Mechanism of action in thalidomide teratogenesis

In this commentary, we describe a model to explain the mechanism of the emb ryopathy of thalidomide. We propose that thalidomide affects the following pathway during development: insulin-like growth factor 1 (IGF-1) and fibrob last growth factor 2 (FGF-2) stimulation of the transcription of alpha v an d beta 3 integrin subunit genes. The resulting alpha v beta 3 integrin dime r stimulates angiogenesis in the developing limb bud, which promotes outgro wth of the bud. The promoters of the IGF-1 and FCF-2 genes, the genes for t heir binding proteins and receptors, as well as the alpha v and beta 3 gene s, lack typical TATA boxes, but instead contain multiple GC boxes (GGGCGG). Thalidomide, or a breakdown product of thalidomide, specifically binds to these GC promoter sites, decreasing transcription efficiency of the associa ted genes. A cumulative decrease interferes with normal angiogenesis, which results in truncation of the limb. Intercalation into G-rich promoter regi ons of DNA may explain why certain thalidomide analogs are not teratogenic while retaining their anti-tumor necrosis factor-alpha (TNF-alpha) activity , and suggests that we look elsewhere to explain the action of thalidomide on TNF-alpha. On the other hand, the anti-cancer action of thalidomide may be based on its antiangiogenic action, resulting from specific DNA intercal ation. The tissue specificity of thalidomide and its effect against only ce rtain neoplasias may be explained by the fact that various developing tissu es and neoplasias depend on different angiogenesis or vasculogenesis pathwa ys, only some of which are thalidomide-sensitive. (C) 2000 Elsevier Science Inc.