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Binding Characteristics of a Major Protein in Rat Ventral Prostate Cytosol That Interacts with Estramustine, a Nitrogen Mustard Derivative of 17ß-Estradiol

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Binding Characteristics of a Major Protein in Rat Ventral Prostate Cytosol That Interacts with Estramustine, a Nitrogen Mustard Derivative of 17ß-Estradiol [CANCER RESEARCH 39, 5155-5164, December 1979] 0008-5472/79/0039-OOOOS02.00 Binding Characteristics of a Major Protein in Rat Ventral Prostate Cytosol That Interacts with Estramustine, a Nitrogen Mustard Derivative of 17ß-Estradiol BjörnForsgren, Jan-Àke Gustafsson, Ake Pousette, and Bertil Hogberg AB Leo Research Laboratories. Pack. S-251 00 Helsingborg, Sweden [B.F.. B.H.], and Departments of Chemistry and Medical Nutrition. ¡J-ÄG.. A P.¡and Pharmacology [BH.], Karolinska Institute!. S-104 01 Stockholm 60. Sweden ABSTRACT causes atrophy of the testes and accessory sex organs; re duces the uptake of zinc by the prostate; depresses the 5a- The tissue distribution of [3H]estramustine, the dephospho- reductase, arginase, and acid phosphatase activities in the rylated metabolite of estramustine phosphate (Estracyt), in the male rat was compared to that of [3H]estradiol 30 min and 2 hr prostate; and affects lipid and carbohydrate metabolism (10, 11, 20, 29, 31 -33, 42). Although the observed effects in many following i.p. administration. In contrast to estradiol, estramus respects are similar to estrogenic effects, several experimental tine was found to be efficiently concentrated in the ventral and clinical results indicate that estramustine phosphate affects prostate gland by a soluble protein. The binding characteristics normal and neoplastic prostate tissue in a way that cannot be of this protein were studied in vitro using cytosol preparations attributed solely to its antigonadotropic or weak estrogenic of the gland. With a dextran-coated charcoal technique, the properties (15, 16, 30, 38). protein was found to bind estramustine with a broad pH opti Plym Forshell and Nilsson (35), using labeled compounds (1 mum between pH 7 and pH 8.5, with an apparent Kd of 10 to to 10 mg/kg body weight), found considerably higher levels of 30 nw, and with a binding capacity of about 5 nmol/mg cytosol radioactivity in the rat ventral prostate following i.v. administra protein. The estramustine/protein complex was not retained tion of estramustine phosphate than after administration of by DNA-cellulose. None of the natural steroids tested inhibited the binding of 10 nw [3H]estramustine by more than 35% estradiol phosphate or estradiol. The main metabolite of estra mustine phosphate in the ventral prostate was identified as its (progesterone), even when added in 4500-fold excess. The dephosphorylated congener estramustine. Estramustine was presence of a nitrogen mustard moiety at position 3 of the also the main metabolite in peripheral human blood after i.v. or steroid was necessary for high-affinity binding to the protein. P.O. (single dose) administration of estramustine phosphate The protein was calculated to constitute about 20% of the total (34). cytosol protein content. Using estramustine of high specific radioactivity, Forsgren and Hogberg (8) and Hpisaeter (17) have shown the presence INTRODUCTION of a macromolecule in the cytosol from the rat ventral prostate that binds estramustine. This macromolecule has a molecular Estramustine phosphate [Estracyt; 1,3,5(10)-estratriene- weight of 40,000 to 50,000, a Stokes' radius of 2.9 nm, a 3,17/?-diol-3-A/-bis(2-chloroethyl)carbamate 17/?-dihydrogen frictional ratio of 1.2, a sedimentation coefficient of 3.5 to 4S, phosphate (NSC 89199)] was introduced in 1966 as a thera and an isoelectric point of 5 (9). peutic agent in the treatment of prostatic carcinoma. It has Since this macromolecule appeared to occur in substantial been used mainly in patients with advanced carcinoma of the quantities in the rat ventral prostate, it was conceivable that it prostate who do not respond to conventional endocrine ther might play an important role in the tissue localization of estra apy. Clinical experience shows that objective and/or subjective mustine and in the mechanism of action of estramustine phos remissions are obtained in 20 to 50% of these cases, including phate in prostatic tissue. We have therefore investigated the regression of original tumor and soft tissue and skeletal métas binding kinetics and ligand specificity of this macromolecule tases, as well as relief of pain (for references, see Ref. 18). as well as estramustine uptake in different organs. The mechanism of action of estramustine phosphate is com plex. Studies in humans and animals have shown that the drug decreases testosterone1 and gonadotropin levels in serum; MATERIALS AND METHODS 1The abbreviations and trivial names used are: testosterone, 17/i-hydroxy-4- Chemicals androsten-3-one; estradiol, 17/i-estradiol; dihydrotestosterone, 17/i-hydroxy-5a- androstan-3-one; dihydroepiandrosterone, 3/i-hydroxy-5-androsten-1 7-one; an- The radioactive compounds used were [3H]estramustine drostanediol, Su-androstane-3/J. 17/i-diol; ethynylestradiol. 17o-ethynyl- ([2,4,6,7-3H]estradiol, 3-A/-bis(2-chloroethyl)carbamate; 80 to 1.3.5(10)-estratriene-3,17/j-diol; BSA. bovine serum albumin; TLC, thin-layer 107 Ci/mmol), [3H]estradiol ([2,4,6,7-3H]estradiol; 91.3 Ci/ chromatography; TEK(01)DG, 0.01 M Tris-HCI/0.001 M EDTA/0.25 mM dithio- threitol/10% (v/v) glycerol/0.01 M KCI; TEK(15)DG, 0.01 M Tris-HCI/0.001 M mmol), and [3H]dihydrotestosterone ([1,2,4,5,6,7-3H]dihydro- EDTA/0.25 mM dithiothreitol/10% (v/v) glycerol/0.15 M KCI; TEK(40)DG, 0.01 testosterone; 80 Ci/mmol). [3H]Estramustine was synthesized M Tris-HCI/0.001 M EDTA/0.25 mM dithiothreitol/10% (v/v) glycerol/0.40 M at AB Leo, and [3H]estradiol and [3H]dihydrotestosterone were KCI; DCC, dextran-coated charcoal; androstenediol, 5-androstene-3/i,1 7/i-diol; pregnenolone, 3/J-hydroxy-5-pregnen-20-one; androstenedione. 4-androstene- obtained from New England Nuclear Chemicals GmbH, Dreiei- 3,17-dione; 19-nortestosterone, 17/3-hydroxy-19-nor-4-androsten-3-one; dexa- methasone, 9«-fluoro-1iß.17o,21 -trihydroxy-lou-methyl-l ,4-pregnadiene- chenhain, West Germany. The compounds were routinely pu 3,20-dione; diethylstilbestrol.3,4-bis(p-hydroxyphenyl)-3-hexene. rified before use to at least 99% purity by chromatography on Received March 8. 1979; accepted September 10, 1979. Sephadex LH-20 using the solvent systems toluene/methanol DECEMBER 1979 5155 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1979 American Association for Cancer Research. B. Forsgren et a!. (85/1 5, v/v) for estramustine and estmadiol and toluene/meth 55 sec for cooling. The homogenate was centrifuged for 1 hr anol (90/1 0, v/v) for dihydrotestostemone. at 105,000 x g (Beckman L2-65B on L5-65 ultracentnifuge In addition to estramustine phosphate (LS 299) and estra with an SW 56 or SW 27 rotor; Beckman Instruments, Inc., mustine (LS 275), the following unlabeled nitrogen mustard Palo Alto, Calif.). The cytosol (supennatant) was freed from the steroid derivatives synthesized at AB Leo were used: estrone, floating lipid layer and, when not used immediately, stored in 3-N-bis(2-chloroethyl)carbamate (LS 271); estradiol, 17$-ace 0.5-mI portions at —30°.Allpreparation steps were carried out tate, 3-N-bis(2-chloroethyl)cambamate (LS 289); estradiol, 17$- at 0—4°.Theprotein concentration of the cytosol preparations, N-bis(2-chloroethyl)carbamate (LS 298); estradiol, 3-N-bis(2- determined according to the method of Lowry et a!. (24) using chloroethyl)cambamate, 17$-propionate (LS 358); androster BSA as a standard, was in the range of 10 to 30 mg/mI. For one, 3a-N-bis(2-chlomoethyl)cambamate(LS 451 ); dehydroepi the in vitro studies, the cytosol was diluted with a suitable androstemone,3$-N-bis(2-chloroethyl)carbamate (LS 452); es volume of TEK(O1)DG buffer. tradiol, 3,1 7$-bis[N-bis(2-chlomoethyl)carbamate](LS 453); es tmadiol,3-N-bis(2-chlomoethyl)cambamate,17$-tnimethyl acetate Scintillation Counting (LS 470); androstenediol, 3$-N-bis(2-chloroethyl)carbamate (LS 524); dihydrotestostemone, 17$-N- bis(2 - chlomoethyl) Scintillation counting was performed using a Packard Tn cambamate(LS 543); ethynylestradiol, 3-N-bis(2-chloroethyl)- CambModel 2650 liquid scintillation spectrometer on a Philips cambamate(LS 675); estniol, 3-N-bis(2-chloroethyl)cambamate PW 4510/00 liquid scintillation analyzer (N.y. Philips' Gloei (LS 161 1); estniol, 16a-acetate, 3-N-bis(2-chloroethyl)carba lampen-fabnieken, Eindhoven, The Netherlands). Both instru mate (LS 2035); and 17a-estmadiol, 3-N-bis(2-chloroethyl)- ments were equipped with an external standard for calculation cambamate(LS 2179). of dpm. Soluene-treated samples, however, were analyzed The estrogen sulfates used were synthesized at AB Leo, using the internal standard procedure, involving recounting of while estrogen glucumonidesand other unlabeled steroids were the samples following addition of tnitiated toluene. obtained from Sigma Chemical Co., St. Louis, Mo., as were Tris, dithiothmeitol, dithioerythnitol, charcoal (Nomit A), BSA, Calculations various proteases, RNase A, DNase I, and calf thymus DNA All calculations and curve constructions except for those in (type I, sodium salt). Cellulose (Cellex 410) was purchased Chart 7 were made by means of a Hewlett-Packard 9820A from BioRad Laboratories, Richmond, Calif., and purified ac calculator equipped with a Model 9862A calculator plotter cording to the method of Alberts and Hemnick(1) before use. (Hewlett-Packard Calculator Products Division, Loveland, Gelatin was bought from Difco Laboratories, Inc., Detroit, Mich. Cob.). EDTA and precoated aluminum sheets (aluminum oxide 60 F254,neutral, type E) for TLC were purchased from E. Merck In Vivo Studies AG, Dammstadt, West Germany. Chemicals were of analytical grade quality from E. Merck AG and BDH Chemicals Ltd., Distribution Studies. Two experiments were performed, one Poole, England. Sephadex LH-20, Sephadex G-25 Medium, with [3H]estmamustineand the other with [3H]estradiol.
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