Elsevier

The Lancet

Volume 363, Issue 9423, 29 May 2004, Pages 1802-1811
The Lancet

Review
Thalidomide

https://doi.org/10.1016/S0140-6736(04)16308-3Get rights and content

Summary

Despite its history as a human teratogen, thalidomide is emerging as a treatment for cancer and inflammatory diseases. Although the evolution of its clinical application could not have been predicted from the tragedy associated with its misuse in the past, its history serves as a lesson in drug development that underscores the need to understand the molecular pharmacology of a compound's activity, including associated toxicities. Here, we summarise the applications for thalidomide with an emphasis on clinical trials published over the past 10 years, and consider our knowledge of the molecular pharmacology of the drug in the context of clinical trial data, attempting to provide a mechanism-guided understanding of its activity.

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

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.

Conflict of interest statement

None declared.

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