Hypothesis: thalidomide embryopathy-proposed mechanism of action.

We propose that thalidomide affects the following pathway during limb development: Growth factors (FGF-2 and IGF-I) attach to receptors on limb bud mesenchymal cells and initiate some second messenger system (perhaps SP-1), which activates alphav and beta3 integrin subunit genes. The resulting alphav beta3 integrin proteins stimulate angiogenesis in the developing limb bud. Several steps in this pathway depend on the activation of genes with primarily GC promoters (GGGCGG). Thalidomide, or a hydrolysis or metabolic breakdown product, specifically binds to GC promoter sites and inhibits the transcription of those genes. Inhibition of the genes interferes with normal angiogenesis, which results in truncation of the limb.