Published online 11 May 2009 | Nature | doi:10.1038/news.2009.462

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How thalidomide makes its mark

Drug's effects on embryonic blood-vessel growth may be the source of malformed limbs.

Thalidomide babyThalidomide's effect on growing blood vessels may have caused birth defects in thousands of children.National Cancer Institute

More than 50 years after the drug thalidomide hit the market as a remedy for nausea in pregnant women, researchers may finally have pinned down how it causes severe birth defects.

Their results show that the drug's ability to block the development of new blood vessels may be behind the deformed limbs of children born to women who took thalidomide early in pregnancy. The finding could contribute to the development of a similar compound that does not have the same ill-effects.

By the time Thalidomide was withdrawn in 1961 up to 10,000 children had been born with malformed limbs and other birth defects. Since then, it has come back onto the market as a treatment for leprosy and a form of cancer called multiple myeloma. In the United States access to thalidomide is tightly regulated, and women must submit a negative pregnancy test each month before they can refill a prescription. But the drug is more readily available in some other countries, allowing thalidomide's characteristic birth defects to resurface.

It was while watching a television news report about African children born to mothers who had taken thalidomide to treat leprosy that Neil Vargesson of the University of Aberdeen, UK, decided he wanted to study the drug. "I looked at that and thought, 'well that has to be stopped'," he says. "You can't have this drug out there doing that."

Troublesome therapy

But thalidomide is a difficult drug to study. The compound has to be metabolically activated in the liver, where it is broken down into potentially more than 100 different compounds. Each of those — or some combination — could be the cause of deformed limbs. Furthermore, thalidomide does not cause such severe birth defects in commonly used laboratory animals such as mice and rats.

Vargesson's collaborator, pharmacologist William Figg of the National Cancer Institute in Bethesda, Maryland, began to identify and isolate thalidomide's many metabolites, allowing Vargesson and his collaborators to test the effects of these compounds in chickens — an animal model in which thalidomide does cause birth defects.

Their search yielded a compound that is chemically and structurally similar to thalidomide-breakdown products, and that causes severe limb defects. The compound, called CPS49, has been shown to inhibit the development of new blood vessels.

Strikingly, when CPS49 was administered at a point in chick development corresponding to that at which thalidomide was often used in pregnant women, the compound selectively affected limb development, leaving the rest of the embryo untouched. This is because at that time blood vessels in the body of the embryo are relatively mature, says Vargesson, whereas vessels in the limbs are just beginning to form.

This was further supported by the finding that when CPS49 was applied earlier in chick development, when more blood vessels had yet to be laid down, the embryos died. Meanwhile, if the compound was applied later, the limb malformations were less severe. The research will be published online this week in the Proceedings of the National Academy of Sciences1.

Sifting through hypotheses

Over the years, Vargesson has counted more than 30 different hypotheses that have tried to account for thalidomide's tragic effects, and inhibition of blood-vessel growth was one of them. But few of those hypotheses had substantial data behind them, and the new work firmly establishes blood-vessel inhibition as an important cause, says Jürgen Knobloch, a cell biologist at the University of Cologne in Germany.

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Knobloch and his colleagues previously showed that stress caused by chemically reactive forms of oxygen occurs in the cells of developing limbs that are exposed to the drug2. "As a consequence, some signalling pathways are downregulated that are essential for survival of these cells," he says. Given that Vargesson's results show that changes in gene expression occur only after blood-vessel growth is inhibited, Knobloch believes that this oxidative stress may be downstream of the effects on blood vessels.

The results are important for explaining the effects of thalidomide on arms and legs, but do not address other important birth defects caused by the drug, such as effects on nerves and ears, says Lewis Holmes of the MassGeneral Hospital for Children in Boston, Massachusetts. "That's the mystery that remains," he says. 

  • References

    1. Therapontos, C., Erskine, L., Gardner, E. R., Figg, W. D. & Vargesson, N. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0901505106 (2009).
    2. Knobloch, J., Shaughnessy, J. D. Jr & Ruther, U. FASEB J. 21, 1410–1421 (2007). | Article | PubMed | ChemPort |
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