Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various diseases, including acquired immunodeficiency syndrome (AIDS) and graft-versus-host disease (GVHD). The effectiveness of the drug in these diseases has been attributed to its specific inhibitory activity on tumor necrosis factor-alpha (TNF-alpha) production. Because TNF-alpha, a cytokine mediating host defence and immune regulation, with a wide range of activities, has deleterious pathophysiological effects in various diseases, including AIDS, tumors, rheumatoid arthritis and diabetes, its production-regulators are attractive lead compounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has afforded a number of phenyl- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-alpha production has been obtained. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists.
 ...
PMID:Novel biological response modifiers derived from thalidomide. 956

Although thalidomide (alpha-phthalimidoglutarimide) is a potent teratogen, in recent years it has become widely used in the treatment of a variety of diseases. Despite many studies, the mechanism of its teratogenic action is still not clear. Recently we reported that only the glutarimide moiety bound to rat embryonic DNA. This result could explain our earlier observation, that thalidomide induced alteration in the secondary structure of rat embryonic DNA. In this study it was shown that [glutarimide-2-14C]-thalidomide also interacts with the DNA of rabbit embryos. This interaction is a possible explanation for the diverse types of malformations caused by thalidomide and may also account for its immunosuppressant action which makes it useful in the treatment of graft-versus-host disease.
 ...
PMID:Interaction of thalidomide with DNA of rabbit embryos: a possible explanation for its immunosuppressant and teratogenic effects. 1048 93