Basement membrane biosynthesis as a target for developing inhibitors of angiogenesis with anti-tumor properties

Basement membrane biosynthesis as a target for developing inhibitors of angiogenesis with anti-tumor properties. Basement membrane (BM) exerts profound influence on endothelial cell (EC) behavior. In addition BM is a structural element of blood vessels; in fact at some point of their formation blood vessels are bare EC tubes lined with the BM produced by these EC. We thought, therefore, that a quantitative relationship must exist between the rate of BM synthesis and angiogenesis, and that interfering with BM synthesis must have an effect on angiogenesis. This was found experimentally in the chick chorioallantoic membrane (CAM) system. It was shown that the rate of BM collagen biosynthesis can serve as a biochemical index of angiogenesis and that inhibitors of BM synthesis prevent angiogenesis. GPA 1734 (8,9-dihydroxy-70-methyl-benzo(b)quinolizinium bromide), which inhibits proline and lysine hydroxylations in type IV collagen formation, suppresses angiogenesis in the CAM. Similarly, D609 (tricyclodecan-9-yl-xanthate), which inhibits BM synthesis by an as yet unknown mechanism, also prevents angiogenesis. Structurally related analogs of GPA 1734 and D609 that have no effect on BM biosynthesis are also without effect on angiogenesis. The aforementioned inhibitors of angiogenesis GPA 1734 and D609 have a dose-dependent inhibitory effect on tumor growth in rats bearing Walker 256 carcinosarcoma, without any obvious toxic effects. This effect is probably related to angiosuppression, since structurally related analogs that do not inhibit angiogenesis are without antitumor properties. Also GPA 1734 and D609 have no direct cytotoxic effects on Walker 256 cells in vitro. These results suggest that a search for agents that are specific inhibitors of BM synthesis may provide novel angiosuppressors with potential application in tumor chemotherapy. There are many enzymatic steps in the biosynthesis and assembly of BM that are possible targets for developing inhibitors of angiogenesis. Such inhibitors are not expected to have serious side effects for short-term treatment, since both BM synthesis and angiogenesis are extremely slow processes under physiological conditions.