- Email: [email protected]
Do antiestrogens and antiprogestins act as hormone antagonists or receptor-targeted drugs in breast cancer?
TIPS - April 1987 [Vol. 81 .._._
.. _ _ ,_ . / : :, $ ’ f : : __...a__ ~~~ ..,I ‘.“-__7“__..” _+ _ L.‘.”7-. j ! __c_. ._1 __<, _._L.. . _:‘...._ j :i__ +.,,_r. I : . L.....) : . . ..: .^ .._..
Do antiestrogens and antiprogestins act as hormone antagonists or receptortargeted drugs in breast cancer? Henri Rochefort Sex-steroid anti-hormones are selective therapeutic agents acting specifically on endocrine-related ca?lcercells which contain a sufficient concentration of the related intracellular receptors. Antiestrogens are effective in the therapy of estrogen receptors positive breast cancers, but the mechanism of ‘their ant&moral activity may not be simply explained by their antiestrogenic activities. Both progestins and the progestin antagonist RU486 paradoxically inhibit the growth of some breast cancer cells in vitro and in vivo. Moreover, antiestrogens and antiprogestins behave as receptor-mediated cytostatic and cytotoxic drugs even in the complete absence of their agonist. Henri Rochefort therefore proposes that sex steroid antagonists inhibit breast cancergrowth not only through their antihormonal activity, but also more directly as antimitogenic drugs targeted to nuclei via specific hormone receptors. Antihormones are drugs which inhibit hormone action at the gene level by specificaiiy preventing hormones from binding to their receptors’+. In contrast to metabolic hormones such as glucocorticoids or insulin, which are essential for life, sex steroids are not vital. Moreover, sex steroid receptors are mostly concentrated in sexual target organs and their concentrations are often higher in cancer cells than in normal cells5. Sex steroid hormone antagonists such as antiestrogens and antiandrogens are therefore used with success to treat hormone-dependent cancer$. The mechanism of their antagonist activities on gene expression is not totally understood but can be partly explained by altered activation of the receptor’. The mechanism by which they inhibit the growth of hormonedependent canrers.appears to be even more mysterious. We have reconsidered this mechanism of action on the basis of recent find-
Hemi Rochefort is Professor ofCellBiology at the PaAte’ de MPdecine, UniversitC de Montpellier 1, and Head oflNSERM U 148.62, rue de Navacelles, 34100 Montpellier, trance. @ 1%‘. Ekvier
Publications,
Cambridge
ings on the antiproliferative effects of progestin#, antiprogestins9,10 and antiestrogens”. RU486: an antiprogestin and antimitogen The steroid analog RU486 prevents progestin and glucocorticoid action by interacting strongly but inefficiently with the progesterone receptor (PR) and the glucocorticoid receptor respectively12, and has been shown to induce termination of early pregnancy13. This antagonist is a Is-nor steroid bearing a side chain similar to that of antiestrogens l3 *I4(Fig. 1). In two human breast cancer cell lines (T47D and MCF7), progestins inhibit cell proliferation via the PRs,lo. The antiprogestin RU486 was therefore expected to stimulate the growth of these cells. Surprisingly, the antagonist was even more efficient than the agonist in preventing cell growthgJo. This action was independent of the glucocorticoid receptor and estrogen treatment increased its efficiency, probably by increasing the concentration of PR sites. The antiproliferative effect of RU486 appeared thus to be PR-mediated. Theoretically, RU486 could be
0165 - 6147/87/$M,OO
acting as a progestin through partial agonist activity” (Fig. 2, mechanism 1). However, RU486 appears to be a full progestin antagonist, since it is unable to stimulate the synthesis of the three known progesterone-regulated roteins in breast cancer cellslo,P5,16. Therefore, its antiproliferative activity may be due to a direct effect of the drug-progesterone receptor complex (Fig. 2, mechanism 2) but not to its progestin or antiprogestin activity. The fact that RU486 also displays some PR-mediated cytotoxic activity’l, in addition to a major cytostatic activity, supports such a direct and receptor-mediated mechanism. These in-vitro pharmacological studies have suggested the use of this antiprogestin in the treatment of PR-positive breast cancers. A preliminary clinical trial with RU486 in tamoxifen-resistant advanced breast cancers suggests, in fact, a good long-term tolerance of the drug and a partial responsiveness of the metastatic disease17. Antiestrogens: estrogen receptortargeted antimitogens? The antiestrogen, tamoxifen, acts classically on estrogen receptor (ER)-containing ceYs by inhibiting the Gtogenic effect of estrogenslA (Fig. 3, mechanism 1). However, tamoxifen appears to be more efficient in patients6 and in cultured cells that are apparently not exposed to estrogens -4 and its antiproliferative effect appears to be more drastic than the simple removal of estrogen from culture medium. This apparent paradox has led some authors to propose that antiestrogens might act via specific antiestrogen binding sites other than ERla. However, antiestrogens are more efficient in ER-positive cancers than in ERnegative cancersI and there is a general consensus that their action is mediated by ERla. It is therefore possible that tamoxifen is acting via one of two major mechanisms, both mediated by the estrogen receptor (Fig. 3). The first one classically implies that the drug acts via its passive antihormonal activity by preventing the stimulatory effect of estrogens. This mechanism has been difficult to exclude, since estrogens act at very low (picomolar) concentrations and it might be impossible to eliminate totally from the environ-
TPS- April1987[Vol.81
127
tyuN\
For instance in the tamoxifenresponsive breast cancer cells (MCF 7), but not in its antiestrogen resistant variant (R27, RTX6), tamoxifen blocks the production in the culture medium of a 52 kDa mitogenie protease3S23.By the same ERmediated mechanism, antiestiogens might also trigger growth factor inhibitors (an antiestrogenspecific protein that is different from the estrogen-induced proteins has been reported in MCF7 cells’“) or modulate endonucleases activities to actively induce cell death=.
i
.,HOH & HO
DES
4-Hydroxytamoxifen
Hypothesis While antiestrogens and the antiprogestin RU486 appear to act via the estrogen and progesterone receptor respectively, their antiproliferative activities are difficult to explain by their antagonist or partial agonist activities. I therefore propose an alternative mechanism which assumes that the antagonist can block cell proliferation and induce cell death directly and more efficiently than by simply inhibiting or mimicking the action of its corresponding hormone. In this hypothesis, the specific intracellular receptors, whereby steroid hormones are normally routed into cells, are
,N’
MO20
RU486
Fig. 1. Strudure of two antihormones. an antiestrogen (#=hydroxytamo.xifen) and an antiprogestin (RlJ486) compared to the structure of the corresponding agonists, an estrogen (diethylstiboestrot, DES) and a progestin (R5020). Both antagonists have a similar side chain added to the structure of the agonist.
ment?,19. Moreover estrogen-like compounds, even those with low affinity for the ER, might behave as full estrogen agonists, as was shown for dihydrotestosterone” and more recently with the pH indicator phenol red2’ normally present in culture medium. However; we have recently found that both tamoxifcn and d-hydroxytamoxifen were growth inhibitors of MCF 7 cells cultured without phenol red (Mignon and Boubon, unpublished results). A simple antiestrogenic mechanism being unlikely, I therefore propose a second mechanism by which antiestrogens would exert an effect independent of their antihormonal activity. Thus, Phydroxytamoxifen, an active metabolite of tamoxifen, has a cytotoxic effect at low concentrations on ERpositive cells in culture”, whereas estrogen dq!eYon does not seem to induce cytolysis2G. The binding of antiestrogens to the ER is sufficient to partly activate the receptor and to trigger some but not all estrogenic responses22s23
‘)
no progestin induced proteins
ProgestinDirect inhibition like responses 4
I
1
Ceil proliferation
I
Fig. 2. Two possible mechanisms of action of antiprogestin mediated by the progesterone receptor. 1. Hormonal mechanism: RU466 isacting as a partial agonist through its progesbn activity, as other pmgesttns. However rio pmgestin-specific effect of RU466 is known in breasi cancer &ils. 2. Direct receptor mediated inhibition of unknown mechanisms: inductkm of growth factors inhibitors, endonucleases, etc. . . or decreased pmdMim of mitogens by other
TIPS - April 1987 Dfol. SJ
128
rIlitOgWlSWnhibitiOn + I
I
+-
Cell ProWration
I
Fit. 3. Two posalblemschan~sms of action of an&&vgens media&d by theesbagen=Wk. 1. AnWwmonat mechanism (decreased pmduction of mitogens) by inhibit&g estmgen stimulation. 2. Dit& rscaptor-mediated inhibition of unknown mechanisnx induction of gtnvth fador tnh,Aitors, ando-etc... ordecmasedprooktfonofmitvgensbyothermechanismsasfwmechanismtwvofanti-
also used to concentrate syrZ~&c drugs and transport the resulting drug-receptor complex to appropriate sites in target celJ nuclei, provided that the drug has an affinity and concentration sufficient to compete efficiently with the corresponding endogenous hormones. The mechanism by which the drug-receptor complex triggers events leading to cell growtt arrest and cell death is unknowns, although there is now more information about the mechanism of regulation of gene expression by the complex. Footprinting experiments suggest that in vivo the antagonist induces an altered conformation of the receptor which prevents its recognition of physiological regulatory sites. The glucocorticoid-responsive element of tyrosine amino transferase is recognized in viva by the receptor-glucocorticoid complex but not by the receptorRU486 complexz6. However, proteins interacting with the receptor may he involved in vivo since in vitro, the purified progesterone receptor recognizes specifically the same progestin responsive element whether it binds to progesterone or to its antagonist RU486 (Ref. 27).
The sex steroid antihonnones are therefore antiproliferative drugs whose selectivity of action is clearly due to their affinity for the corresponding steroid receptors. By contrast, the reason for their cytotoxicity and antiproliferative activity is unknown but the side chain of tamoxifen and RLJ486 may play a common role in these activities as shown by comparing several analo s with or without these chains g ,*3a28. Several prerequisites appear to be necessary for these drugs to be active: (1) they must be analogs of a hormone having (by itself or via its metabolic activation) a high affinity for the receptor; (2) the tumor has to contain sufficiently high concentrations of the relevant receptor; this occurs in well differentiated cancers which can then be improved by hormonal manipulation; (3) the drug must act via this receptor and not via metabolic receptors that are scattered throughout the organism. This hypothesis may serve to stimulate new clinical trials with several available steroid hormone antegonists (antiestrogens, antiprogestins, antiandrogens) in cancers having sufficient concentrations of the corresponding sex-steroid receptors (breast, endometrium, prostate, pancreas, melanoma, etc.). It could also serve as a guide for synthesizing and testing new cytotoxic drugs which bind specifically on sex-steroid receptorsZ9. Acknowledgement I am indebted to my colleagues in INSERM Unit 148 who have made work reviewed here possible and to Drs J. B. LePecq, E. Baulieu, L. Israel and P. G. Gill for stimulating discussions and to ROUSSELUCLAF Laboratories for providing the drugs. Misses E. Barr% and M. Egea typed the manuscript. The work was supported by the ‘Institut National de la SantC et de la Recherche Medicale’ (INSERM), the University of Montpellier 1, and the ‘Ligue Nationale Frangaise contre le Cancer’. References 1 Jensen, E. V., Jacobson,
H. I., Smith, S., Jungblut, P. W. and DeSombre, E. R. (1972) Gynecol. Invest. 2,108-123 2 Lippman, M. E., Bolan, G. and Huff, K. (1976) Cancer Res. 36,4595 3 Rochefort, H., Bardon, S., Chalbos, D.
4
5
6 7
and Vignon, F. (1984) I. Steroid Biochem. 20,105-110 Katzenellenboeen. B. S.. Miller, M. A., Mullick, A. &d. Sheen, Y. Y. (1985) Breast Cancer Res. Treat. 5, 231-243 Isotalo, H., Tryggvason, K., Vierikko, I’., Kauppil, A. Vihko, R. (1983) Anticancer Res. 3.331-335 Pzlshof. T. and Mouridsen. H. T. 119831 Eur. 1. dancer. Clin. Oncol. i9,175&1770 Patterson, J. S., Battersky, L. A. and Edwards, D. J. (1981) in Review on Endocrine-Related Cancer (Suppl. 9), f;i 563-582, Pharmaceuticals Division
8 Vignon, F., Bardon, S., Chalbos, D. and Rochefort, H. (1983) J. Clin. Endocrin. Metnb. 56,1124-1130 9 Bardon, S., Vignon, F., Chalbos, D. and Rochefort. H. (1985) L Clin. Endocria. Metab. 60; 692-697 . 10 Horwitz, K. (1985) Endocrinology 116, 2236-2245 11 Bardon, S., V&non, F., Montcourrier, P. and Rochefort, H. Cancer Res. (in press) 12 Sakiz, E., Euvrard, C. and Baulieu, E. E. jiS84) in Endorrino!ogy (Labrie, F., Pro&, L., eds), pp. 239-242, International Congress Series 655, Excerpta Medica 13 Herrmann. W.. Wvss. R.. Riondel. A.. Philibert, b., Teut&h; C.,’ Sakiz, E.‘and Bauiieu, E. E. (1983) C. R. Acad. Sci. Paris 294,933 14 Murphy, L.C. and Sutherland, R. L. (1985) Endocrinology 116,1071-1078 15 Chalbos, D. and Rochefort, H. (1984) Biochem. Biophys. Res. Commun. 121, 42i-427 16 Chalbos, D. and Rochefort, H. (1984) J. Biol. Chem. 259,1231-1238 17 Maudelonde. T.. Romieu. G.. Ulmann. A., Pujol, f-i., Grenier, j., Khalaf, S.; Cavali6, G. and Rochefort, H. (1986) in Hormonal Manivulation of Cancer Idin. J. G. M., ed). Riven Press ’ ’ ’ 18 Sutherland, R. L., Murphy, L. C., Foo, M. S., Green, M. D., Gyioume, A. M. and Krozowski, 2. S. (1980) Nature 88, 27%275 19 Vigr?or?, F., Te:qui, M., Westiey, B., Derocq, D. and Rochefort, H. (1980) Endocrinology 106,107~1086 20 Rochefort, H. and Garcia, M. (1984) Phnrmac. Ther. 23,19%216 21 Berthois. Y.. Katzenellenboeen. I. A. and Katieneienbogen, 8. S. (7998) Proc. Nat1 Acad. Sri. USA 83.2496-2500 22 P.ochefort, H., Borgna, J. L. (1981) ll’atwre 292,257-259 23 Westlev, 8.. Mav. F. E. B.. Brown. A.M. e., Kkst, .A., Chambon, P.; Lippman, M. E. and Rochefort, H. (1984) 1. Biol. Chem. 259.1003&10035 24 Bronze& D. A.; Silverman, S. and Lippman, M. E. (1985) The Endocrine Society, 67th Annual Meeting, June 19-21, Baltimore MD, Abstract no. 1007, T .e Endocrine Societv. Bethesda 25 Bowen, I. D. and Lo&shin, R. A. (eds) (1981) in Cell Death in Biology and Pathology, Chapman and Hall 26 Becker, P. B., Gloss, B., Schmid, W., Strihle, U. and Schiitz, G. (1986) Nature 324.686-688 27 Baiily, A., Le Page, C., Rauch, M. and Mile;rom, E. (1986) EMBO 1.5,3235-3241 28 Rorxe, E. A. &td katzenellbnbogen, B. S. (1981) Cancer Res. 41,1257-1262 29 Raus, J., Martens, H. and Leclercq, G. (eds) (1980) Q&toxic Estrogens in Hormone Receptive Tumors, Academic Press
.. _ _ ,_ . / : :, $ ’ f : : __...a__ ~~~ ..,I ‘.“-__7“__..” _+ _ L.‘.”7-. j ! __c_. ._1 __<, _._L.. . _:‘...._ j :i__ +.,,_r. I : . L.....) : . . ..: .^ .._..
Do antiestrogens and antiprogestins act as hormone antagonists or receptortargeted drugs in breast cancer? Henri Rochefort Sex-steroid anti-hormones are selective therapeutic agents acting specifically on endocrine-related ca?lcercells which contain a sufficient concentration of the related intracellular receptors. Antiestrogens are effective in the therapy of estrogen receptors positive breast cancers, but the mechanism of ‘their ant&moral activity may not be simply explained by their antiestrogenic activities. Both progestins and the progestin antagonist RU486 paradoxically inhibit the growth of some breast cancer cells in vitro and in vivo. Moreover, antiestrogens and antiprogestins behave as receptor-mediated cytostatic and cytotoxic drugs even in the complete absence of their agonist. Henri Rochefort therefore proposes that sex steroid antagonists inhibit breast cancergrowth not only through their antihormonal activity, but also more directly as antimitogenic drugs targeted to nuclei via specific hormone receptors. Antihormones are drugs which inhibit hormone action at the gene level by specificaiiy preventing hormones from binding to their receptors’+. In contrast to metabolic hormones such as glucocorticoids or insulin, which are essential for life, sex steroids are not vital. Moreover, sex steroid receptors are mostly concentrated in sexual target organs and their concentrations are often higher in cancer cells than in normal cells5. Sex steroid hormone antagonists such as antiestrogens and antiandrogens are therefore used with success to treat hormone-dependent cancer$. The mechanism of their antagonist activities on gene expression is not totally understood but can be partly explained by altered activation of the receptor’. The mechanism by which they inhibit the growth of hormonedependent canrers.appears to be even more mysterious. We have reconsidered this mechanism of action on the basis of recent find-
Hemi Rochefort is Professor ofCellBiology at the PaAte’ de MPdecine, UniversitC de Montpellier 1, and Head oflNSERM U 148.62, rue de Navacelles, 34100 Montpellier, trance. @ 1%‘. Ekvier
Publications,
Cambridge
ings on the antiproliferative effects of progestin#, antiprogestins9,10 and antiestrogens”. RU486: an antiprogestin and antimitogen The steroid analog RU486 prevents progestin and glucocorticoid action by interacting strongly but inefficiently with the progesterone receptor (PR) and the glucocorticoid receptor respectively12, and has been shown to induce termination of early pregnancy13. This antagonist is a Is-nor steroid bearing a side chain similar to that of antiestrogens l3 *I4(Fig. 1). In two human breast cancer cell lines (T47D and MCF7), progestins inhibit cell proliferation via the PRs,lo. The antiprogestin RU486 was therefore expected to stimulate the growth of these cells. Surprisingly, the antagonist was even more efficient than the agonist in preventing cell growthgJo. This action was independent of the glucocorticoid receptor and estrogen treatment increased its efficiency, probably by increasing the concentration of PR sites. The antiproliferative effect of RU486 appeared thus to be PR-mediated. Theoretically, RU486 could be
0165 - 6147/87/$M,OO
acting as a progestin through partial agonist activity” (Fig. 2, mechanism 1). However, RU486 appears to be a full progestin antagonist, since it is unable to stimulate the synthesis of the three known progesterone-regulated roteins in breast cancer cellslo,P5,16. Therefore, its antiproliferative activity may be due to a direct effect of the drug-progesterone receptor complex (Fig. 2, mechanism 2) but not to its progestin or antiprogestin activity. The fact that RU486 also displays some PR-mediated cytotoxic activity’l, in addition to a major cytostatic activity, supports such a direct and receptor-mediated mechanism. These in-vitro pharmacological studies have suggested the use of this antiprogestin in the treatment of PR-positive breast cancers. A preliminary clinical trial with RU486 in tamoxifen-resistant advanced breast cancers suggests, in fact, a good long-term tolerance of the drug and a partial responsiveness of the metastatic disease17. Antiestrogens: estrogen receptortargeted antimitogens? The antiestrogen, tamoxifen, acts classically on estrogen receptor (ER)-containing ceYs by inhibiting the Gtogenic effect of estrogenslA (Fig. 3, mechanism 1). However, tamoxifen appears to be more efficient in patients6 and in cultured cells that are apparently not exposed to estrogens -4 and its antiproliferative effect appears to be more drastic than the simple removal of estrogen from culture medium. This apparent paradox has led some authors to propose that antiestrogens might act via specific antiestrogen binding sites other than ERla. However, antiestrogens are more efficient in ER-positive cancers than in ERnegative cancersI and there is a general consensus that their action is mediated by ERla. It is therefore possible that tamoxifen is acting via one of two major mechanisms, both mediated by the estrogen receptor (Fig. 3). The first one classically implies that the drug acts via its passive antihormonal activity by preventing the stimulatory effect of estrogens. This mechanism has been difficult to exclude, since estrogens act at very low (picomolar) concentrations and it might be impossible to eliminate totally from the environ-
TPS- April1987[Vol.81
127
tyuN\
For instance in the tamoxifenresponsive breast cancer cells (MCF 7), but not in its antiestrogen resistant variant (R27, RTX6), tamoxifen blocks the production in the culture medium of a 52 kDa mitogenie protease3S23.By the same ERmediated mechanism, antiestiogens might also trigger growth factor inhibitors (an antiestrogenspecific protein that is different from the estrogen-induced proteins has been reported in MCF7 cells’“) or modulate endonucleases activities to actively induce cell death=.
i
.,HOH & HO
DES
4-Hydroxytamoxifen
Hypothesis While antiestrogens and the antiprogestin RU486 appear to act via the estrogen and progesterone receptor respectively, their antiproliferative activities are difficult to explain by their antagonist or partial agonist activities. I therefore propose an alternative mechanism which assumes that the antagonist can block cell proliferation and induce cell death directly and more efficiently than by simply inhibiting or mimicking the action of its corresponding hormone. In this hypothesis, the specific intracellular receptors, whereby steroid hormones are normally routed into cells, are
,N’
MO20
RU486
Fig. 1. Strudure of two antihormones. an antiestrogen (#=hydroxytamo.xifen) and an antiprogestin (RlJ486) compared to the structure of the corresponding agonists, an estrogen (diethylstiboestrot, DES) and a progestin (R5020). Both antagonists have a similar side chain added to the structure of the agonist.
ment?,19. Moreover estrogen-like compounds, even those with low affinity for the ER, might behave as full estrogen agonists, as was shown for dihydrotestosterone” and more recently with the pH indicator phenol red2’ normally present in culture medium. However; we have recently found that both tamoxifcn and d-hydroxytamoxifen were growth inhibitors of MCF 7 cells cultured without phenol red (Mignon and Boubon, unpublished results). A simple antiestrogenic mechanism being unlikely, I therefore propose a second mechanism by which antiestrogens would exert an effect independent of their antihormonal activity. Thus, Phydroxytamoxifen, an active metabolite of tamoxifen, has a cytotoxic effect at low concentrations on ERpositive cells in culture”, whereas estrogen dq!eYon does not seem to induce cytolysis2G. The binding of antiestrogens to the ER is sufficient to partly activate the receptor and to trigger some but not all estrogenic responses22s23
‘)
no progestin induced proteins
ProgestinDirect inhibition like responses 4
I
1
Ceil proliferation
I
Fig. 2. Two possible mechanisms of action of antiprogestin mediated by the progesterone receptor. 1. Hormonal mechanism: RU466 isacting as a partial agonist through its progesbn activity, as other pmgesttns. However rio pmgestin-specific effect of RU466 is known in breasi cancer &ils. 2. Direct receptor mediated inhibition of unknown mechanisms: inductkm of growth factors inhibitors, endonucleases, etc. . . or decreased pmdMim of mitogens by other
TIPS - April 1987 Dfol. SJ
128
rIlitOgWlSWnhibitiOn + I
I
+-
Cell ProWration
I
Fit. 3. Two posalblemschan~sms of action of an&&vgens media&d by theesbagen=Wk. 1. AnWwmonat mechanism (decreased pmduction of mitogens) by inhibit&g estmgen stimulation. 2. Dit& rscaptor-mediated inhibition of unknown mechanisnx induction of gtnvth fador tnh,Aitors, ando-etc... ordecmasedprooktfonofmitvgensbyothermechanismsasfwmechanismtwvofanti-
also used to concentrate syrZ~&c drugs and transport the resulting drug-receptor complex to appropriate sites in target celJ nuclei, provided that the drug has an affinity and concentration sufficient to compete efficiently with the corresponding endogenous hormones. The mechanism by which the drug-receptor complex triggers events leading to cell growtt arrest and cell death is unknowns, although there is now more information about the mechanism of regulation of gene expression by the complex. Footprinting experiments suggest that in vivo the antagonist induces an altered conformation of the receptor which prevents its recognition of physiological regulatory sites. The glucocorticoid-responsive element of tyrosine amino transferase is recognized in viva by the receptor-glucocorticoid complex but not by the receptorRU486 complexz6. However, proteins interacting with the receptor may he involved in vivo since in vitro, the purified progesterone receptor recognizes specifically the same progestin responsive element whether it binds to progesterone or to its antagonist RU486 (Ref. 27).
The sex steroid antihonnones are therefore antiproliferative drugs whose selectivity of action is clearly due to their affinity for the corresponding steroid receptors. By contrast, the reason for their cytotoxicity and antiproliferative activity is unknown but the side chain of tamoxifen and RLJ486 may play a common role in these activities as shown by comparing several analo s with or without these chains g ,*3a28. Several prerequisites appear to be necessary for these drugs to be active: (1) they must be analogs of a hormone having (by itself or via its metabolic activation) a high affinity for the receptor; (2) the tumor has to contain sufficiently high concentrations of the relevant receptor; this occurs in well differentiated cancers which can then be improved by hormonal manipulation; (3) the drug must act via this receptor and not via metabolic receptors that are scattered throughout the organism. This hypothesis may serve to stimulate new clinical trials with several available steroid hormone antegonists (antiestrogens, antiprogestins, antiandrogens) in cancers having sufficient concentrations of the corresponding sex-steroid receptors (breast, endometrium, prostate, pancreas, melanoma, etc.). It could also serve as a guide for synthesizing and testing new cytotoxic drugs which bind specifically on sex-steroid receptorsZ9. Acknowledgement I am indebted to my colleagues in INSERM Unit 148 who have made work reviewed here possible and to Drs J. B. LePecq, E. Baulieu, L. Israel and P. G. Gill for stimulating discussions and to ROUSSELUCLAF Laboratories for providing the drugs. Misses E. Barr% and M. Egea typed the manuscript. The work was supported by the ‘Institut National de la SantC et de la Recherche Medicale’ (INSERM), the University of Montpellier 1, and the ‘Ligue Nationale Frangaise contre le Cancer’. References 1 Jensen, E. V., Jacobson,
H. I., Smith, S., Jungblut, P. W. and DeSombre, E. R. (1972) Gynecol. Invest. 2,108-123 2 Lippman, M. E., Bolan, G. and Huff, K. (1976) Cancer Res. 36,4595 3 Rochefort, H., Bardon, S., Chalbos, D.
4
5
6 7
and Vignon, F. (1984) I. Steroid Biochem. 20,105-110 Katzenellenboeen. B. S.. Miller, M. A., Mullick, A. &d. Sheen, Y. Y. (1985) Breast Cancer Res. Treat. 5, 231-243 Isotalo, H., Tryggvason, K., Vierikko, I’., Kauppil, A. Vihko, R. (1983) Anticancer Res. 3.331-335 Pzlshof. T. and Mouridsen. H. T. 119831 Eur. 1. dancer. Clin. Oncol. i9,175&1770 Patterson, J. S., Battersky, L. A. and Edwards, D. J. (1981) in Review on Endocrine-Related Cancer (Suppl. 9), f;i 563-582, Pharmaceuticals Division
8 Vignon, F., Bardon, S., Chalbos, D. and Rochefort, H. (1983) J. Clin. Endocrin. Metnb. 56,1124-1130 9 Bardon, S., Vignon, F., Chalbos, D. and Rochefort. H. (1985) L Clin. Endocria. Metab. 60; 692-697 . 10 Horwitz, K. (1985) Endocrinology 116, 2236-2245 11 Bardon, S., V&non, F., Montcourrier, P. and Rochefort, H. Cancer Res. (in press) 12 Sakiz, E., Euvrard, C. and Baulieu, E. E. jiS84) in Endorrino!ogy (Labrie, F., Pro&, L., eds), pp. 239-242, International Congress Series 655, Excerpta Medica 13 Herrmann. W.. Wvss. R.. Riondel. A.. Philibert, b., Teut&h; C.,’ Sakiz, E.‘and Bauiieu, E. E. (1983) C. R. Acad. Sci. Paris 294,933 14 Murphy, L.C. and Sutherland, R. L. (1985) Endocrinology 116,1071-1078 15 Chalbos, D. and Rochefort, H. (1984) Biochem. Biophys. Res. Commun. 121, 42i-427 16 Chalbos, D. and Rochefort, H. (1984) J. Biol. Chem. 259,1231-1238 17 Maudelonde. T.. Romieu. G.. Ulmann. A., Pujol, f-i., Grenier, j., Khalaf, S.; Cavali6, G. and Rochefort, H. (1986) in Hormonal Manivulation of Cancer Idin. J. G. M., ed). Riven Press ’ ’ ’ 18 Sutherland, R. L., Murphy, L. C., Foo, M. S., Green, M. D., Gyioume, A. M. and Krozowski, 2. S. (1980) Nature 88, 27%275 19 Vigr?or?, F., Te:qui, M., Westiey, B., Derocq, D. and Rochefort, H. (1980) Endocrinology 106,107~1086 20 Rochefort, H. and Garcia, M. (1984) Phnrmac. Ther. 23,19%216 21 Berthois. Y.. Katzenellenboeen. I. A. and Katieneienbogen, 8. S. (7998) Proc. Nat1 Acad. Sri. USA 83.2496-2500 22 P.ochefort, H., Borgna, J. L. (1981) ll’atwre 292,257-259 23 Westlev, 8.. Mav. F. E. B.. Brown. A.M. e., Kkst, .A., Chambon, P.; Lippman, M. E. and Rochefort, H. (1984) 1. Biol. Chem. 259.1003&10035 24 Bronze& D. A.; Silverman, S. and Lippman, M. E. (1985) The Endocrine Society, 67th Annual Meeting, June 19-21, Baltimore MD, Abstract no. 1007, T .e Endocrine Societv. Bethesda 25 Bowen, I. D. and Lo&shin, R. A. (eds) (1981) in Cell Death in Biology and Pathology, Chapman and Hall 26 Becker, P. B., Gloss, B., Schmid, W., Strihle, U. and Schiitz, G. (1986) Nature 324.686-688 27 Baiily, A., Le Page, C., Rauch, M. and Mile;rom, E. (1986) EMBO 1.5,3235-3241 28 Rorxe, E. A. &td katzenellbnbogen, B. S. (1981) Cancer Res. 41,1257-1262 29 Raus, J., Martens, H. and Leclercq, G. (eds) (1980) Q&toxic Estrogens in Hormone Receptive Tumors, Academic Press