Beckie Bell was desperate. suffering from a rare illness called Behcet's disease, she had mouth ulcers eating away the tissues of her cheeks, the roof of her mouth and even her throat. "You could lift my upper lip and look right into my sinuses," says Bell, who had to be hospitalized and fed intravenously. But she was not beyond hope. She had heard about a drug called thalidomide that could cure these ulcers and begged her doctor to obtain it from the Brazilian manufacturer. He did. And within 36 hours of treatment, she sat up in her hospital bed and announced: "I'm going home." The sores had closed. "For me, thalidomide was a miracle," says Bell. "The hardest thing was just getting it."
Anyone old enough to remember the assassination of John F. Kennedy knows why. In the late 1950s and early 1960s, millions of people in 46 countries took the drug as a sedative. For most, it produced no ill effects. But at least 10,000 pregnant women took thalidomide in their first trimester -- and gave birth to babies with missing or stunted limbs, feet where their legs should have been, flippers instead of arms. Photos of the deformed infants stunned the world, and regulatory agencies vowed "never another thalidomide." In the United States, the drug was banned before it could ever come to market. Yet the drug did not die out: made in Brazil for years, it has recently emerged as a potential treatment for ailments from cancer to severe eye problems (chart). The pills are even circulating on the AIDS underground as a cure for mouth ulcers. If clinical trials ultimately bear out any of the new claims, thalidomide could be on the U.S. market in as little as three years.
Thalidomide's rehabilitation began accidentally in 1965, when an Israeli doctor administered it as a sedative to six leprosy patients and found that it also cleared up certain skin lesions. But Dr. Gilla Kaplan at Rockefeller University wanted to know why it worked. In 1989, she and a team of scientists at Rockefeller began studying the drug and found that it inhibited production of a substance in the immune system called tumor necrosis factor alpha (TNFa). This discovery was the Rosetta stone of thalidomide, unlocking dozens of potential new applications. Elevated levels of TNFa cause such symptoms as fevers, weight loss and tissue damage in most infectious diseases, as well as immune disorders like graft-versus-host disease. Small amounts of TNFa are necessary, however, for the immune system to function. "It's the classic double-edged sword of immune response," says Kaplan. The advantage of thalidomide was that it inhibited production of TNFa, but didn't block it completely.
Given a range of possibilities, Kaplan decided to start testing thalidomide in tuberculosis patients, some of whom had AIDS. In more than 80 cases now, she has seen thalidomide stop the wasting process that emaciates TB and AIDS sufferers alike. In 1993, Kaplan announced an additional finding: in the test tube, at least, thalidomide inhibits replication of the HIV-1 virus. If it works as well in humans -- and many drugs don't -- it could theoretically delay the onset of full-blown AIDS. "I don't want to raise false hopes," says Kaplan. "No convinc-ing placebo-controlled studies have been done." But clinical trials with the National Institutes of Health are set to begin this fall.
As welcome as an HIV treatment would be, says Harvard ophthalmologist Robert D'Amato, thalidomide could find an even larger market: 3 million victims of diabetic retinopathy and macular degeneration -- the nation's two leading causes of blindness. Ironically, the reason is linked to birth defects. Thalidomide, it seems, prevents the formation of new blood vessels. A developing fetus cannot form arms and legs unless blood vessels invade the embryonic "limb bud" tissue. But in adults, the formation of new blood vessels almost always indicates disease. In diabetic retinopathy and age-related macular degeneration, capillaries grow unchecked in the eye; thalidomide might prevent both. And D'Amato is also investigating whether it could help slow the development of cancer. "A tumor cannot grow unless it is being fed by thousands of new blood vessels," he says.
But thalidomide still has side effects. Sedation -- the drug's original purpose -- is one. Peripheral nerve damage is another, in long-term users. And who can forget birth defects? If the FDA approves thalidomide, fertile women will have to take it in conjunction with contraceptives and regular pregnancy tests. But not all candidates for the drug are female -- or young. Macular degeneration afflicts the elderly; 87 percent of American AIDS patients are male. "It's a Catch-22 situation," says Dr. Georgia Vogelsang of Johns Hopkins. "If you provide thalidomide, there's a risk someone somewhere will have a deformed child. If you don't provide it, hundreds of patients around the world will die." It may be a gamble. But growing numbers of scientists are willing to consider it.
Thalidomide was once banned because it caused severe birth defects. But researchers are discovering new uses. It:
Clears up lesions caused by a complication of leprosy
Seems to cure graft-versus-host disease in bone-marrow-transplant recipients
Appears to stop drastic weight loss in TB and AIDS patients
Inhibits replication of the HIV-1 virus in vitro
Could prevent the two leading causes of blindness
May inhibit tumors