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Gene Interaction and Disease

mmunomodulatory effects of thalidomide have an important role in pathogenesis (FIG. 1). There is also evidence that thalidomide might inhibit TNF-α that is derived from other cellular sources that have been activated by inflammatory stimuli, such as microglia and Langerhans cells17,18. The fact that thalidomide inhibits TNF-α explains its therapeutic effect in patients with ENL, as they have extremely high levels of TNF-α in their blood and in dermatological lesions. Most importantly, this finding led to the initial use of thalidomide in several, small open-label studies in which increased TNF-α production is associated with disease19, such as AIDS-related Kaposi’s sarcoma and cachexia, rheumatological disease, Crohn’s disease, cerebral malaria, multiple sclerosis, psoriasis, sepsis, tuberculosis and some cancers6,20. Thalidomide inhibits angiogenesis. The next crucial discovery that uncovered the clinical potential of thalidomide came in 1994, when thalidomide was found to inhibit angiogenesis — the formation of new blood vessels, which is a crucial process in the growth and metastasis of solid tumours. Judah Folkman was one of the first researchers to associate angiogenesis with tumour development in the early 1970s and it was from his laboratory that the inhibitory effect of thalidomide on angiogenesis was demonstrated. He believed that the classical congenital defects that are caused by thalidomide treatment — abnormal limb development — were caused by the inhibition of blood-vessel growth in the developing fetal limb bud. Using a rabbit cornea micropocket assay, it was demonstrated that thalidomide could, in fact, inhibit basic fibroblast growth factor (bFGF)-induced angiogenesis21. However, despite this study, it is worth noting that the link between the teratogenic properties of thalidomide and its anti-angiogenic activity remains unproven. Other groups have more recently demonstrated that thalidomide mediates inhibitory effects on mesenchymal proliferation in the limb bud22 and induces embryonic oxidative stress23. Irrespective of these findings, the anti-angiogenic properties of thalidomide sparked a huge interest in its use for the treatment of cancer. T