibitors of BM collagen biosynthesis prevent angiogenesis by interfering with the formation of an essential component of the vessel wall. The search for such inhibitors may be a new approach in the development of antiangiogenic agents.