We searched MEDLINE and PubMed databases with the term thalidomide associated with the terms mechanism, pharmacology, analogues, and clinical trials. Historical information was taken from reviews. We restricted our search to English-language papers published between 1970 and 2003, and excluded clinical abstracts as a general rule. Articles were selected on the basis of their relevance in both basic science and clinical diseases.
ReviewThalidomide
Section snippets
Structure and bioactivity
The thalidomide molecule is a racaemic glutamic acid analogue, consisting of S(−) and R(+) enantiomers that interconvert under physiological conditions (Figure 1, Figure 2).7 The S(−) form potently inhibits release of tumour necrosis factor (TNF) α from peripheral mononuclear blood cells,8 whereas the R(+) form seems to act as a sedative, probably mediated by sleep receptors in the forebrain.9
One of the unique chemical aspects of thalidomide is that the parent compound undergoes spontaneous
Mechanism of action
The mechanisms that underlie the immunomodulatory, anti-inflammatory, and antiangiogenic properties of thalidomide are also unclear, although modulation of inflammatory cytokines such as TNFα, γ interferon, interleukin 10, interleukin 12, cyclo-oxygenase 2 (COX-2), and possibly the nuclear factor k B (NF-kB) transcription factor, are involved.
TNFα regulates inflammatory cascades and represents a therapeutic target in inflammatory diseases, some of which have been associated with raised
Dermatological
Interest in thalidomide resurfaced in 1965 after, by chance discovery,3 it was found to be beneficial in erythema nodosum leprosum, a vasculitic complication of leprosy characterised by painful subcutaneous nodules, fever, and other constitutional symptoms. Short-term improvement was seen in 52% of patients who received 100 mg four times daily in a double-blind, randomised trial against aspirin.34 Responses were seen in 70–80% of patients on thalidomide versus 25% in other placebo-controlled
Thalidomide analogue development
Our laboratory has developed 118 novel thalidomide analogues. Preclinical assessment of some of these analogues has revealed their potent antiangiogenic activity in ex-vivo aortic ring, and in in-vitro endothelial cell proliferation and tube formation assays.159 Furthermore, certain analogues have shown significant antitumour activity in prostate cancer xenograft preclinical models. Clinical assessment of promising lead compounds will result in the development of thalidomide-like drugs that
Search strategy
Conflict of interest statement
None declared.
References (159)
- et al.
Thalidomide in the treatment of leprosy
Microbes Infect
(2002) - et al.
Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization
Exp Eye Res
(1997) - et al.
Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent
Biochem Pharmacol
(1998) - et al.
Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells
Immunopharmacology
(1998) - et al.
Mechanism of action in thalidomide teratogenesis
Biochem Pharmacol
(2000) - et al.
Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines
Blood
(1999) - et al.
Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy
Blood
(2000) - et al.
Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma
Blood
(2001) - et al.
Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity
J Biol Chem
(2001) - et al.
The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance
Biochim Biophys Acta
(2000)