Mechanism Of Thalidomide Research Articles

Thalidomide: emerging role in cancer medicine.

Thalidomide--removed from widespread clinical use by 1962 because of severe teratogenicity--has antiangiogenic and immunomodulatory effects, including the inhibition of tumor necrosis alpha factor. It has now returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was approved by the U.S. Food and Drug Administration in 1998, and more recently certain malignancies, including multiple myeloma. Although thalidomide's mechanism of action remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials have confirmed benefit in relapsed disease, and the role of thalidomide in treating newly diagnosed patients is currently under study. Its use in other tumors is under evaluation, with promise in renal cell carcinoma, prostate cancer, glioma, and Kaposi's sarcoma. Activity has also been demonstrated in chronic graft-versus-host disease and in symptom relief as part of palliative care.

Thalidomide is an inhibitor of angiogenesis.

Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.

4 Thalidomide and Congeners as Anti-inflammatory Agents

This chapter discusses the findings on new indications for the “classical drug” thalidomide that are different from its original use as a sedative-hypnotic drug as well as on those of a few “novel analogs” that may be superior to thalidomide in certain respects. The teratogenicity of thalidomide, and the same is true for any other teratogen, depends on several factors, the most important of which seem to be administration in the sensitive period (i.e., the organogenesis), the species, the genotype of the recipient, the dose size, the route of administration, and possibly other environmental conditions. The teratogenic effect of thalidomide has provided a considerable stimulus for research into the biochemical reactions and the possible mechanism of action of the drug. Many hypothetical explanations of thalidomide's mechanism of action on a molecular basis have been raised, but most of them have remained speculative or have gained no experimental support. Congenital malformations have not been restricted to the action only of thalidomide. Many other physical and chemical agents have been known for a long time to exert similar effects.