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However the drug had to be immediately withdrawn from the market following a rapid rise in a severe birth defect called phocomelia, previously a rare condition, being linked to the exposure of thalidomide in the uterus. The link between Thalidomide and the severe teratogenic effect was worked out by two independently working physicians McBride and Lenz in 1961 by which time there were reported cases of about 6000-10000 affected children (Lenz, 1988).
Interest in the drug was re-kindled a few years later following an unexpected discovery of anti inflammatory activity of Thalidomide in reactive lepromatous leprosy. However it was not until 1991 that interest in the drug intensified after its anti-tumour necrosis factor- activity was discovered (Sampio, 1991). The newly stimulated interest resulted in a significant amount of information on the potential of this drug and its mode of action in a number of diseases with a particular interest in cancer.
Thalidomide is -N-phthalimidoglutarimide (C13H10N2)4 having a molecular weight of 258.2. It is a glutamic acid derivative and is related structurally to neuropharmaceuticals bemegride (-ethyl–methyl-glutaramide C18H13NO2) which is an analeptic drug and glutethimide (-ethyl–phenyl-glutarimide C15H23NO4) which is a sedative and antiepileptic drug. A broad range of immunomodulatory and anti tumour properties other than sedation differentiates thalidomide from these drugs. Halidomide has a phthalimide ring on the left side and a glutaramide ring on the right side with an asymmetric carbon atom at 3′ position of the glutarimide ring (Mujagic et al., 2002).
Thalidomide exists as a racemic mixture of its S and R isomers which interconvert rapidly at physiological pH. The drug is eliminated following pH dependent, non-enzymatic, spontaneous hydrolysis into multiple metabolites which are chemically inactive through non-renal pathways which minimises drug interaction risks. It is believed to have a half life of approximately five hours (Gordon and Goggin, 2003).
Mechanism of action of thalidomide is complex and is incompletely understood despite the growing interest in the drug. However the properties are related to antiangiogenesis, immune modulation and cytokine regulation. The anti-angiogenesis property of Thalidomide interrupting basic fibroblast growth factor (bFGF) and vascular endothelial growth factor(VEGF) mediated processes was first reported by D’Amato et al. (1994). Thalidomide also reportedly induces the degradation of TNF – mRNA to inhibit TNF- synthesis (Moreira et al., 1993). Studies have also shown the role of thalidomide in blocking nuclear factor (NF)-B activation though IB kinase activity inhibition (Keifer et al., 2001). Other mechanisms of action of the drug include downregulation of adhesion molecules as demonstrated in experimental models (Geitz, 1996), co-stimulation of human T cells, mainly CD8+ subset cell proliferation along with the stimulation of IL-2 and IFN- production, while inhibition of cytokines IL-6 and IL-12 production (Moller et al., 1997). Thalidomide is also involved in the reduction of free radicals that is believed to have a hand in oxidative DNA damage (Richardson et al, 2002).
A study designed to understand the