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Thalidomide: From Villain to Cancer Fighter

© David Olle

Thalidomide has a notorious reputation. Developed in Germany in 1954, it was considered non-toxic, and the ideal drug for treating the symptoms of nausea and insomnia in pregnant women. It was widely used until it was found to be the cause of severe birth defects in 8,000 to 12,000 children whose mothers had taken the drug in the first trimester of pregnancy. The U.S. largely escaped this disaster due to the watchful eye of Dr. Francis Kelsey and colleagues of the Food and Drug Administration. She refused to approve the use of the drug in the U.S. because of concerns of neurological symptoms from long-term use.

The drug began its transformation in 1965, when an Israeli dermatologist discovered that thalidomide was remarkably effective in improving lesions, fever and night sweats in patients with leprosy. Due to the adverse history of the drug, it was not until 1998 when the FDA granted approval to Celgene to market thalidomide for the treatment of acute leprosy. FDA imposed very strict guidelines, since the agency was well aware of the tendency of some physicians to prescribe "off-label" uses of drugs (non-approved uses).

During this period, laboratory animal studies indicated that thalidomide had immunosuppressive properties. A few human volunteers from the 1980's onwards indicated that thalidomide was beneficial in patients with autoimmune diseases such as rheumatoid arthritis, lupus, and Behcet's disease. Researchers subsequently found that thalidomide has many other clinically useful properties.

There are three primary mechanisms of thalidomide action:

1. Reduction of Inflammation

Thalidomide has potent anti-inflammatory activity, which accounts for its effectiveness in treating leprosy. Researchers found that this action is due to inhibition of tumor necrosis alpha (TNF), a signaling molecule secreted by cells of the immune system in response to infection. Although the inflammatory process has an important role in wound healing, tumor cells can co-opt some of the signaling molecules for their purposes, including invasion, migration and metastasis. 3Total inhibition of TNF is not desired, however, as it could have deleterious effects on the immune process. This would be particularly important if one of the objectives of cancer therapy is to stimulate the immune system to attack cancer cells.

2. Inhibition of Angiogenesis

Angiogenesis is the formation of new blood vessels, and is an essential process for the continuing growth of tumors. Dr Judah Folkman, one of the first workers in the field, believed that the birth defects caused by thalidomide were due to inhibition of blood-vessel growth in the developing fetal limb bud. This theory remains unproven, and other researchers have presented evidence that thalidomide may exert other inhibitory effects on the growing fetus. The anti-angiogenic properties of thalidomide remain of great interest in the treatment of cancer.

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