The Scientist 15[2]:1, Jan. 22, 2001
The Return of Thalidomide
Once-feared drug finds new applications
By Ricki Lewis
As the legendary phoenix rose from the ashes, so the drug thalidomide, responsible for severe birth defects across Europe in the early 1960s, is rising again and finding new uses. At the 42nd annual meeting of the American Society of Hematology held in San Francisco on December 4, 2000, researchers reported promising results with thalidomide in patients with multiple myeloma or myelodysplasias, a group of proliferative disorders of the bone marrow.
The drug, sold as Thalomid by Celgene Corp. of Warren, N.Y., was approved in 1998 to treat complications of leprosy. Analogs and derivatives of thalidomide that temper the famed and feared teratogenic effect are in the pipeline too. "We are developing new compounds to harness the beneficial aspects of this drug, while minimizing the negative attributes, to offer patients new therapies in fatal and debilitating diseases," reports Sol J. Barer, president of Celgene.
The German company Chemie Grunenthal originally developed thalidomide as a sedative in 1957. In the early 1960s, what seemed to be an epidemic of birth defects swept Europe, particularly the United Kingdom and Germany. Thousands of babies were born with what doctors at first thought was phocomelia, an inherited failure of the limbs to complete development, forming instead flipper-like appendages. But gene frequencies do not just suddenly skyrocket, so epidemiologists sought another, more likely explanation: what did the mothers of these infants have in common? A culprit soon emerged: thalidomide, widely used to stem morning sickness. Unfortunately, the drug had other effects on the four- to six-week embryo, during the critical period for limb formation.
Thanks to Frances Kelsey, an astute medical officer at the Food and Drug Administration, the drug, called Kevadon, failed to get the thumbs up in the United States. Kelsey wrote a handwritten memo stating that the decision not to market Kevadon "was based on peripheral neuritis symptoms in adults"--a tingly numbness in the fingers. It was an historic move. "The standards for drug development were strengthened as a result of the thalidomide experience and, in the U.S., enormously enhanced the prestige and power of the Food and Drug Administration," recalls Barer.
Despite its devastation to the embryo, early on thalidomide looked to have promise in other areas. "In 1964, a physician treating leprosy patients in Israel for a painful condition known as erythema nodosum leprosum (ENL) prescribed thalidomide as a sedative. Surprisingly, the drug alleviated the symptoms of this painful condition. From that point onward, thalidomide was the therapy of choice, including designation by the World Health Organization," Barer says. Celgene received approval to market the drug for ENL on July 16, 1998, along with a strategy (called STEPS, the "System for Thalidomide Education and Prescribing Safety") to ensure safe and specific use.
Thalidomide's effects on the rapidly dividing cells of embryos suggested that it might squelch cancer cells too. "What was unique about thalidomide was its powerful teratogenicity, which could be related to anti-cancer effects. In the 1960s, two large studies addressed possible anti-cancer effects, but that changed with the discovery of the birth defects. So, what we are doing now is just reinventing the whole thing," notes S. Vincent Rajkumer, an assistant professor of medicine at the Mayo Clinic in Rochester, Minn. His group and others are systematically testing the effects of the drug on a variety of cancer types. "For solid tumors, I'm not hopeful, but for hematological malignancies, patients may respond better," he adds. A success story in the making appears to be the use of thalidomide to treat multiple myeloma, a malignancy of plasma cells.
Multiple Myeloma and Thalidomide
When a B lymphocyte (cell) is stimulated by exposure to antigen, it divides and differentiates into plasma cells, which secrete antibodies. In multiple myeloma, overabundant plasma cells produce a characteristic "myeloma protein" that is detectable in serum, and Bence Jones protein, found in urine--two diagnostic hallmarks of the condition. Symptoms arise from proliferating plasma cells in bone marrow crowding out other cells. "These include anemia, infections, weakness, bone pain, release of calcium, and protein that can clog the kidneys," reports Rajkumer. Miles of extra capillaries form and snake through the bone, and is the angiogenesis run amok that heralds cancer. Some studies on multiple myeloma patients correlated increased angiogenesis with poor prognosis.
Multiple myeloma is the second most common cancer of the blood, but accounts for only 1 percent of all cancer cases. In the United States, 40,000 people have multiple myeloma, and about 13,000 new cases are diagnosed each year. It is notoriously resistant to chemotherapy.
A link between multiple myeloma and thalidomide emerged in the wake of the infamous over-reporting of Judah Folkman's work on angiogenesis inhibitors in 1998.1,2 "It all started when interest in angiogenesis inhibitors went through the roof. But endostatin and angiostatin were years off, and the only available drug with potent anti-angiogenic effects was thalidomide," recalls Rajkumer. When the wife of a patient with multiple myeloma called Folkman, she was referred to Bart Barlogie, at the Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences in Little Rock, who was working with thalidomide. "[The patient] and a few others were treated and had a remarkable response," notes Rajkumer, "That was for patients with relapsed multiple myeloma."3,4
The first patient was treated in December 1997. Soon after, 83 others who had failed standard chemotherapy received thalidomide. They had an impressive 32 percent response rate. Success was defined as no progression, measured by decreased levels of myeloma protein or Bence Jones protein, or fewer plasma cells in bone marrow. Several other research groups demonstrated similar success rates for relapsing cases.
Rajkumer decided to investigate whether thalidomide might help newly diagnosed individuals as well. He reported on a pilot study at the American Society of Hematology meeting that six of 16 patients given escalating doses of thalidomide had responded.5 A few patients required dose levels to be lowered due to severe skin rashes, and the neuritis that initially warned off FDA approval of thalidomide in pregnancy surfaced as a side effect. Still, thalidomide remains promising for more advanced cases of multiple myeloma. "If a patient is relapsing, he or she has nothing to lose. Many choose to stay on thalidomide and treat the neuritis," comments Rajkumer.
On the Matter of Mechanism
Thalidomide's actions are multiple and mysterious. "The problem in studying thalidomide is that it doesn't do anything in vitro. When you put thalidomide in water, you get 20+ metabolites. Perhaps a liver metabolite is required. You need a good in vitro assay to understand the mechanism," explains Rajkumer.
The anti-angiogenesis hypothesis of thalidomide's action in multiple myeloma makes sense: bones develop extra capillaries, so an agent that squelches new blood vessel formation should starve the cancer. And thalidomide does inhibit vascular endothelial growth factor and basic fibroblast growth factor;2 but the mechanistic story isn't straightforward.
"The feeling was that anti-angiogenesis was why [thalidomide] worked," says Rajkumer. "But a problem has been that Barlogie's group couldn't find good correlation between how patients did and if microvessels were gone. We found this too. Was it angiogenesis inhibition, or something else? But that [problem] alone doesn't negate the hypothesis," adds Rajkumer, noting that it is difficult to assess microvasculature in three dimensions.
Barlogie and colleagues acknowledged this puzzlement in their 1999 paper and suggested possible alternative mechanisms based on other known activities of the enigmatic drug: oxidative damage to DNA, increased secretion of interleukin-2 and interferon-gamma by CD8 T cells, and an altered distribution of cellular adhesion molecules (CAMs). The CAMs are critical in enabling plasma cells to bind to stromal cells in the marrow. Thalidomide's action might also have something to do with its inhibition of tumor necrosis factor alpha production, says Barer.6
Finding New Applications
People have found cures without knowing mechanisms since ancient peoples brewed willow bark tea to soothe fever, an early application of aspirin. And so it is for thalidomide, as researchers continue to discover its healing effects.
Azra Raza at Rush Cancer Institute at Rush-Presbyterian-St. Luke's Medical Center in New York City found a 41 percent partial response rate among 51 individuals with myelodysplasia following thalidomide treatment, eight of whom no longer required frequent transfusions to treat the condition, which progresses to cancer. Rangaswamy Govindarajan, an assistant professor of medicine at the University of Arkansas for Medical Sciences, led a pilot study of thalidomide in conjunction with the standard chemotherapeutic drug irinotecan used to treat metastatic colorectal cancer. Of seven patients, one went into remission, two had partial remission, one required less chemotherapy, and one halted treatment because of extreme sleepiness, a side effect of thalidomide.7
At Celgene, the sky's the limit for thalidomide's potential applications. The company has provided it, under an emergency FDA approval, to treat more than 70 forms of cancer and various skin, digestive, and immunological diseases, relates Barer. It may also be useful in treating AIDS-associated cachexia (wasting) and tuberculosis, he adds.
Understanding the precise mechanism of thalidomide's varied actions should enable researchers to pick and choose among its many effects. Celgene is already well on the way to this goal, with a class of "distant relatives" that inhibit TNF alphas and are currently in clinical trials to treat Crohn's disease and colorectal cancer. The company is developing "true analogs" of thalidomide that in animal trials lack the parent compound's teratogenicity, and in Phase I human studies, are not sedating. The National Cancer Institute will test the compounds to treat brain tumors, prostate cancer, and Kaposi's sarcoma, Barer explains.
As the subject of an ever-increasing number of meeting abstracts and published articles, and the focus of some 150 clinical trials, thalidomide's association with tragedy may be nearing an end.
Ricki Lewis (rickilewis@nasw.org) is a contributing editor for The Scientist.
References
1. J. Folkman, "Angiogenesis in cancer, vascular, rheumatoid and other diseases." Nature Medicine,1:27-31, 1995.
2. G. Kolata, "A cautious awe greets drugs that eradicate tumors in mice," New York Times, May 3, 1998, p. F1.
3. S. Singhal et al., "Antitumor activity of thalidomide in refractory multiple myeloma," New England Journal of Medicine, 341:1565-71, 1999.
4. N. Raje, K. Anderson, "Thalidomide--a revival story," NEJM, 341:1606-09, 1999.
5. S.V. Rajkumar et al., "Life-threatening toxic epidermal necrolysis with thalidomide therapy for myeloma," NEJM, 343:972, 2000.
6. E.P. Sampaio et al., "Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes," Journal of Experimental Medicine, 173:699-703, 1991.
7. R. Govindaragan et al., "Effect of thalidomide on gastrointestinal toxic effects of irinotecan," The Lancet, 356:566-7, 2000.
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