RU 486: How Abortion Politics Have Impacted on a Potentially Useful Drug of Broad Medical Application William Regelson Perspectives in Biology and Medicine, Volume 35, Number 3, Spring 1992, pp. 330-338 (Article) Published by Johns Hopkins University Press DOI: https://doi.org/10.1353/pbm.1992.0026
For additional information about this article https://muse.jhu.edu/article/405793
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RU 486: HOW ABORTION POLITICS HAVE IMPACTED ON A POTENTIALLY USEFUL DRUG OF BROAD MEDICAL APPLICATION WILLIAM REGELSON*
If RU 486 (Mifepristone) were not an abortifacient [1-5], it would represent a medical breakthrough of broad applicability. Unfortunately, right-to-life anti-abortion advocates have called RU 486 the "human pesticide," and they have effectively threatened Roussel-Uclaf and its
parent firm, Hoechst AG, with organized worldwide economic retribu-
tion unless the drug is withdrawn. Bill Price, president of Texas United for Life has said: "We are of
course trying to use every bit of political leverage and political clout that we have to keep it [RU 486] out of the U.S." [6]. The success of right-tolife political clout is seen in the unprecedented efforts of Congressman Robert Doman (R-CA) and others, who in June 1990 convinced the
Food and Drug Administration (FDA) to put RU 486 on an FDA import alert embargo [7, 8]. Under the FDA embargo, in order to get laboratory supplies of RU 486, a researcher must contact the FDA or risk confisca-
tion. This cumbersome process has no medical basis, as no clinical application of RU 486 is possible without FDA Investigational New Drug (IND) approval. In addition, RU 486's use in abortion in France is highly restricted and limited to its combined use with prostaglandin E2 [4, 5], another drug not available in the United States. There is no evidence
that RU 486 constitutes a public threat, and as Ron Wyden, chair of the House Committee on Small Business stated, "an embargo sends a message around the world that this drug is dangerous, and that the FDA is prejudiced against it." Representative Wyden is making a strong congressional effort to reverse the embargo [9]. RU 486, or Mifepristone, is best known as an anti-progestin [10]. The ?Department of Medicine, Medical College of Virginia, Virginia Commonwealth Uni-
versity, Richmond, Virginia 23298-0001.
© 1992 by The University of Chicago. AU rights reserved. 0031-5982/92/3503-0781$01.00
330
William Megebon ¦ RU 486 and Abortion Politics
drug is also a potent blocker of corticosteroid receptors [4, 11 — 15], and
in preliminary clinical study, RU 486 has shown significant activity in the treatment of breast cancer, inoperable meningioma, and Cushing's disease [11, 12, 16-18]. RU 486 has suggested value in aiding cervical dilation, lactation, and the treatment of endometriosis [1, 4].
RU 486 will be useful wherever progesterone or corticosteroid blocking agents have clinical application. Its block to corticosteroid action has shown unequivocal success in the treatment of Cushing's syndrome [11, 13, 14, 18], a disease of excess adrenocortical secretion. RU
486 has reversed the osteoporosis, thinning of skin, muscle atrophy, obesity, adult onset diabetes, depression, hypertension, and immunosuppression associated with this disease. Cushing's can be characterized
as a model for much of the symptomatology of aging [19]: there is data in human and animal models that the syndrome of aging may involve enhanced or prolonged response to corticosteroids [20]. For this reason, RU 486 could have broad but useful application for both stressmediated disease and many of the degenerative diseases [20, 21] seen with progressive age. In addition, many tumors—including breast, bowel, kidney, hepatomas, endometrial cancer, and fibrosarcomas—can show corticosteroid dependency [11, 22—26], suggesting that RU 486 may have clinical value against a broader range of inoperable tumors than those that are progesterone dependent. However, we need more
chronic toxicity data [27], as prolonged chronic use could enhance fi-
brosis or scarring [28] and inhibit acute stress responses (i.e., shock). We
will only know the true therapeutic index of this drug if we can clinically test it in chronic studies.
Our own efforts to establish clinical trials with RU 486 were initially focused on its application to the treatment of advanced breast cancer and its potential value in AIDS. In breast cancer, our interest was based on a successful preliminary 1987 phase I study, in estrogen-positive,
chemotherapy-refractory breast cancer patients in Montpelier, France [29]. RU 486 produced objective tumor regression (6 of 22) that was prolonged (>3 months) in four patients. Clinical relief of bone pain (7 of 23) was seen, with a decline in carcinoembryonic antigen (CEA) tumor markers in 8 patients. In support of these objective and subjective clini-
cal results, there is also growing in vitro data showing that RU 486 can directly inhibit breast cancer cell proliferation [30, 31]. Most recently,
André Ulmann, clinical research director of Roussel-Uclaf, has said that
Roussel-Uclaf is negotiating with the National Cancer Institute (NCI) for a breast cancer clinical study. However, there are apparently no such studies underway in France, despite the successful clinical study in 1987, and Dr. Ulmann indicates that they are not eager to financially support such studies.
We met with Roussel-Uclaf regarding alternative medical uses for RU
Perspectives in Biology and Medicine, 35, 3 ¦ Spring 1992 | 331
486 in January 1989. With the help of Roussel-Uclaf, a United States meeting was planned in April 1989 to organize a cooperative RU 486 breast cancer study for patients who had failed previous therapy. This would have involved a cooperative study under the NCI aegis of the Cancer Acute Leukemia Group B (CALGB) study group, involving 25
major hospital and university groups. However, this meeting was can-
celed when, in March, right-to-life advocates threatened an international boycott of Hoechst AG, the parent company of Roussel-Uclaf [9,
32]. A year later, Georgetown University's Lombardi Cancer Center also
expressed an interest in conducting a study of RU 486 in breast cancer, but was stymied by the unwillingness of Roussel-Uclaf to provide financial support. In addition to our interest in RU 486 for its role in treating cancer
patients, following our Paris meeting and with the help of the Lasker Foundation, an attempt was made to expedite National Institute of Health (NIH) interest in AIDS treatment. However, the threatened boycott also stopped this activity. Hoechst AG, with a 51 percent majority stock holding position in Roussel-Uclaf, in March 1985 assured right-tolife advocates that there would be no further clinical development of RU 486. Because of this, it was obvious that RU 486 would not be made
available in the United States for any new medically oriented clinical studies. It is disturbing to find that most recently Ariel Mouttet, director of Roussel-Uclaf's international marketing, has stated that "it is totally crazy to test the efficacy of RU 486 on AIDS" [33]. However, RU 486 has application for HIV infection, based on data that there is a serum factor in AIDS patients that enhances corticosteroid lympholysis [34].
In addition, the immune upregulating or restorative action of RU 486,
as seen in Cushing's disease [14, 18] and proven in animal models [35, 36], suggests that RU 486 should be looked at as a stimulus to immune response where it might counteract the immunosuppression seen in aging, in cancer, or in viral or stress-related diseases [11, 12]. One concept of RU 486 action, pertinent to anti-tumor action, is that it may enhance IL-2 lymphokine mobilization that is inhibited by gluco-
corticoids [36]. In another area, RU 486 may influence how corticoste-
roids modulate hippocampal function [20], which may be important
to stress-related effects on memory impairment. This is possibly what
prompted recent reported clinical interest in the treatment of senile dementia and depression by RU 486. In addition, there is evidence that RU 486 can modulate adrenal medullary opioid responses to stress [21], which could also be a factor in stress-mediated disease.
In efforts to obtain research support for anti-aging rodent studies, we approached Dr. Ulmann, who stated that "although they will supply the drug for basic research studies, they will do nothing to financially support such studies." Roussel-Uclaf's clinical efforts have not ade332
William Regehon ¦ RU 486 and Abortion Politics
quately sponsored medical studies, but their efforts in abortion have resulted in approved release of the drug for this purpose in Great Brit-
ain, and there have been statements made of its planned release in Scandinavia and the Netherlands for this purpose. In addition, studies of RU 486's use as a contraceptive are said to be planned or underway in Sweden. However, providing RU 486 for population control creates strong opposition. As an example, a "Committee of Inquiry" was set up in Rome, and dire reports of RU 486 side effects in abortion emanate
from this group [37]. The negative publicity generated has related solely to contragestation, and in view of RU 486's preliminary clinical success in breast cancer, meningioma, and Cushing's disease [1 1], we have to ask why Roussel-Uclaf persists in calling to public attention the abortifacient action of this drug rather than its noncontroversial alternative role as a medically useful steroid antagonist.
The clinical development of RU 486 is inconsistent. On the one hand, Roussel-Uclaf is actively fostering the abortifacient application of RU 486 in countries where this is politically feasible; on the other hand, alternative medical applications are neglected or delayed. If RousselUclaf is truly afraid of economic threats, it should provide the drug to smaller, non—boycott-vulnerable companies or to a nonprofit founda-
tion that could fully develop the product. The size of the medical constituency that can benefit from RU 486 far exceeds those opposed to it because of its abortifacient action.
Roussel-Uclaf and Hoechst must seek to serve the "crisis constituency" of those severely ill or debilitated. Even in areas that do not have the
crisis implications, RU 486 has significant value. As mentioned earlier,
RU 486 is of value in endometriosis, which produces menstrual pain and reduces fertility in 10 percent of women of reproductive age [1, 4].
RU 486 also has value in inducing cervical dilatation in labor and in enhancing lactation [I]. All these potential or proven applications must be made visible to the public to create a constituency that could prevail upon Roussel-Uclaf to provide the funds and coordinated effort to ex-
pand their basic research and clinical testing. If the 400,000 women in this country with breast cancer could be shown the potential value of this drug, they and their families would become an important source of agitation for RU 486's availability. RU 486 also reverses and prevents corticosteroid-induced hypertension in rat models [14, 38]. There are
58 million hypertensives in the United States, and although no clinical studies with RU 486 have been performed, clinicians and the public must be made aware of the obvious need for such studies. RU 486 has
potential value in alleviating stress-mediated disease, and it may have a possible place in delaying renal failure in damaged kidneys [39]. Its value in reducing symptomatology in Cushing's patients suggests that it may have value in osteoporosis, which involves the clinical complications Perspectives in Biology and Medicine, 35, 3 ¦ Spring 1992 | 333
of hip fractures (225,000 patients per year), as well as in age-related diabetes, which includes neuropathy, accelerated atherosclerosis, and renal failure. As mentioned earlier, the reversal of corticosteroid immu-
nosuppression [11, 35, 36] provides a potential place for RU 486 in treating AIDS (one million patients), and also indicates RU 486's use as
a modulator of resistance to infection, particularly in the elderly [11, 12, 40].
In another clinical area, the weight gain produced by progesterone in cancer patients suggests that a progesterone antagonist could have
wider clinical value in the physiologic control of morbid obesity. RU
486 has recently been shown to stimulate production of corticotrophin
releasing factor (CRF), resulting in brown fat mobilization that decreases obesity in rodents [41]. RU 486 promotes both differentiation and the sensitivity of adipocytes to adenyl cyclase and epinephrine [42], and the role of adrenalectomy as a factor in decreasing obesity is well known [43]. RU 486 mobilizes the fat deposits induced by corticosteroids in
Cushing's disease, and thus RU 486 might permit one to do this in a pharmacologically controlled fashion. In view of the cosmetic health
consciousness of this nation, it is ironic that calling attention to RU 486's potential muscle stimulating [44] and anti-obesity action [41—44] might help stimulate public interest in the availability of RU 486 even more effectively than our concerns for those with cancer and AIDS.
Currently, the fight for RU 486 availability has focussed on its use in
abortion. As part of the freedom of choice, pro-abortion effort, Representative Barbara Boxer (D-CA) stimulated 70 of her colleagues in Congress to request that Rousell-Uclaf make the drug available [45]. In March 1990, John van DeKamp, the attorney general of California, sought to open the state of California to RU 486 for intrastate testing, manufacturing, and marketing under California's FDA, which is independent of the United States FDA. Roussel-Uclaf was not interested [45,
46], but if the California effort had been supported, it would have resulted in some interesting constitutional questions, particularly in view of the FDA embargo. New states' rights issues would have developed as
to who takes precedence in governing intrastate drug studies. It is the obvious intent of the pro-life forces to reverse Roe v. Wade, and they are keenly aware that medical availability of RU 486 would create a black market that would compromise their control of pregnancy. If Roe v. Wade is repealed, a new Dredd-Scott decision will de-
velop, dividing our country along pharmaceutical Mason—Dixon lines that can only lead to illegal use of abortifacients. An example of this
problem in past history was seen in the illegal use of the chemotherapeutic anti-cancer agent methotrexate, dangerously used as an abortifacient
during the period before Roe v. Wade legalized the procedure. The only possible compromise to meet this eventuality is for RU 486 to be made 334 I William Regekon ¦ RU 486 and Abortion Politics
available as a controlled licensed substance, i.e., as a schedule II or III
drug in similar fashion to prescription controls used for narcotics or barbiturates. RU 486 would be made available to patients only via tightly licensed, controlled prescription forms for specific abortion or nonabortion medical use. However, to do this would be a blatant surrender
to one group's religious beliefs at the expense of another's need, and even then a compromise of this type would not solve the issue for very long. Future drug development of any progesterone or corticosteroid antagonist would be blocked by anti-abortion forces because of an implied threat to pregnancy for any steroid antagonist. The difficulty is already apparent, in that there is a Schering drug, with similar properties to RU 486, which—although not tainted with the abortion tissue— will have similar problems on clinical entry because it could interfere with pregnancy [8].
The clinical availability of RU 486 is both a moral and governmental issue. In France, when faced in September 1988 with governmental pressure, Roussel-Uclaf was given the ideal excuse to continue drug studies, as they were able to say they were forced to make the drug available. We must provide a similar climate of public concern to get
Roussel-Uclaf to respond. In June 1990, the American Medical Association (AMA) came out with a resolution supporting RU 486's clinical applicatiion in abortion. Fifteen hundred scientists, academicians, and health-care workers have signed petitions, and over 200,000 petitions demanding the availability of this drug have been presented to RousselUcalf though the help of the Feminist Majority Foundation [46]. Most importantly, for the first time, the American Association for the Advancement of Science (AAAS), at its national meeting in February 1991,
has gone on record favoring the broad medical availability of this drug. The crisis constituency—those with the syndromes of aging, cancer, hypertension, diabetes, etc.—must be stimulated to add their protests to petitions already circulated [46]. In lieu of White House cooperation, our patients and scientific and medical community should find a way to prevail directly upon the French Minister of Health to force RousselUclaf to more energetically develop studies of RU 486's medical application both in France and abroad. This is not just a moral issue but a financial one: the French government, which owns 36 percent of Roussel-Uclaf, is not getting a fair return for their money in view of the potentially vast worldwide market involving medical needs. Above all, we need visible scientific conferences, workshops, and discussion to make scientists, physicians, and the public aware of the potential medical value of this drug [40]. We need ethical balance that gives attention to the living as well as the unborn, and this issue must become part of a vigorous public debate that will make this drug available for clinical study.
Perspectives in Biology and Medicine, 35, 3 · Spring 1992 | 335
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1.Baulieu, E. -E. RU 486 as an anti-progesterone steroid; from receptor to contragestion and beyond. JAMA 262:1808-1814, 1989. 2.Palca, J. The pill of choice: News and comments. Science 245:1319—1324, 1989.
3.Baulieu, E-E., Segal, S. J., eds. The Anti-Progestin Steroid RU 486 and Human Fertility Control. New York: Plenum Press, 1984. 4.Ulmañn, ?., Teutsch, G. and Philibert, D. RU 486. Scientific American 262:42-48, 1990.
5.Silvestre, L., DuBois, C, Rennault, M., et al. Voluntary interruption ôf pregnancy with Mifepristone (RU 486) and a prostaglandin analogue. N. Engl. J. Med. 322:645-648, 1990. 6.Benedek, E. The Dallas Morning News. p. Cl, C7, 3 Dec 1990. 7.Foreman, J. Boston Globe, Nov. 19, 1990. 8.Brown, C. The aborted pill. New York Woman May: 93-97, 1990. 9.Wyden, R. U.S. House of Representatives Committee on Small Business. 19 Nov. 1990, Cong. Ree, 1991. 10.Kekkonen, R., Alfthan, H., Haukkamam, M., et al. Interference with ovu-
lation by sequential treatment with the anti-progesterone RU 486 and syn-
thetic progestin. Fertility and Sterility 53:747-750, 1990. 11.Regelson, W., Loria, R., and Kalimi, M. Beyond abortion: RU 486 and
the needs of the crisis constituency. JAMA 264:1026-1027, 1990.
12.Regelson, W. RU 486: A "pro-life" perspective. Medical Aspects of Human Sexuality 24(12):55-57, 1990.
13.Bertagna, X., Basin, C, Picard, F., et al. Peripheral anti-glucocorticoid
action of RU 486 in man. Clin. Endocrinol. 28:537-541, 1988. 14.NiEMAN, K., Chrousos, G. P., Kellner, C, et al. Successful treatment of
Cushing's syndrome with the glucocorticoid antagonist RU 486. /. Clin.
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15.Markwalder, T. M., Waelti, E. Cited by Baulieu, E.-E. RU 486 as an
anti-progesterone steroid: From receptor to contragestion and beyond.
Jama 262:1808-1814, 1989. 16.Grunberg, S. N., Weiss, M. H., and Spitz, I. M. Treatment of Unresectable
Meningioma with the Anti-Progestational Agent RU 486. Los Angeles: University of Southern California, in press, 1991. 17.Blankenstein, M. A., Blaauw, G., and Lamberts, S. W. J. Progestin and estrogen receptors in human meningiomas, gliomas and brain metastasis. J. Neurooncol. 1:179-189, 1983. 18.Bertagna, O., Bertagna, C, Laudat, M. -H., et al. Pituitary adrenal response to the anti-glucocorticoid action of RU 486 in Cushing's syndrome. /. Clin. Endocrinol. Metab. 63:639-643, 1986.
19.Regelson, W., and Sinex, M. The evidence for pituitary and thyroid control of aging: Is age reversal a myth or reality? The search for a "death hormone." In Intervention in Aging Process, Pt. B, pp. 3—52. New York: A. R.
Liss, 1983. 20.Kerr, D. S., Campbell, L. W., Hao, S. Y., et al. Corticosteroid modulation
of hippocampal potentials: Increased effect with aging. Science 245:15051509, 1989.
21.Jefferys, D., Funder, J. W. Glucocorticoids, adrenal medullary opioids and the retention of a behavioral response after stress. Endocrinol. 121:10061009, 1987.
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22.Phillips, P. D., and Cristofalo, V. J. Classification system based on the functional equivalency of mitogens that regulate WI-38 cell proliferation. Exp. Cell Res. 175:396-403, 1988. 23.Tutton, P. L, and Barkla, D. H. Steroid hormones as regulators of the
proliferative action of normal and neoplastic epithelial cells. Anticancer Res. 8:451-456, 1988.
24.Laue, L., Peacock, J., Brandon, D. D., et al. Glucocorticoid receptor medi-
ated effects on rat fibrosarcoma growth. Cancer Res. 48:2703-2706, 1988.
25.Kraznai, A., Krajesi, P., Any, P., et al. Lymphocyte receptors in cancer patients. Oncology 45:257-259, 1988. 26.Vihko, R., Isotalo, H., Kauppila, A., et al. Female sex steroid receptors in gynecologic malignancies: Clinical correlates. Steroid Biochem. 19:827-832, 1983.
27.Heikinheimo, C. Pharmacokinetics of the anti-progesterone RU 486 during multiple dose administration./. Steroid Biochem. 32:21-25, 1989. 28.Laue, L., Kawai, S., Brandon, D. D., et al. Receptor mediated effects of glucocorticoids on inflammation: Enhancement of the inflammatory response with a glucocorticoid antagonist. /. Steroid Biochem. 29:591-598, 1988.
29.Romieu, G., Maudelonde, T., Ulmann, A., et al. The anti-progestin RU 486 in advanced breast cancer: Preliminary clinical trial. Bull. Cancer 74:455-461, 1987.
30.Horwitz, K. B. The anti-progestin RU 38486: Receptor mediated progestin
versus anti-progestin actions in the management and treatment of breast cancer. Seminars in Oncology 15:14-19, 1988. 31.Bardon, S., Vignon, F., Chalbos, D., et al. RU 486: A progestin and glucocorticoid antagonist inhibits the growth of breast cancer cells via the progesterone receptor./. Clin. Endocrinol. Metab. 50:692-697, 1985. 32.Wickenden, D. Drug of choice: The side effects of RU 486. New Republic 203:24-27, 1990.
33.Finter, L. French abortion drug RU 486: U.S. Research battles heat up. JNCI 83:316-317, 1991. 34.Klein, A., Bruser, B., Robinson, J. B., et al. Effect of a non-viral fraction of acquired immunodeficiency syndrome plasma on the vulnerability of lymphocytes to Cortisol./. Endocrinol. 112:259-264, 1987. 35.Emilie, D., Galanaud, P., Baulieu, E. -E., et al. Inhibition of in vitro immu-
nosuppressive effects of glucocorticosteroids by a competitive antagonist RU 486. Immunol. Letters 8:183-186, 1984.
36.Daynes, R. A., and Araneo, B. A. Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and
interleukin 4. Eur. J. Immunol. 19:2319, 1989. 37.Hughes, S. New Scientist May 5: 21, 1990. 38.Kalimi, M. The role of the anti-glucocorticoid RU 486 on dexamethasone
induced hypertension in rats. Am. J. Physiol. 256E:682-685, 1989.
39.Walser, M., and Ward, L. Progression of chronic renal failure is related to glucocorticoid production. Kidney International 34:859—866, 1988. 40.Kahn, C. A drug that prevents life and extends it. Longevity Nov.: 20—22, 1990.
41.Hardwick, A. J., Linton, E. A., and Rothwell, N. J. Thermogenic effects of the anti-glucocorticoid RU 486 in the rat. Endocrinology 124:1684, 1989. 42.Danhaive, P. A., and Rousseau, G. G. Binding of glucocorticoid antagonists to androgen and glucocorticoid hormone receptors in rat skeletal muscle. /. Steroid Biochem. 24:481-486, 1986. Perspectives in Biology and Medicine, 35, 3 ¦ Spring 1992
337
43.Freedman, M. R., Horwitz, B. ?., and Stern, J. S. Effect of adrenalectomy
and glucocorticoid replacement on development of obesity. Am. J. Physiol. 250-.R595-R607, 1986.
44.Kickson, R. C, Calassi, T. M., Capaccio, J. ?., et al. Limited resistance
of hypertrophied skeletal muscle to glucocorticoids. /. Steroid Biochem. 24:1179-1183, 1986.
45.Bass, M., and Howes, J. Reproductive Health Technologies Project: The Progress of RU 486 in 1990. Washington, D.C.: Tides Foundation, 1991.
46.Mishell, D. R. Quoted by Schuster, L. International Medical News Group. In press, 1991.
HIROSHIMA EVENING
Were you here, old man, were you anywhere near? Stooped and alone you shuffle along, soft step on the concrete, steadfastly slipping past the neon lights of a hamburger stand, into the endless dark.
Come back, old man! I still want to know.
Did you wake from young dreams in this place? Were you here, were you anywhere near when it happened? Or were you on an earlier night crouched above a far-off sea,
elated and trembling, and hurtling full-throttle toward another history? William C. Campbell
338
William Regekon ¦ RU 486 and Abortion Politics
For additional information about this article https://muse.jhu.edu/article/405793
Access provided at 28 Nov 2019 14:19 GMT from Reading University (+1 other institution account)
RU 486: HOW ABORTION POLITICS HAVE IMPACTED ON A POTENTIALLY USEFUL DRUG OF BROAD MEDICAL APPLICATION WILLIAM REGELSON*
If RU 486 (Mifepristone) were not an abortifacient [1-5], it would represent a medical breakthrough of broad applicability. Unfortunately, right-to-life anti-abortion advocates have called RU 486 the "human pesticide," and they have effectively threatened Roussel-Uclaf and its
parent firm, Hoechst AG, with organized worldwide economic retribu-
tion unless the drug is withdrawn. Bill Price, president of Texas United for Life has said: "We are of
course trying to use every bit of political leverage and political clout that we have to keep it [RU 486] out of the U.S." [6]. The success of right-tolife political clout is seen in the unprecedented efforts of Congressman Robert Doman (R-CA) and others, who in June 1990 convinced the
Food and Drug Administration (FDA) to put RU 486 on an FDA import alert embargo [7, 8]. Under the FDA embargo, in order to get laboratory supplies of RU 486, a researcher must contact the FDA or risk confisca-
tion. This cumbersome process has no medical basis, as no clinical application of RU 486 is possible without FDA Investigational New Drug (IND) approval. In addition, RU 486's use in abortion in France is highly restricted and limited to its combined use with prostaglandin E2 [4, 5], another drug not available in the United States. There is no evidence
that RU 486 constitutes a public threat, and as Ron Wyden, chair of the House Committee on Small Business stated, "an embargo sends a message around the world that this drug is dangerous, and that the FDA is prejudiced against it." Representative Wyden is making a strong congressional effort to reverse the embargo [9]. RU 486, or Mifepristone, is best known as an anti-progestin [10]. The ?Department of Medicine, Medical College of Virginia, Virginia Commonwealth Uni-
versity, Richmond, Virginia 23298-0001.
© 1992 by The University of Chicago. AU rights reserved. 0031-5982/92/3503-0781$01.00
330
William Megebon ¦ RU 486 and Abortion Politics
drug is also a potent blocker of corticosteroid receptors [4, 11 — 15], and
in preliminary clinical study, RU 486 has shown significant activity in the treatment of breast cancer, inoperable meningioma, and Cushing's disease [11, 12, 16-18]. RU 486 has suggested value in aiding cervical dilation, lactation, and the treatment of endometriosis [1, 4].
RU 486 will be useful wherever progesterone or corticosteroid blocking agents have clinical application. Its block to corticosteroid action has shown unequivocal success in the treatment of Cushing's syndrome [11, 13, 14, 18], a disease of excess adrenocortical secretion. RU
486 has reversed the osteoporosis, thinning of skin, muscle atrophy, obesity, adult onset diabetes, depression, hypertension, and immunosuppression associated with this disease. Cushing's can be characterized
as a model for much of the symptomatology of aging [19]: there is data in human and animal models that the syndrome of aging may involve enhanced or prolonged response to corticosteroids [20]. For this reason, RU 486 could have broad but useful application for both stressmediated disease and many of the degenerative diseases [20, 21] seen with progressive age. In addition, many tumors—including breast, bowel, kidney, hepatomas, endometrial cancer, and fibrosarcomas—can show corticosteroid dependency [11, 22—26], suggesting that RU 486 may have clinical value against a broader range of inoperable tumors than those that are progesterone dependent. However, we need more
chronic toxicity data [27], as prolonged chronic use could enhance fi-
brosis or scarring [28] and inhibit acute stress responses (i.e., shock). We
will only know the true therapeutic index of this drug if we can clinically test it in chronic studies.
Our own efforts to establish clinical trials with RU 486 were initially focused on its application to the treatment of advanced breast cancer and its potential value in AIDS. In breast cancer, our interest was based on a successful preliminary 1987 phase I study, in estrogen-positive,
chemotherapy-refractory breast cancer patients in Montpelier, France [29]. RU 486 produced objective tumor regression (6 of 22) that was prolonged (>3 months) in four patients. Clinical relief of bone pain (7 of 23) was seen, with a decline in carcinoembryonic antigen (CEA) tumor markers in 8 patients. In support of these objective and subjective clini-
cal results, there is also growing in vitro data showing that RU 486 can directly inhibit breast cancer cell proliferation [30, 31]. Most recently,
André Ulmann, clinical research director of Roussel-Uclaf, has said that
Roussel-Uclaf is negotiating with the National Cancer Institute (NCI) for a breast cancer clinical study. However, there are apparently no such studies underway in France, despite the successful clinical study in 1987, and Dr. Ulmann indicates that they are not eager to financially support such studies.
We met with Roussel-Uclaf regarding alternative medical uses for RU
Perspectives in Biology and Medicine, 35, 3 ¦ Spring 1992 | 331
486 in January 1989. With the help of Roussel-Uclaf, a United States meeting was planned in April 1989 to organize a cooperative RU 486 breast cancer study for patients who had failed previous therapy. This would have involved a cooperative study under the NCI aegis of the Cancer Acute Leukemia Group B (CALGB) study group, involving 25
major hospital and university groups. However, this meeting was can-
celed when, in March, right-to-life advocates threatened an international boycott of Hoechst AG, the parent company of Roussel-Uclaf [9,
32]. A year later, Georgetown University's Lombardi Cancer Center also
expressed an interest in conducting a study of RU 486 in breast cancer, but was stymied by the unwillingness of Roussel-Uclaf to provide financial support. In addition to our interest in RU 486 for its role in treating cancer
patients, following our Paris meeting and with the help of the Lasker Foundation, an attempt was made to expedite National Institute of Health (NIH) interest in AIDS treatment. However, the threatened boycott also stopped this activity. Hoechst AG, with a 51 percent majority stock holding position in Roussel-Uclaf, in March 1985 assured right-tolife advocates that there would be no further clinical development of RU 486. Because of this, it was obvious that RU 486 would not be made
available in the United States for any new medically oriented clinical studies. It is disturbing to find that most recently Ariel Mouttet, director of Roussel-Uclaf's international marketing, has stated that "it is totally crazy to test the efficacy of RU 486 on AIDS" [33]. However, RU 486 has application for HIV infection, based on data that there is a serum factor in AIDS patients that enhances corticosteroid lympholysis [34].
In addition, the immune upregulating or restorative action of RU 486,
as seen in Cushing's disease [14, 18] and proven in animal models [35, 36], suggests that RU 486 should be looked at as a stimulus to immune response where it might counteract the immunosuppression seen in aging, in cancer, or in viral or stress-related diseases [11, 12]. One concept of RU 486 action, pertinent to anti-tumor action, is that it may enhance IL-2 lymphokine mobilization that is inhibited by gluco-
corticoids [36]. In another area, RU 486 may influence how corticoste-
roids modulate hippocampal function [20], which may be important
to stress-related effects on memory impairment. This is possibly what
prompted recent reported clinical interest in the treatment of senile dementia and depression by RU 486. In addition, there is evidence that RU 486 can modulate adrenal medullary opioid responses to stress [21], which could also be a factor in stress-mediated disease.
In efforts to obtain research support for anti-aging rodent studies, we approached Dr. Ulmann, who stated that "although they will supply the drug for basic research studies, they will do nothing to financially support such studies." Roussel-Uclaf's clinical efforts have not ade332
William Regehon ¦ RU 486 and Abortion Politics
quately sponsored medical studies, but their efforts in abortion have resulted in approved release of the drug for this purpose in Great Brit-
ain, and there have been statements made of its planned release in Scandinavia and the Netherlands for this purpose. In addition, studies of RU 486's use as a contraceptive are said to be planned or underway in Sweden. However, providing RU 486 for population control creates strong opposition. As an example, a "Committee of Inquiry" was set up in Rome, and dire reports of RU 486 side effects in abortion emanate
from this group [37]. The negative publicity generated has related solely to contragestation, and in view of RU 486's preliminary clinical success in breast cancer, meningioma, and Cushing's disease [1 1], we have to ask why Roussel-Uclaf persists in calling to public attention the abortifacient action of this drug rather than its noncontroversial alternative role as a medically useful steroid antagonist.
The clinical development of RU 486 is inconsistent. On the one hand, Roussel-Uclaf is actively fostering the abortifacient application of RU 486 in countries where this is politically feasible; on the other hand, alternative medical applications are neglected or delayed. If RousselUclaf is truly afraid of economic threats, it should provide the drug to smaller, non—boycott-vulnerable companies or to a nonprofit founda-
tion that could fully develop the product. The size of the medical constituency that can benefit from RU 486 far exceeds those opposed to it because of its abortifacient action.
Roussel-Uclaf and Hoechst must seek to serve the "crisis constituency" of those severely ill or debilitated. Even in areas that do not have the
crisis implications, RU 486 has significant value. As mentioned earlier,
RU 486 is of value in endometriosis, which produces menstrual pain and reduces fertility in 10 percent of women of reproductive age [1, 4].
RU 486 also has value in inducing cervical dilatation in labor and in enhancing lactation [I]. All these potential or proven applications must be made visible to the public to create a constituency that could prevail upon Roussel-Uclaf to provide the funds and coordinated effort to ex-
pand their basic research and clinical testing. If the 400,000 women in this country with breast cancer could be shown the potential value of this drug, they and their families would become an important source of agitation for RU 486's availability. RU 486 also reverses and prevents corticosteroid-induced hypertension in rat models [14, 38]. There are
58 million hypertensives in the United States, and although no clinical studies with RU 486 have been performed, clinicians and the public must be made aware of the obvious need for such studies. RU 486 has
potential value in alleviating stress-mediated disease, and it may have a possible place in delaying renal failure in damaged kidneys [39]. Its value in reducing symptomatology in Cushing's patients suggests that it may have value in osteoporosis, which involves the clinical complications Perspectives in Biology and Medicine, 35, 3 ¦ Spring 1992 | 333
of hip fractures (225,000 patients per year), as well as in age-related diabetes, which includes neuropathy, accelerated atherosclerosis, and renal failure. As mentioned earlier, the reversal of corticosteroid immu-
nosuppression [11, 35, 36] provides a potential place for RU 486 in treating AIDS (one million patients), and also indicates RU 486's use as
a modulator of resistance to infection, particularly in the elderly [11, 12, 40].
In another clinical area, the weight gain produced by progesterone in cancer patients suggests that a progesterone antagonist could have
wider clinical value in the physiologic control of morbid obesity. RU
486 has recently been shown to stimulate production of corticotrophin
releasing factor (CRF), resulting in brown fat mobilization that decreases obesity in rodents [41]. RU 486 promotes both differentiation and the sensitivity of adipocytes to adenyl cyclase and epinephrine [42], and the role of adrenalectomy as a factor in decreasing obesity is well known [43]. RU 486 mobilizes the fat deposits induced by corticosteroids in
Cushing's disease, and thus RU 486 might permit one to do this in a pharmacologically controlled fashion. In view of the cosmetic health
consciousness of this nation, it is ironic that calling attention to RU 486's potential muscle stimulating [44] and anti-obesity action [41—44] might help stimulate public interest in the availability of RU 486 even more effectively than our concerns for those with cancer and AIDS.
Currently, the fight for RU 486 availability has focussed on its use in
abortion. As part of the freedom of choice, pro-abortion effort, Representative Barbara Boxer (D-CA) stimulated 70 of her colleagues in Congress to request that Rousell-Uclaf make the drug available [45]. In March 1990, John van DeKamp, the attorney general of California, sought to open the state of California to RU 486 for intrastate testing, manufacturing, and marketing under California's FDA, which is independent of the United States FDA. Roussel-Uclaf was not interested [45,
46], but if the California effort had been supported, it would have resulted in some interesting constitutional questions, particularly in view of the FDA embargo. New states' rights issues would have developed as
to who takes precedence in governing intrastate drug studies. It is the obvious intent of the pro-life forces to reverse Roe v. Wade, and they are keenly aware that medical availability of RU 486 would create a black market that would compromise their control of pregnancy. If Roe v. Wade is repealed, a new Dredd-Scott decision will de-
velop, dividing our country along pharmaceutical Mason—Dixon lines that can only lead to illegal use of abortifacients. An example of this
problem in past history was seen in the illegal use of the chemotherapeutic anti-cancer agent methotrexate, dangerously used as an abortifacient
during the period before Roe v. Wade legalized the procedure. The only possible compromise to meet this eventuality is for RU 486 to be made 334 I William Regekon ¦ RU 486 and Abortion Politics
available as a controlled licensed substance, i.e., as a schedule II or III
drug in similar fashion to prescription controls used for narcotics or barbiturates. RU 486 would be made available to patients only via tightly licensed, controlled prescription forms for specific abortion or nonabortion medical use. However, to do this would be a blatant surrender
to one group's religious beliefs at the expense of another's need, and even then a compromise of this type would not solve the issue for very long. Future drug development of any progesterone or corticosteroid antagonist would be blocked by anti-abortion forces because of an implied threat to pregnancy for any steroid antagonist. The difficulty is already apparent, in that there is a Schering drug, with similar properties to RU 486, which—although not tainted with the abortion tissue— will have similar problems on clinical entry because it could interfere with pregnancy [8].
The clinical availability of RU 486 is both a moral and governmental issue. In France, when faced in September 1988 with governmental pressure, Roussel-Uclaf was given the ideal excuse to continue drug studies, as they were able to say they were forced to make the drug available. We must provide a similar climate of public concern to get
Roussel-Uclaf to respond. In June 1990, the American Medical Association (AMA) came out with a resolution supporting RU 486's clinical applicatiion in abortion. Fifteen hundred scientists, academicians, and health-care workers have signed petitions, and over 200,000 petitions demanding the availability of this drug have been presented to RousselUcalf though the help of the Feminist Majority Foundation [46]. Most importantly, for the first time, the American Association for the Advancement of Science (AAAS), at its national meeting in February 1991,
has gone on record favoring the broad medical availability of this drug. The crisis constituency—those with the syndromes of aging, cancer, hypertension, diabetes, etc.—must be stimulated to add their protests to petitions already circulated [46]. In lieu of White House cooperation, our patients and scientific and medical community should find a way to prevail directly upon the French Minister of Health to force RousselUclaf to more energetically develop studies of RU 486's medical application both in France and abroad. This is not just a moral issue but a financial one: the French government, which owns 36 percent of Roussel-Uclaf, is not getting a fair return for their money in view of the potentially vast worldwide market involving medical needs. Above all, we need visible scientific conferences, workshops, and discussion to make scientists, physicians, and the public aware of the potential medical value of this drug [40]. We need ethical balance that gives attention to the living as well as the unborn, and this issue must become part of a vigorous public debate that will make this drug available for clinical study.
Perspectives in Biology and Medicine, 35, 3 · Spring 1992 | 335
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HIROSHIMA EVENING
Were you here, old man, were you anywhere near? Stooped and alone you shuffle along, soft step on the concrete, steadfastly slipping past the neon lights of a hamburger stand, into the endless dark.
Come back, old man! I still want to know.
Did you wake from young dreams in this place? Were you here, were you anywhere near when it happened? Or were you on an earlier night crouched above a far-off sea,
elated and trembling, and hurtling full-throttle toward another history? William C. Campbell
338
William Regekon ¦ RU 486 and Abortion Politics
