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Lack of Evidence for Aromatase in Human Prostatic Tissues: Effects of 4-Hydroxyandrostenedione and Other Inhibitors on Androgen Metabolism1

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Lack of Evidence for Aromatase in Human Prostatic Tissues: Effects of 4-Hydroxyandrostenedione and Other Inhibitors on Androgen Metabolism1 (CANCER RESEARCH 49. 6551-6555. December I, 1989] Lack of Evidence for Aromatase in Human Prostatic Tissues: Effects of 4-Hydroxyandrostenedione and Other Inhibitors on Androgen Metabolism1 A. M. H. Brodie,2 C. Son, D. A. King, K. M. Meyer, and S. E. Inkster Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, Maryland 21201 ABSTRACT enzyme in vitro (7). Our studies in rats treated with 4-OHA demonstrated reduction in ovarian vein estradiol concentrations The effects of 4-hydroxyandrostenedione (4-OHA) and other aroma- tase inhibitors, 10-propargylestr-4-ene-3,17-dione and imidazo|l,5-a|- and inhibition of ovarian aromatase, concomitant with regres sion of carcinogen (dimethylbenzanthracene)-induced mam 3,4,5,6-tetrahydropyrin-6-yl-(4-benzonitrile), as well as 5a-reductase in hibitors /V./V-diethyW-methyl-S-oxo^-aza-Sa-androstane-n/J-carboxy- mary tumors (8). We have also shown that 4-OHA treatment amide and 4-methyl-3-oxo-4-aza-androsta-5-ene-17-ol were investigated inhibits peripheral aromatization in male Rhesus monkeys (9). in prostatic tissue from six patients with benign prostatic hypertrophy This compound is now being evaluated for the treatment of and seven patients with prostatic cancer, and from normal men at autopsy. breast cancer. Plasma estradiol and estrone levels were found We attempted to measure aromatase activity in the tissue incubations by to be significantly reduced in postmenopausal patients with quantitating 'IM) released from androstenedione or testosterone labeled advanced disease treated with 4-OHA. Partial or complete at the C-l position. High performance liquid Chromatograph} and thin tumor regression occurred in 30% of 4-OHA-treated patients layer chromatography were used to isolate steroid products. Although (10, 11). Recently, a small group of men with prostatic cancer the amount of 3H2Oreleased was at least twice that of the heat-inactivated have been treated with 4-OHA. A subjective response to treat tissue samples, no estrone or estradiol was detected on high performance liquid chromatography. The 'I !..() release was significantly inhibited by ment was observed in a high proportion of these patients (12). 4-OHA and jV,/V-diethyl-4-metnyl-3-oxo-4-aza-5a-androstane-17/3-car- It is therefore of interest to determine whether aromatase is boxyamide, but not by the other aromatase inhibitors. 4-OHA also present in prostatic tissue and/or whether 4-OHA has an effect inhibited 5or-reductase in both benign prostatic hypertrophy and cancer on androgen metabolism in primary carcinoma tissue, as well tissue, although to a lesser extent than A'tA'-diethyl-4-methyl-3-oxo-4- as in BPH, which might be associated with the response. aza-5a-androstane-17/3-carboxyamide. The other aromatase inhibitors In this study, we attempted to use the 3H2O assay as an were without effect on 5a-reductase. Our results indicate that 'IM) indirect assessment of estrogen production. This method de released from [l/3-'H]androstenedione and [l,2,6,7-3H]androstenedione pends upon the loss of hydrogen atoms at the C-l/3 and C-2ß does not correlate with estrogen formation and may be the result of other positions of the androgen substrate during aromatization (13). metabolic reactions. Although it appears that the prostate lacks aroma Thus, when substrates are labeled with tritium at these posi tase, 4-OHA may be of benefit in patients with benign prostatic hyper tions, 3H2O is formed equivalent to each mole of estrogen trophy or prostatic cancer by inhibiting this enzyme in peripheral tissue. produced. The method has been widely used by ourselves and others to measure aromatization in the human placenta and rat ovary (8). We have also employed the product isolation proce INTRODUCTION dure to quantitate estrogens directly, as well as to identify other products of androgen metabolism. We found that the two DHT3 is of primary importance in the growth of normal and methods do not provide equivalent results of estrogen produc pathological prostatic tissue (1,2). Although estrogen has been tion in the prostate. shown to be involved in controlling androgen biosynthesis in the testis, the importance of this hormone in the prostate, to either regulate steroid biosynthesis or to affect growth, is un MATERIALS AND METHODS clear. However, estrogen receptors have been identified (3, 4) Chemicals. [l,2,6,7-3H]Androstenedione (92.7 Ci/mmol), [l/3-3H]an- and greater than normal levels of estradiol have been detected drostenedione (27.8 Ci/mmol), [7-3H]testosterone, -androstenedione, in stroma of BPH (5), which suggests that estrogens may have -estradiol, and -estrone (24.5 Ci/mmol), [4-uC]estrone, -estradiol, a role in this disease. -testosterone, -dihydrotestosterone (57 Ci/mmol), and -androstenedi During the past few years, we have been developing selective one (59 Ci/mmol) were obtained from NEN Research Products (Du inhibitors of aromatase (estrogen synthetase) (6). If estrogen pont) (Boston, MA). The distribution of tritium labeling on [1,2,6,7- does mediate growth of prostatic tissue, these inhibitors might 3H]androstenedione was: la, 19.9%; 1/3,6.7%; 2a + 6a, 32.4%; Iß+ be of value in treating diseases of the prostate, such as BPH 6/3, 13.1%; la, 21.2%; and 7/3, 6.7%; and on [l/J-3H]androstenedione and cancer. We have determined that 4-OHA is a potent was: 1«,24%; and 1/3, 76%. The scintillation fluid used was 3a70B competitive inhibitor which also causes inactivation of the from Research Products Inc. (Mt. Prospect, IL). Organic solvents were HPLC grade from J. T. Baker. Ether (USP) was purchased from Received 3/27/89; revised 8/7/89; accepted 8/14/89. Mallinkrodt. Unlabeled steroids, glucose-6-phosphate. glucose-6-phos- The costs of publication of this article were defrayed in part by the payment phate dehydrogenase, and NADPH were purchased from Sigma Chem of page charges. This article must therefore be hereby marked advertisement in ical Co. (St. Louis, MO). accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by N1H grant CA-27440. Presented in part at the 8th International Inhibitors. Preparation of 4-OHA was carried out as previously Congress of Endocrinology. Kyoto. Japan, 1988, and the American Association described (8). Another steroidal aromatase inhibitor, PED (14), was for Cancer Research, New Orleans. Louisiana, 1988. 2To whom requests for reprints should be addressed, at Department of kindly provided by Dr. J. O. Johnston (Merrell Research Labs., Cincin Pharmacology and Experimental Therapeutics. School of Medicine, University nati, OH). The nonsteroidal aromatase inhibitor CGS 16949A (15) was of Maryland, 655 W. Baltimore St.. Baltimore. MD 21201. donated by Ciba-Geigy Research Laboratory (Summit, NJ). The 5a- 3The abbreviations used are: DHT, dihydrolestosterone; 4-OHA, 4-hydroxy- reductase inhibitors 4-MA (16) and L659110 were gifts from Dr. G. androstene-3,17-dione; BPH. benign prostatic hypertrophy; HPLC, high perform Rasmusson (Merck, Sharp and Dohme Research Laboratories, Rah- ance liquid chromatography; PED. 10-propargylestr-4-ene-3,17-one;4-MA, jV,/V- diethyl-4-methyl-3-oxo-4-aza-5«-androstane-17fi-carboxyamide; TLC, thin layer way, NJ). Progesterone was also used to inhibit 5a-reductase in some chromatography: CGS 16949A, imidazo[1.5-«]3.4.5.6-tetrahydropyrm-6-yi-(4- experiments. benzonitrile); L659110. 4-methyl-3-oxo-4-aza-androsta-5-ene-17-ol. Tissues. BPH and primary prostatic carcinoma tissues were obtained 6551 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1989 American Association for Cancer Research. AROMATASE AND 5<r-REDUCTASE INHIBITOR STUDIES IN THE PROSTATE by iransurcthral prostatectomy or by bilateral dissection and radical T 2000 rctropubic prostatectomy, in the case of some cancers. Normal prostate and testis were obtained from the Immediate Autopsy Service of the Pathology Department. Tissues were immediately frozen at -70°C ••1500 until analysis. BPH or carcinoma tissue was homogenized (60 mg/ml) in 0.1 M phosphate buffer (pH 7.4) at 4°C.Each incubation was carried s out in duplicate, or in some cases triplicate, and contained 30 mg O homogenate, or heat-inactivated homogenate from the same tissue o S sample with or without inhibitor compound (5 ^M) and tritium-labeled -•500 E substrate, in I ml phosphate buffer. For the 'H2O assay, incubations were carried out with 200,000 dpm or 2 x 10* dpm [l-'Hjandrostene- dione. To increase the level of detection of estradiol and estrone, greater amounts of activity were used when both 'H2O and estrogen product 10 15 20 30 35 40 isolation assays were performed, at least 10 pCi of [l,2,6,7-'H]andro- FRACTION TIME (minutes) stenedione and [T-'HItcstosterone, as indicated in the appropriate tables Fig. I. HPLC elution profile of steroid metabolism by prostatic cancer tissue and figures. The reaction was started by the addition of the cofactor incubated with 16.55 >jCi[1.2.6,7-3H]androstenedione.[4-MC|steroids( (were solution (0.5 mg NADPH, 2 mg glucose-6-phosphate, and 2.5 ID added to the incubates to serve as markers for estradiol (E2), estrone (A-i), glucose-6-phosphate dchydrogcnase per ml) and was terminated after testosterone (7"). androstenedione (A), and DHT. The major peaks of tritium 2 h at 37°Cbythe addition of 4 ml organic solvent. Unlabeled steroids. activity ( ) were identified as 5iï-androstane-3a,17^-diol (28 ml). 5«-andros- 2-4 ng each, and 4-l4C-labclcd steroids (3000 dpm), androstenedione, tanedionc (.11 ml), and 5<i-androstan-3«-oI-17-onc(35 ml). testosterone, estrone, estradiol, and DHT, were added to each sample.
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