Effects of Thalidomide, Cytochrome P-450 and TNF-.ALPHA. on Angiogenesis in a Three-dimensional Collagen Gel-culture.

The anti-angiogenic effects of thalidomide were examined in mouse aortae grown in a three-dimensional collagen gel-culture. In our in vitro model, (±)-thalidomide and (-)-thalidomide exhibited no anti-angiogenic effects. On the other hand, when the culture was treated with thalidomide plus cytochrome P-450, both types of thalidomides significantly inhibited angiogenesis. Co-administration of 100 μg/ml thalidomide plus 200 μg/ml cytochrome P-450 inhibited angiogenesis more strongly than thalidomide plus cytochrome P-450 at other concentrations (10 μg/ml + 200 μg/ml and 100 μg/ml + 20 μg/ml). To study the relation between the anti-angiogenic effect and TNF-α, we also evaluated the concentration of TNF-α in the culture medium. We found that the concentration of TNF-α was correlated to the strength of the anti-angiogenic effect. The inhibition of angiogenesis by thalidomide and cytochrome P-450 takes place through a suppression of TNF-α and involves the metabolism of the thalidomide.