In Vivo and in Vitro Pharmacological Studies of Aminoglutethimide As an Aromatase Inhibitor1

Home , Aromatase inhibitor, Hydrocortisone, Methasone

[CANCER RESEARCH (SUPPL.) 42, 3353s-3359s, August1982] 0008-5472/82/0042-0000$02.00 In Vivo and in Vitro Pharmacological Studies of Aminoglutethimide as an Aromatase Inhibitor1

R. J. Santen, S. J. Santner, N. Tilsen-Mallett, H. R. Rosen, E. Samojlik, and J. D. Veldhuis

Department of Medicine, Division of Endocrinology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033

Abstract agents such as phÃ©nobarbital were known to alter drug metab olism (2, 5), we first examined the effect of AG on the metabolic Use of steroid biosynthesis inhibitors to suppress estrogen clearance of several synthetic and endogenous steroids as well production is a logical strategy in the treatment of women with as on its own metabolism. Stimulated by the studies of Thomp hormone-dependent breast cancer. The clinical availability of aminoglutethimide as an inhibitor of cytochrome P-450-medi- son and Siiteri (21 , 22), we then evaluated the ability of AG to block aromatase in vivo and in vitro and its relative potency ated steroid hydroxylations prompted study of the precise pharmacological and biochemical effects of this drug. Phar- compared to other aromatase inhibitors (1 8). Our data demonstrated that AG accelerates its own metab macokinetic studies revealed that aminoglutethimide alters its own metabolic clearance rate as well as that of dexametha- olism as well as that of dexamethasone but does not alter the metabolic clearance of hydrocortisone, medroxyprogesterone sone, a synthetic glucocorticoid. The metabolic clearance rates of other steroids such as hydrocortisone, medroxyprogester- acetate, androstenedione, and estrone. When given with re placement hydrocortisone, AG blocks estrogen synthesis at 3 one acetate, androstenedione, and estrone are not altered by sites: the adrenal cortex; extraglandular peripheral tissues aminoglutethimide. These findings led to development of a containing aromatase; and breast carcinoma tissue itself. practical regimen of escalating aminoglutethimide dosage in combination with hydrocortisone for treatment of patients with breast carcinoma. Further studies focused upon the biochem MATERIALS AND METHODS ical mechanism of estrogen suppression with aminoglutethi MCR mide. In vivo, isotopie kinetic data demonstrated that amino As described in detail previously, standard methods for determining glutethimide inhibits peripheral aromatase by 95 to 98% in MCR were used for the steroid hormones (1 8, 20). Briefly, 3H-steroids postmenopausal women. In vitro experiments indicated that were injected i.v. as a single bolus or as constant infusions. Plasma aminoglutethimide can effectively block aromatase directly in samples were obtained at frequent intervals, and the 3H-steroids were human breast tumors as well. With respect to relative potency, quantitated after extensive purification and MC recovery corrections. aminoglutethimide is a 10-fold more potent aromatase inhibitor The MCR of AG was determined after a single p.o. administration by than is testololactone but is less potent than are 4-hydroxyan- measuring plasma disappearance of unlabeled drug (1 2). drostenedione and several brominated androstenedione deriv atives. Taken together, these studies suggest that aminoglu Aromatase Activity tethimide blocks estrogen production at three sites in women In Vivo Studies. The method of MacDonald er al. (1 1) was used to with breast carcinoma: the adrenal cortex, extraglandular pe measure the aromatization of androstenedione to estrone in vivo. ripheral tissues containing aromatase, and breast carcinoma Briefly, [3H]androstenedione (A4) and ['"C]estrone (Ei) were infused tissue itself. under equilibrium conditions. The percentage of conversion (p value) of [3H]androstenedione to estrone

Introduction A4-E, While AG2 was initially introduced in the United States as an anticonvulsant, subsequent clinical observations demonstrated was determined from the ratio of [14C]estrone to [3H]estrone in plasma its potent inhibitory effects on adrenal steroid biosynthesis (3, 7, 9, 14). By binding to cytochrome P-450 complexes, AG after correction for recovery losses and exhaustive purification to make 14C:3H ratios constant. The data were then confirmed in urine by blocks the cholesterol side-chain cleavage enzyme as well as measuring p values using 72-hr pools of urine the C-21, C-11, and C-18 steroid hydroxylases (4, 7, 9, 10, 23). Cash et al. (3) first conceived the use of AG as a form of A". E, "medical adrenalectomy" for treatment of metastatic breast P = BU carcinoma in patients who were otherwise candidates for sur In Vitro Studies. The 3H2O method of Thompson and Siiteri (21 ) as gical adrenalectomy. Griffiths era/. (8) later reported beneficial effects in 3 of 9 such women treated. Our group then studied modified by Reed and Ohno (15) and Weisz (24) was used to measure aromatization in placental microsomes, rat brain, and breast tumor the use of AG, focusing primarily on its precise pharmacological homogenates. The exact technique involves incubation with [1/8- effects and mechanism of action. Since other antiepileptic 3H]androstenedione, separation of 3H2O from nonaromatized steroid, 1 Presented at the Conference "Aromatase: New Perspectives tor Breast and recovery and quantitation of 3H2O. The validation of this assay for Cancer," December 6 to 9, 1981, Key Biscayne. Fla. Supported in part by use in breast tumors will be published elsewhere.3 To compare inhibi- National Cancer Institute Contract CB-NCI-53851, The Core Endocrine Labora tory, and Specialized Cancer Center Grant 1P30 CA18450, awarded by the 3 Santner, S. J.. Rosen, H., Osawa, Y., and Santen, R. J. Comparison of National Cancer Institute, Department of Health, Education, and Welfare. aminoglutethimide, testololactone, 4-OH androstenedione, and brominated, 2 The abbreviations used are: AG, aminoglutethimide; MCR, metabolic clear chlorinated, and nitrogenated androstenedione dÃ©rivÃ¢tesasinhibitors of aroma ance rate. tase. Breast Cancer Research and Treatment, submitted for publication, 1982.

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tors in microsomes, dose-response curves were constructed using drostenedione, and estrone did not differ before or during identical incubation conditions for each compound. [1 /8-3H]Androstene- treatment with AG (Table 1). dione (8 pmol) was incubated with 10 jug of placental microsomes at room temperature for 20 min, resulting in an activity of about 50 pmol Effects of AG on Aromatase estrone formed per mg protein per hr. When studying inhibitors in breast tumor tissue, 400 to 1000 jug of crude homogenate were In Vivo. The p value of A" to E, conversion, a direct in vivo incubated with 80 pmol [l/i-3H]androstenedione for 60 min at 30Â°. measurement of aromatase, was determined prior to and during Activities ranged from 10 to 60 pmol estrone formed per g protein per AG treatment in women with metastatic breast carcinoma. hr. Consequently, 50% inhibitory concentrations of drugs can only be Blood studies showed that AG inhibited this enzyme by 98% compared in experiments where conditions are identical. from 1.65 Â±0.28% to 0.04 Â±0.01 % ( p < 0.01 ; Chart 1). As Steroid Radioimmunoassays further confirmation of this observation, we found the p value

Steroids were measured after plasma extraction and Celile column in 2 of these same women using the urinary method chromatography by standard radioimmunoassay methods as described to be inhibited by 95% (Table 2). Demonstration of radiochem- previously. Assay sensitivity, precision, recoveries, and normal ranges ical purity (by measuring constant 3H:14C ratios) served to for the various steroids have been documented in detail from our validate the steroid isolation techniques used. Thus, at the laboratory (17). blood levels achieved (i.e., 30 /UM),AG blocks extraglandular Aromatase Inhibitors aromatization nearly completely (i.e., by 95 to 98%). Another means of estimating the degree of aromatase inhi The AG used was a gift from the CIBA-GEIGY Corp., Ardsley, N. Y. bition was to measure plasma levels of estrone and estradici in Dr. Yoshio Osawa (Medical Foundation of Buffalo, Inc., Buffalo, N. Y.) women receiving AG. The control group for this analysis was provided the brominated and nitroso compounds. Testololactone was a group of postmenopausal women who had undergone sur obtained from the Squibb Corp. Dr. Angela Brodie (University of Mary land School of Medicine, Baltimore, Md.) provided the 4-hydroxyan- gical adrenalectomy to remove endogenous estrogen sources. drostenedione. As shown in Chart 2, estrone and estradiol fell to similar levels in response to either AG-hydrocortisone or surgical adrenal ectomy. These data provide further evidence of aromatase Results suppression with AG. Effects of AG on MCRs In Vitro. Initial studies identified the frequency with which aromatase is present in individual breast tumor homogenates. AG Metabolism. AG accelerated its own metabolism from a Of 25 tumors studied (Chart 3), 21 contained detectable basal value of 2.6 Â±0.3 (S.E.) liters/24 hr to 5.3 Â±1.4 liters/ amounts of aromatase. The range of activity varied from a low 24 hr after 1 to 2 weeks of drug administration (Table 1). This of 5 pmol estrone per g protein per hr to a high of 80 pmol effect may partially explain the resolution of soporific side estrone per g protein per hr (Chart 3). It should be noted that, effects of AG which are most severe during the initial adminis tration of drug. Based upon this finding, we currently administer 500 mg of AG daily for 2 weeks and then escalate the dose to 1000 mg daily thereafter. Synthetic and Endogenous Steroids. AG markedly accel erates the metabolism of the synthetic glucocorticoid, dexa- 20- methasone, from basal values of 145 Â±26.6 liters/24 hr to 568 Â± 127 liters/24 hr (p < 0.02) after 2 weeks of drug administration (Table 1). In contrast, the MCR of the endoge LU nous steroid hydrocortisone is not altered or is altered only t 1.5- minimally [basally 159 Â±22 liters/24 hr; treatment, 192 Â±37 Ã¯< (not significant)]. Consequently, hydrocortisone is preferred to Ã¯o ZZ dexamethasone as replacement glucocorticoid in patients re LU O ceiving AG. The MCR of medroxyprogesterone acetate, an- i ILO-

O Table 1 o: Effect of AG on drug and steroid MCRs < AGa (li AG (liters/ CompoundAG 24hr)2.6 ters/24hr)5.3 0.5- Â± 0.3o Â± 1.4 DexamethasoneMedroxyprogesterone26.62096145 Â± 1272419568 Â± <0.02NSC

Â±314 Â±355 acetate CortisolAndrostenedione 159Â±221572 192Â±371638 NSNSNS BASAL ON AMINOGLUTETHIMIDE Chart 1. Effect of AG on aromatization of androstenedione (AM) to estrone Â±241 Â±234 (Â£,)as measured in blood. Points, individual patients studied before (basal) and EstroneBefore 1897 Â±221During 1885 Â±292P<0.01 during treatment with 1000 mg of AG and 40 mg of hydrocortisone daily. 0 AG administered for at least 1 week. Horizontal lines, mean value for all patients. Downward sloping lines connect 6 Mean Â±S.E. individual studies before and during treatment. From Santen et al. (18). repro c NS, not significant. duced with permission of the Journal of Clinical Endocrinology and Metabolism.

3354s CANCER RESEARCH VOL. 42

Table 2 Effect of AG on aromatizaron: urine method During treatment (1000 mg AG Pretreatment daily)

(cpm)8501683402982583H(cpm)b2371913943362921.913H:"C4.801.131.161.131.13"C(cpm)a361132071672903H(cpm)"6261223327390.103H:14C166.50.200.160.160.13 stepSubjectPurification 3CeliteTLCITLC

IITLC IIITLC acetatep{%)"CIV, Estrone

Subject5CeliteTLCITLC

IITLC IIITLC acetatep{%)232809771674134357461558050310001.082.480.760.750.750.7411032031357610241304553953890.0811.90.170.130.090.09IV, Estrone

a Counts marked for spillover but not for aliquot volume. 13The 14C:3Hspillover ratio was 0.088 for this experiment.

ESTRONE ESTRADICI

ce O An=37 o a: 40 10 LU m Z Z> 12 00 o.

20 5-10 10-15 15-20 20-25 25-30 30-35 60-80

AROMATASE ACTIVITY (pmol E,/g protein/hr) Chart 3. Aromatase activity in individual breast tumor homogenates. NO. less than 5 pmol estrone per g protein per hr. Ei, estrone.

BASAL TREATMENT BASAL TREATMENT Chart 2. Comparison of estrone and estradici levels before treatment (basal) ' HUMAN PLACENTAL MICROSOMES.. and after surgical adrenalectomy or during AG administrator Symbols, mean; ' HUMAN BREAST TUMORS bars, S.E.; numbers with bars, number of patients included in the particular -oâ€”o RAT BRAIN measurement indicated. â€¢¿,AG;O, surgical treatment. From Santen et al. (18), 80 reproduced with the permission of the Journal of Clinical Endocrinology and Metabolism. o E 60 at minimally detectable levels of aromatase activity, 3H2O m x counts from the tumors were at least 2-fold higher (120 to 140 z es 40 cpm) than were background counts of buffer blanks (60 to 80 cpm) or blanks using maximum concentrations of aromatase inhibitor (60 cpm). 20 In 6 breast tumor homogenates, AG inhibited aromatase in a dose-dependent fashion with 50% inhibition at a concentra tion of 13 /IM (Chart 4). The aromatase in human breast tumors appeared similar to that from human placenta and rat hypotha- 10 100 lamic homogenates in its inhibitory response to AG. Dose- CONCENTRATION OF AG response curves (experimental conditions were identical for Chart 4. Inhibitory concentrations of AG necessary to block aromatization in each tissue except for the fact that placenta! preparations various tissues. Shaded area, 95% confidence limits of aromatization inhibition in tumors containing no inhibitor. Points, mean; bars, S.E. The rat brain hypotha- contained 125 ng of microsomal protein versus 400 to 1000 lamic experiment involved duplicate determinations at each dose level in one /ig of crude homogenate for the breast tumors) revealed that experiment.

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AG produced 50% inhibition of placental aromatase (6 ,uM)and of hypothalamic aromatase (8 JUM)(Chart 4). In addition, the dose-response slopes for human placenta, breast carcinoma, and rat brain aromatase were similar.

Relative Potency of AG as an Aromatase Inhibitor

Two aromatase inhibitors are currently available for clinical use in the United States, AG and testololactone. We examined the relative potency of AG versus testololactone and also 17-OH/ 17-OH versus compounds currently in the preclinical phase of testing. Preg . *â€¢Prog Because of the limited availability of breast tumors, placental DHEAâ€”Â»-Androstenedione microsomes served as the source of aromatase for these comparisons. All compounds were tested under conditions of identical enzyme and substrate concentrations. In this system, AG inhibited aromatase at 10-fold lower drug concentrations than did testololactone (Chart 5). 4-Hydroxyandrostenedione, Chart 6. Diagrammatic representation of the effect of AG on conversion of on the other hand, was 30-fold more potent than was AG and cholesterol to pregnenolone (cholesterol side-chain cleavage enzyme), on ^^ÃŸ- 300-fold more than was testololactone. Combinations of AG hydroxylation (conversion of 11-deoxycortisol to cortisol and conversion of 11 - deoxycorticosterone to corticosterone), and on 18-hydroxylation (corticosterone with testololactone or 4-hydroxyandrostenedione produced ad to aldosterone production). AG also facilitates the conversion of A5- to A''- ditive but not synergistic effects (data not shown). Brominated steroids. The overall effect is the inhibition of ketosteroids, glucocorticoids, and compounds such as 6a-bromoandrostenedione, 6/?-bromoan- mineralocorticoids with incomplete suppression of androgen production. Preg, drostenedione, and 16-bromoandrostenetrione were 10- to pregnenolone; Prog, progesterone; DOC, 11-deoxycorticosterone; Ã•7-OH Preg, 17-hydroxypregnenolone; 77-OH Prog, 17-hydroxyprogesterone; DHEA, dehy- 100-fold more potent than was AG. A series of nitrogen-con droepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate. taining drugs such as 17-imino-3-methoxy-3,5-androstadiene were much less potent (data not shown).

Discussion

Previous data from several investigative groups demon strated that AG inhibits adrenocortical secretion of the ketosteroids, glucocorticoids, and mineralocorticoids but incompletely blocks androgen production (7, 9, 13, 14, 17) (Chart 6). More recent observations indicate that AG also acts at 2 sites distal to the adrenal, breast cancer tissue aromatase (Site II) and the aromatase from normal extraadrenal tissues such as fat, mus cle, and liver (1, 18, 21) (Chart 7, Site III). The concentrations of AG achieved in plasma (i.e., 30 /Â¿M)appear sufficient

Androst^^^EsttenedioneoneExtraglandular

4-OH 80 ANDROSTENEDIONE

Breast Carcinoma Aromatase 40 Chart 7. Diagrammatic representation of the 3 sites of AG action. Site I, inhibition of adrenal steroidogenesis. Interruption of cortisol production neces sitates replacement with exogenous hydrocortisone. Site II, blockade of aroma tization directly in breast carcinoma tissue. Site III, inhibition of aromatization in 20 extraglandular tissues which include liver, fat, and muscle predominantly.

to block aromatase effectively at Sites II and III (12). Direct

0.01 0.1 1.0 10 100 1000 isotopie kinetic studies indicate that Site 3 is inhibited 95 to 98% by AG given in standard doses (i.e., 1000 mg daily). CONCENTRATION OF INHIBITOR ly.MI Chart 5. Comparison of aromatization inhibition produced by 4-hydroxyan Indirect in vitro studies (Chart 4) predict a similar degree of drostenedione, AG, and testololactone. Shaded area, 95% confidence limits of inhibition in the tumor itself (Site II). Thus, it is possible that the inhibition in homogenates incubated without inhibitor. Note that substrate con major effect of AG is a direct blockade of estrogen synthesis centrations and aromatase activities differ Â¡nthis experiment and in Chart 4. Consequently, absolute inhibitory concentrations cannot be compared between by the breast carcinoma itself. Comparison of tissue levels of Charts 4 and 5. estrone and estradici measured by gas liquid chromatography-

3356s CANCER RESEARCH VOL. 42

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1982 American Association for Cancer Research. Discussion mass spectrometry with plasma concentrations during AG ther of liver microsomal cortisol 6/3-hydroxylase by diphenylhydantoin or phÃ©no barbital. An explanation for the increased excretion or 6-hydroxycortisol in apy are necessary to study this question directly. humans treated with these drugs. Life Sci., 4: 1091-1098. 1965. Measurable levels of plasma estrogen persist after AG treat 6. Coombes, R. C., and T. J. Powles. Adjuvant aminoglutethimide therapy for postmenopausal patients with breast cancer: Progress Report. Cancer Res. ment in postmenopausal women. Does this observation suggest (Suppl.). 42: 3415S-3419S, 1982. that the aromatase inhibition produced by AG is not complete 7. Gower, D. B. Modifiers of steroid-hormone metabolism. A review of their in such patients? Contrary evidence from isotopie kinetic stud chemistry, biochemistry and clinical applications. J. Steroid Biochem.. 5. 501-523, 1974. ies supports the concept of nearly total (i.e., 95 to 98%) 8. Griffiths, C. T., Hall, T. C., Saba, Z., Barlow, J. J., and Nevinny, H. B. blockade of aromatization. Furthermore, estrogen levels in Preliminary trial of aminoglutethimide in breast cancer. Cancer (Phila.), 32: 31-37, 1973. postmenopausal women after surgical adrenalectomy or in 9. Hughes, S. W. M.,and Burley, D. M. Aminoglutethimide. A "side-effect" women after both oophorectomy and adrenalectomy are similar turned to therapeutic advantage. Postgrad. Med. J., 46. 409-416, 1970. to those found in women receiving AG (25). These additional 10. Kowal, J. Adrenal cells in tissue culture. IV. Use of an inhibitor of steroid data also suggest that AG completely blocks endogenous synthesis for the study of ACTH action. Endocrinology, 85. 270-279, 1969. 11. MacDonald, P. C., Rombaut, R. O.. and Siiteri, P. K. Plasma precursor of estrogen production. It is possible that the residual estrogens estrogen. I. Extent of conversion of plasma A4-androstenedione to estrone found after surgical ablative therapy or AG reflect dietary in normal male and nonpregnant, normal, castrate and adrenalectomized estrogens or precursor hormones. Further studies using syn females. J. Clin. Endocrinol., 27. 1103-1111, 1967. 12. Murray, F. T., Santner, S.. Samojlik, E. A., and Santen, R. J. Serum thetic diets and also more potent aromatase inhibitors such as aminoglutethimide levels: studies of serum half-life, clearance and patient 4-hydroxyandrostenedione are required to identify the mech compliance. J. Clin. Pharmacol.. 19: 704-711, 1979. 13. Newsome, H. H., Jr., Brown. P. W.. Terz, J. J., and Lawrence. W., Jr. anisms for residual estrogen production. Medical adrenalectomy and plasma steroids in advanced breast carcinoma. Our pharmacological studies demonstrated that AG exerts a Surgery (St. Louis), 83. 83-89, 1978. 14. Philbert, M., Laudaut, M. H., and Bricaire, L. H. Etude clinique et biologique wide range of metabolic effects in patients. These include d'un inhibiteur de l'hormonosynthese corticosurrenale: l'-aminoglutethimide. alteration of its own and of dexamethasone metabolism (Table Ann. Endocrinol., 29. 189-209. 1966. 1), blockade of thyroxine synthesis (19), and the facilitation of 15. RÃ©Ã©d.K.,and Ohno, S. Kinetic properties of human placental aromatase. J. the 3/?-ol-dehydrogenase, A4-A5-isomerase pathway (16), Biol. Chem., 25). 1625-1631, 1976. 16. Samojlik, E., and Santen, R. J. Adrenal suppression with aminoglutethimide. among others. Studies by other investigators showed that the III. Comparison of plasma A4 and u5-steroids in postmenopausal women genetically controlled acetylator function, which controls rate treated for breast carcinoma. J. Clin. Endocrinol. Metab., 47: 717-724, of metabolism of a number of drugs, may influence the phar 1978. 17. Samojlik, E., Santen, R. J., and Wells, S. A. Adrenal suppression with macological effects of AG in individual patients (6). These aminoglutethimide. II. Differential effect on plasma androstenedione and considerations must be taken into account when using AG estrogen levels. J. Clin. Endocrinol. Metab., 45. 480, 1977. 18. Santen, R. J., Santner. S., Davis, B. Veldhuis, J., Samojlik, E.. and Ruby, E. clinically. Aminoglutethimide inhibits extraglandular estrogen production in postmen opausal women with breast carcinoma. J. Clin. Endocrinol. Metab., 47: 1257-1265, 1978. Acknowledgments 19. Santen, R. J., Wells, S. A., Conn, N., Demers, L. M., Misbin, R. I., and Foltz, E. L. Compensatory increase in TSH secretion without effect on prolactin The authors wish to thank Matilda Stover for her assistance in the studies of secretion in patients treated with aminoglutethimide. J. Clin. Endocrinol. MCRs. Marlene Thompson provided excellent secretarial assistance in the prep Metab., 45. 739-746, 1977. aration of this manuscript. 20. Tait, J. F., and Burnstein, S. In vivo studies of steroid dynamics in man. In: G. Pincus, K. V. Thinmann, and E. B. Astwood (eds.), The Hormones, pp. 441-519. New York: Academic Press. Inc., 1964. References 21. Thompson. E. A., Jr., and Siiteri, P. K. Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental micro- 1. Abul-Hajj, Y. Significance of estrogen synthesis in human mammary tumors. somes during aromatization of androstenedione. J. Biol. Chem., 249: 5364- Cancer Res. (Suppl.), 42: 3373s-3377s, 1982. 5372, 1974. 2. Brooks, S. M., Werk, E. E., Jr., Ackerman, S. J., Sulivan, I., and Thrasher, 22. Thompson, E. A., Jr., and Siiteri, P. K. The involvement of human placental K. Adverse effects of phÃ©nobarbital on corticosteroid metabolism in patients microsomal cytochrome P-450 in aromatization. J. Biol. Chem., 249: 5373- with bronchial asthma. N. Engl. J. Med., 286: 1125-1128, 1972. 5378, 1974. 3. Cash, R., Brough, A. J., Cohen, M. N. P., and Satoh, P. S. Aminoglutethimide 23. Touitou, Y., Bogdan, A.. Legrand, J. C., and Desgrez, P. Aminoglutethimide (Elipten-CIBA) as an inhibitor of adrenal steroidogenesis. Mechanism of and glutethimide: Effects on 18-hydroxycorticosterone biosynthesis by hu action and therapeutic trial. J. Clin. Endocrinol. Metab., 27: 1239-1248, man and sheep adrenals in vitro. Acta Endocrinol., 80: 517-526, 1975. 1967. 24. Weisz, J. In vitro assays of aromatase and their role in studies of estrogen 4. Cohen, M. P., and Foa, P. P. Aminoglutethimide inhibition of adrenal deso formation in target tissues. Cancer Res., (Suppl.) 42. 3295s-3298s, 1982. lase activity. Proc. Soc. Exp. Biol. Med., 727. 1086-1090, 1969. 25. Worgul, T. J. Residual estrogen secretion following surgical endocrine 5. Conney, A. N., Jacobson, M., Scheidman, K., and Kuntzman, R. Induction ablation. J. CMn. Endocrinol. Metab. 48: E147, 1978 (abstract).

Discussion that we can adequately study the additive situation. We have demon strated so many drug-drug interactions between aminoglutethimide and Dr. Segaloff: I would like to make one point about Dr. Santen's last glucocorticoids that it boggles the mind to think of the possibilities of comment. Since we are talking about eventually treating breast cancer, drug-drug interactions between Teslac and aminoglutethimide. But it if we're getting an additive effect which is a great deal more inhibition remains an interesting question. of aromatization, and this is really what is effective in breast cancer, Dr. Nattolin: It perhaps adds a different dimension if I talk to you you have made a "10-strike." It doesn't have to be synergistic. about ovarian cancer. Ovarian cancers are the most frequent cause of Dr. Santen: This hinges on how well we can determine the degree of death from genital cancer in women, and for some years Drs. Schwartz inhibition of estrogen production. My own feeling is that aminogluteth and Eisenfeldt in our department have been looking at receptor binding. imide and probably testololactone both inhibit aromatization effectively Essentially, half of all ovarian cancers have estrogen and now progestin as measured by isotopie kinetic studies. Our problem is the ability to receptors, often in a level that is found in breast cancers. They started measure very low levels of estrogen in patients that are being treated. a series of patients on tamoxifen, and the drug extended disease-free I think we need to develop better methods of assessing the level of intervals but has not produced cures. Recently, a medical student in production of estrogen during administration of these compounds so our laboratory, Ron Voidess, began to look at aromatization and to

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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1982 American Association for Cancer Research. In Vivo and in Vitro Pharmacological Studies of Aminoglutethimide as an Aromatase Inhibitor

R. J. Santen, S. J. Santner, N. Tilsen-Mallett, et al.

Cancer Res 1982;42:3353s-3357s.

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