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Effects of Aminoglutethimide on A5-Androstenediol Metabolism in Postmenopausal Women with Breast Cancer1

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Effects of Aminoglutethimide on A5-Androstenediol Metabolism in Postmenopausal Women with Breast Cancer1 [CANCER RESEARCH 42, 4797-4800, November 1982] 0008-5472/82/0042-0000802.00 Effects of Aminoglutethimide on A5-Androstenediol Metabolism in Postmenopausal Women with Breast Cancer1 Charles E. Bird,2 Valerie Masters, Ernest E. Sterns, and Albert F. Clark Departments of Medicine [C. E. B., V. M.], Surgery [E. E. S.J, and Biochemistry [A. F. C.], Queen s University and Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7 ABSTRACT women. More recently, we (8) and others (18) reported that the production of A5-androstene-3/8,17/8-diol in normal post- A5-Androstene-3/8,1 7/S-diol has potential estrogenic activity menopausal women is approximately 500 to 700 fig/24 hr. because it is known to bind to receptors and translocate to the AG, in combination with hydrocortisone, has been utilized to nucleus of certain estrogen target tissues. Its role in the biology inhibit estrogen production in patients with breast cancer (21 ). of breast cancer is unclear. Aminoglutethimide plus hydrocor This form of therapy has been termed "medical adrenalec tisone ("medical adrenalectomy") has been used to treat post- tomy," and studies suggest that it is as effective as surgical menopausal women with metastatic breast cancer. adrenalectomy. The hydrocortisone shuts off the basal adre- We studied A5-androstene-3/3,17/?-diol metabolism in post- nocortical production of estrogen precursors; AG not only menopausal women with breast cancer before and during slows down steroid biosynthesis at an early step but also aminoglutethimide-plus-hydrocortisone therapy, utilizing the specifically inhibits the aromatization of A4-androstenedione to constant infusion technique. The metabolic clearance rate for estrone (22). Studies of the effects of AG on the levels of five subjects was 799 ±89 liters/24 hr (470 ±57 liters/24 plasma steroids in women with breast cancer suggested that it hr/sq m) before and 751 ±93 liters/24 hr (444 ±57 liters/ may increase the rate of conversion of 3/8-hydroxy-A5-steroids 24 hr/sq m) during therapy. Plasma A5-androstene-3/S,17/8- to A4-3-ketosteroids (19). Hence, AG could accelerate the diol and A5-androstene-3/8,17/S-diol free index decreased de metabolism of a steroid such as A5-androstene-3/3,17yS-diol, spite absence of change in the metabolic clearance rate. which would remove a potential estrogenic compound from the Increased dehydroepiandrosterone/A5-androstene-3/8,17/S- circulation. This paper reports on the effects of AG-plus-hydro- diol conversion ratios in individual patients suggested an in cortisone therapy on the kinetics of A5-androstene-3/S,17/8-diol crease in 17/6-hydroxysteroid dehydrogenase activity during metabolism. therapy. There were no alterations in the formation of the estrogen precursors testosterone and A4-androstene-3,17- MATERIALS AND METHODS dione. Subjects. Five women (48 to 68 years old) with histologically proven INTRODUCTION breast cancer were studied. All were at least 4 years postmenopausal or 4 years postoophorectomy. Clinical details are given in Table 1. All While A5-androstene-3/?,17/8-diol is of potential importance were fully informed volunteers who had signed a consent form approved as an intermediate in testicular testosterone biosynthesis (24), by an ethics review committee. it itself does not have significant androgenic activity (11 ). The patients were studied prior to AG therapy. They were restudied Recently, it was shown that A5-androstene-3/8,17/8-diol can 7 to 11 weeks after starting therapy, which included AG (250 mg p.o. every 6 hr) and hydrocortisone (10 mg at 8 a.m., 10 mg at 4 p.m., and combine with estrogen receptors and translocate them to the 20 mg at bedtime each day). nuclei in rat uteri (2), dimethylbenzanthracene-induced mam Materials. [7-3H]-A5-Androstene-3/3,17/8-diol (58.6 Ci/mmol), [4- mary tumors (17), and MCF-7 mammary tumor cells (15). In 14C]DHEA (58.8 mCi/mmol), [4-14C>A4-androstene-3,17-dione (55.8 the latter system, it induces the synthesis of progesterone mCi/mmol), [4-'"C]testosterone (57.5 mCi/mmol), and [4-'"C]-5a-an- receptors, a marker of estrogen actions (15). A5-Androstene- drostan-17/?-ol-3-one (57.5 mCi/mmol) were obtained from New Eng 3/8,17/S-diol is found in the nuclei of human mammary tumor land Nuclear Corp. (Dorval, Quebec, Canada). [4-'4C]-A5-Androstene- cells (3). Hence, A5-androstene-3/S,17/8-diol can be considered 3/3,17/S-diol was prepared from [4-'"C]DHEA by reduction with NaBH4 as described previously (23) for the reduction of androstanedione. [4- an estrogen; the significance of these observations in the 14C]ANDRO was prepared from [4-14C]androstanedione using prostatic biology of human breast cancer remains to be determined. A5-Androstene-3/8,17/S-diol is partially derived from circulat cytosol as the source of 3a-hydroxysteroid dehydrogenase as de scribed previously (16); the [4-14C]-androstanedione was prepared ing DHEA3 and its sulfate in women (14). We (7) and others from 5o-androstan-17/8-ol-3-one with chromic oxide (23). The [4-14C> (14) previously reported on the kinetics of metabolism and A5-androstene-3/5,17/3-diol and [4-14C]ANDRO were purified by thin- production of A5-androstene-3/S,17/8-diol in normal young layer and paper chromatography, using systems to be described in the sections outlining the steroid isolations from plasma. All labeled ste 1This research supported by grants from Ontario Cancer Treatment and roids were at least 97% pure as determined chromatographically. Research Foundation (308, Clare Nelson Bequest to Kingston General Hospital) and the Medical Research Council of Canada (MT-1852 and MT-2338). Antisera for the radioimmunoassays were obtained from the following 2 To whom requests for reprints should be addressed. sources: DHEAS (5-1402#7) from Dr. G. Abraham, Torrance, Calif., 3 The abbreviations and trivial names used are: DHEA, dehydroepiandroster- and A5-androstene-3/8,17/6-diol, as a gift, from Dr. K. Roberts, Maison- one (A5-androsten-3/3-ol-17-one); AG, aminoglutethimide; androstanedione, 5a- neuve Hospital, Montreal, Quebec, Canada. androstane-3,17-dione; ANDRÃ’, androsterone (5a-androstan-3a-ol-17-one); All solvents were distilled prior to use. Nonradioactive steroids were DHEAS, dehydroepiandrosterone sulfate; MCR, metabolic clearance rate; FI, free index. obtained from Sigma Chemical Co. (St. Louis, Mo.) and Steraloids Received March 2, 1982; accepted July 15, 1982. (Wilton, N. H.). NOVEMBER 1982 4797 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1982 American Association for Cancer Research. C. E. Bird et al. Table 1 Clinical details on patients Age at Disease- Age at Duration surgery Pathological diag- free in- study of ther- Location of Subject (yr) nosis terval (yr) (yr) Ht (cm) Wt (kg) apy (wk) tumor Response to therapy Previous therapy 1 46 Adenocarcinoma 3.5 53 157 58 50 Bone Stable. Bilateral oophorectomy at Liver Improved. age 49 yr. Chest wall Progressed. Choroid Complete remission. 63 Infiltrating ductal 2 68 164 78 48 Bone No change. Estrogen therapy for 1 (0/4 nodes) Lung Partial clearance on X- year, age 65-66 yr. ray. 59 Infiltrating ductal 4.5 66 157 83 84 Bone 50% reduction in le Estrogen therapy for 1 yr sions. 14 mos., age 64-65 yr. 42 Infiltrating ductal 2 48 160 64 34 Skin Almost complete clear Bilateral oophorectomy at (4/4 nodes) ing of lesion. age 44 yr. 38 Infiltrating adeno- 8.5 48 166 57 32 Bone No change. Bilateral oophorectomy at carcinoma(0/9 age 38 yr. nodes) Methods. Studies were performed with the constant-infusion tech the columns; A5-androstene-3/},17/8-diol was eluted with 40% ethyl nique as described earlier by our laboratory for 5a-androstane-3a,17/8- acetate in ¡sooctane. DHEAS concentrations (used to monitor effec diol in normal young subjects (4). The patients were studied at 8 a.m., tiveness of therapy at inhibiting C,9-steroid production) were measured after an overnight fast. Prior to initiation of the constant-infusion pro on diluted plasma by the radioimmunoassay procedure of Buster and cedure, the patient was recumbent for at least 30 min, and blood was Abraham (9). taken for control plasma hormone assays. Thirty min following a priming The percentage of A5-androstene-3/8,17/?-diol not bound to plasma dose of 6 /iCi [7-3H]-A5-androstene-3/î,17/3-diol, a constant infusion of proteins was measured using our (10) slight modification of the equilib 12 /¿Ci[7-3H]-A5-androstene-3/8,17/8-diol was begun. It was continued rium dialysis method of Forest era/. (12). The A5-androstene-3/?,17/3- for 100 min. Blood was drawn from the opposite arm into chilled diol FI is the product of the plasma concentration of the hormone and heparinized tubes at 70, 90, 110, and 130 min from the time of the percentage unbound. administration of the priming dose. Total steroid administered was Statistical Analysis. Where appropriate, the means of results for different groups were tested for significant differences by Student's f approximately 100 ng. The plasma samples obtained from the above blood samples were analyzed for unconjugated labeled steroids, using test. procedures similar to those described previously (7) for other Ci9- steroids. We looked for [3H]-A5-androstene-3/?,17/8-dione, [3H]DHEA, RESULTS [3H>A"-androstene-3,17-diol, [3H]testosterone and [3H]ANDRO, using the corresponding 14C-steroids to monitor losses. The thin-layer chro- As indicated in "Materials and Methods," 5 postmenopausal matography system was chloroform/methanol (98/2), and the paper women with proven breast cancer and clinical evidence of chromatography system was the Bush B3 solvent mixture [haptane: metastatic disease were studied prior to and during AG-plus- benzene:methanol:water; (33:17:40:10)].
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