Mechanism of action in thalidomide teratogenesis.
In this commentary, we describe a model to explain the mechanism of the embryopathy of thalidomide. We propose that thalidomide affects the following pathway during development: insulin-like growth factor I (IGF-I) and fibroblast growth factor 2 (FGF-2) stimulation of the transcription of alphav and beta3 integrin subunit genes. The resulting alphavbeta3 integrin dimer stimulates angiogenesis in the developing limb bud, which promotes outgrowth of the bud. The promoters of the IGF-I and FGF-2 genes, the genes for their binding proteins and receptors, as well as the alphav and beta3 genes, 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 associated genes. A cumulative decrease interferes with normal angiogenesis, which results in truncation of the limb. Intercalation into G-rich promoter regions 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 intercalation. The tissue specificity of thalidomide and its effect against only certain neoplasias may be explained by the fact that various developing tissues and neoplasias depend on different angiogenesis or vasculogenesis pathways, only some of which are thalidomide-sensitive.
Stephens
T D
TD
Department of Biological Sciences, Idaho State University, Pocatello, ID, USA. steptren@isu.edu
Bunde
C J
CJ
Fillmore
B J
BJ
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D020862:GC Rich Sequence / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D039482:Integrin alpha5; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D013723:Teratogens / Q000633:toxicity*; D013792:Thalidomide / Q000633:toxicity*
D015703:Antigens, CD; D039482:Integrin alpha5; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D013723:Teratogens; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide; D007334:Insulin-Like Growth Factor I; D004247:DNA