Half a century ago, thousands of pregnant women in 46 countries took a drug for morning sickness that would later be discovered to cause severe malformations in developing fetuses. Worldwide, roughly 10,000 affected children nicknamed "thalidomide babies" were born with multiple defects, including the characteristic shortened upper limbs (a condition known as phocomelia, Greek for "seal limbs"), before the drug was discontinued in 1961 after four years on the market.
More recently, thalidomide has made a comeback. In the 1990s the U.S. Food and Drug Administration approved its use in the treatment of both multiple myeloma (a form of cancer that affects plasma cells) and the complications of leprosy. The drug's potent anti-inflammatory and anti-angiogenic (blood vessel-forming) effects make it therapeutically attractive despite its nasty side effects. (Obviously, it is not recommended for women who might be pregnant.) Today, thalidomide trials are ongoing in more than 30 diseases, according to Adis R&D Insight (an online database of drug developments), including arthritis, breast cancer and amyotrophic lateral sclerosis. But the details of how the drug works remain unclear.
A new study published in the March 12 issue of Science has identified one primary target of thalidomide's teratogenicity (potential to cause fetal malformations)—a protein called cereblon. Using zebra fish and chick embryos, Takumi Ito and colleagues from the Tokyo Institute of Technology showed that thalidomide binds to cereblon, causing pectoral fin malformations in zebra fish and the complete absence of forelimbs in chicks. The researchers concluded that thalidomide exerts these effects by inhibiting cereblon function, because genetically induced overproduction of cereblon prevented the malformations. Cereblon's normal function is unknown, but mutations in the gene encoding it are implicated in mild mental retardation.
Previous studies have suggested that thalidomide's therapeutic effects on inflammation, blood vessel formation and cell stress might be partly responsible for its teratogenicity, meaning that eliminating its toxic side effects might also reduce its effectiveness. But little has been reported about thalidomide's direct molecular targets. Ito and colleagues hope the identification of cereblon as a target for thalidomide teratogenicity will lead to rapid screening for similar, safer alternatives. "Because thalidomide is now used for the treatment of multiple myeloma and leprosy, identification of its direct target may allow rational design of more effective thalidomide derivatives without teratogenic activity ," they report.
A safe substitute for thalidomide would be well received. Although the FDA has approved limited thalidomide use, the World Health Organization (WHO) does not recommend it, citing worries over ineffective surveillance and drug misuse. "Today, a number of thalidomide babies continue to be born each year reflecting regulatory insufficiency and widespread use under inadequate supervision," the organization's Web site states. In a related report former WHO Global Leprosy Program team leader Vijaykumar Pannikar wrote, "It cannot be overemphasized that any potential benefit with thalidomide must be balanced with the known toxicity and the accompanying ethical and legal constraints on its use."