When the U.S. Food and Drug Administration awarded final marketing approval for mifepristone (RU-486) in September, womens rights activists rejoiced that the drug, long available elsewhere in the world, would finally provide U.S. women with a nonsurgical abortion option. Lost in the hubbub was mifepristones potential as an anticancer agent.
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The cause for such optimism? Mifepristone blocks cell surface receptors for the hormone progesterone; these receptors are overabundant in some tumors. Tying up the receptors prevents the hormone from reaching tumor cells, slowing or stopping growth in laboratory studies. The successful breast cancer drug tamoxifen works in similar fashion, by blocking receptors for estrogen.
But thats the science. The politics of mifepristone are a lot more complicated.
"If we could get past the political stigma, I certainly think trials are worthwhile and should be pursued," said J. Michael Hayes, Pharm.D., a pharmacologist at H. Lee Moffitt Cancer Center, Tampa. Hayes penned a review article on mifepristones potential in 1994, a year after President Clinton ordered the Department of Health and Human Services to "promote the testing, licensing, and manufacturing" of mifepristone.
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Seven years later, though, a dig through the medical stacks turns up a modicum of pre-clinical papers and almost nothing from the clinic: a few meningioma case studies and three trials (two from outside the United States) reporting outcomes from a few dozen breast and ovarian cancer patients.
The most promising study comes from the Robert Wood Johnson Medical School, Camden, New Jersey. Published earlier this year in Gynecologic Oncology, the phase 2 study of 44 ovarian cancer patients concludes the drug works against some chemotherapy-resistant tumors. One patient is doing well after 3 years, and eight others saw their tumors completely or partially remit. Several other patients withdrew from the study after developing rashes.
The first clinical trials in breast cancer show mixed results. A French study, published in 1987, tested mifepristone in 22 patients with chemotherapy- or tamoxifen-resistant metastatic breast cancer. Twelve patients (55%) showed an initial partial response; the responses lasted for 3 or more months in four patients (18%).
Nearly 10 years elapsed before the next clinical breast cancer study appeared. Authors of a report on a Canadian trial of 28 patients, published in 1996, concluded that the "data do not support [mifepristones] use as a single agent in the management of breast cancer." However, the authors do recommend combining tamoxifen with mifepristone.
Thats exactly what Patricia Schoenlein, Ph.D., and colleagues at the Medical College of Georgia have been doing for the past 3 years under a National Cancer Institute grant. Their work in cell lines pairs the drugs for a one-two antihormone punch. "Weve identified at least one underlying mechanism of the combined therapy. And it does appear that the two drugs act together synergistically," she said. Schoenlein added that her group will soon submit a paper on the research to a journal, and she is confident that interest in combined therapy will take off after publication.
The reason for slow progress in meningioma is the scarcity of patients, said Steven Grunberg, M.D., professor of medicine at the University of Vermont and lead researcher on a National Cancer Institute-funded trial. Springing from the lining of the brain, meningiomas are the second most common brain cancer, comprising 20% of cases. A few years ago researchers observed that the tumors, twice as common in women, tend to shrink and swell during pregnancy. That hormonal clue led to more detailed laboratory studies that suggested meningiomas might respond to mifepristone.
In 1994, the NCI launched the multicenter study, which recently accrued the last of its 192 patients. Grunberg said that the Southwest Oncology Group, which is managing the study with the help of the Eastern Cooperative Oncology Group, is at work analyzing data. Grunberg hopes the phase II study will show mifepristone is effective against the hard-to-treat tumors. But if it does not, it will still offer important safety information. Some patients in the trial took mifepristone for years, in contrast to its one-time use for abortion. "If nothing else, this study is going to generate a large amount of data on tolerability of the drug," said Grunberg.
The Bush Ban
With support from NCI, Grunberg said he had no trouble obtaining mifepristone. But other researchers struggled finding a supply. One reason: an import ban imposed by President Bush in 1989. "Under Reagan and Bush, you had to sneak it in. And some people did sneak it in from China," said Richard Houskenect, M.D., medical director of Danco Laboratories, the New York company distributing mifepristone in the United States. After Bush left office, researchers still shied away from the drug, according to several researchers, including Schoenlein. "I feel like theres been very little momentum," she said.
Much of the blame has been placed squarely at the feet of the French pharmaceutical company Roussel-Uclaf, discoverer of mifepristone in 1980, and German drug giant Hoescht AG, which merged with the French company in 1992.
The drama is detailed elsewhere, notably in an article by Andre Ulmann, M.D., Ph.D., that appeared earlier this year in the Journal of the American Medical Womens Association. Ulmann offers an insiders view; he worked for Roussel in the 1980s, when the company vacillated between abandoning and promoting the drug. At one point, after Roussel executives had decided to withdraw all support for mifepristone, the French minister of health ordered them to reverse this decision. They did, and the drug was approved in France in 1991. The United Kingdom, Sweden, and China quickly followed suit.
But even now the drugs troubles continue in the United States. The FDA has placed tight restrictions on who can dispense mifepristonenot pharmacies, but "qualified" doctors with hospital surgical privileges, access to an emergency room, and the ability to accurately date pregnancies.
Recent news reports suggest that few doctors have jumped through the agencys hoops, and as a result, the drug is scarcely available for women seeking it. But Danco has made a tentative pledge to make it available for research. Houskenect, also an associate professor of obstetrics and gynecology at Mount Sinai School of Medicine, New York, said that "well-written and well-thought out" research protocols would be considered. "Under those circumstances we will be making the drug available," he said.
And if this is not enough to overcome the drugs bad name, Schoelein proposes another solution: "The way you make a more favorable political climate is to publish good quality research," she said.
But high-quality research is expensive, a point not lost on Houskenect. When asked what the National Institutes of Health could do to encourage research, three words dropped from his mouth: "Give. Us. Money." Citing the lack of an approved spending bill for 2001 (as of press time), a spokesman for the National Institutes of Health declined to address whether the agency would increase funding for mifepristone research.
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