Antitumoral and Endocrine Effects of (+)-Vorozole in Rats Bearing Dimethylbenzanthracene-Induced Mammary Tumors Roland De Coster,1 Robert F

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[CANCER RESEARCH 52, 1240-1244, March 1, 1992] Antitumoral and Endocrine Effects of (+)-Vorozole in Rats Bearing Dimethylbenzanthracene-induced Mammary Tumors Roland De Coster,1 Robert F. Van Ginckel, Myriam J. L. Gallons, Nick K. G. Goeminne, and Boudewijn L. E. Janssens Department of Endocrinology and Oncology, Janssen Research Foundation, B-2340 Beerse, Belgium

ABSTRACT effect on cholesterol biosynthesis as well as on other P450- mediated enzymes of adrenal and testicular steroid formation The anlituniiirai activity of vorozole, a potent and specific nonsteroidal and liver steroid metabolism (7, 9-11). Almost all inhibitory aromatase inhibitor, against 7,12-dimethylbenz(a)anthracene-induced es trogen-dependent mammary adenocarcinoma was evaluated in 257 activity of vorozole resides in the dextro enantiomer, R 83842 Sprague-Dawley rats. Twice daily p.o. administation of 1 and 5 mg/kg of (11, 14). In this paper, we report on the antitumoral and the race-mate R 76713 for 42 days induced almost complete regression of endocrine effects of the racemate and its enantiomers in the tumors, inhibited the appearance of new tumors, and reduced multiplicity estrogen-dependent DMBAMnduced mammary tumor model of the remaining tumors. Antitumoral effects observed after ovariectomy in female Sprague-Dawley rats. or treatment with 5 mg/kg twice a day were not significantly different. R 76713, the race-mate, (+)-vnro/ole (both at 2.5 mg/kg twice a day), and MATERIALS AND METHODS ovariectomy all similarly reduced tumor growth at 42 days by 90% or more, lowered the number of existing tumors, and prevented the appear Test Compound. Vorozole (6-[(4-chlorophenyl)(l//-l,2,4-triazol-l- ance of new tumors. The less active levo-enantiomer (-)-vorozole at the yl)methyl]-l -methyl- l//-benzotriazole) (R 76713, (+)-vorozole (R same dose did not alter tumor growth. 83842), and (-)-vorozole (R 83839) were dissolved in 20% polyethylene Vorozole reduced serum estradici to the levels measured in ovariecto- glycol for p.o. dosing by gavage. mized animals. Serum progesterone levels were lowered, but to a much Tumors and Animals. Female Sprague-Dawley rats (IFFA CREDO, lesser extent than after ovariectomy, while serum luteinizing hormone Lyon, France) were gavaged at 50 days of age with 200 mg/kg DMBA and follicle-stimulating hormone concentrations increased, but also much (Sigma Chemical Co., St. Louis, MO) dissolved in sesame oil. The less than after ovariectomy. On the other hand, the androgen levels, animals had been deprived of food but not of water for 6 h prior to which remained undetectable or decreased after ovariectomy, markedly DMBA administration and received 0.9% saline containing 6% glucose rose after vorozole treatment. These endocrine changes, observed in intact to drink afterwards for 8 days (15, 16). female rats, were not detected in ovariectomized animals demonstrating Six weeks after DMBA administration, the mammary glands were the ovarian origin of the endocrine changes induced by vorozole. palpated at weekly intervals. After 64 days, animals with one or more tumors 10 mm in diameter or more were randomized to various treatment groups. Vorozole was given p.o. at a dose of 0.2, 1, and 5 INTRODUCTION mg/kg body weight twice daily for a period of 6 weeks. In a second experiment vorozole, (+)-vorozole and (â€”)-vorozolewere administered Inhibition of aromatase, the enzyme complex which converts p.o. at 2.5 mg/kg twice daily for 42 days. Lower dosages (0.16 and 0.63 androgens to estrogens, has been found to be of therapeutic mg/kg twice a day) of the active enantiomer (+)-vorozole were also value in the endocrine treatment of advanced breast cancer in investigated in a third trial. Groups of control and ovariectomized rats pos tmeniÂ»pausaiwomen (1). Aromatase inhibitors, such us Al - received the vehicle only. These two experiments were pooled since no testonolactone (2), aminoglutethimide (1,3), 4-hydroxyandros- difference could be detected between the control and ovariectomized tenedione (4, 5), and fadrozole (6), have demonstrated clinical groups. Ovariectomy was performed concomitantly with the onset of efficacy. However, these compounds showed low potency, poor treatment. The number and size of the tumors were recorded at least p.o. bioavailability, and/or poor selectivity for steroidogenic once a week and the length and the width of the tumors were measured enzyme(s) other than aromatase (for review, see Ref. l). Re conventionally with calipers. The tumor volume was calculated as cently, we reported on a new nonsteroidal compound, vorozole, Volume = Length x Width2 which is a potent and specific inhibitor of estrogen biosynthesis (7). This new triazole derivative lowered the aromatase activity At the end of the first experiment, the animals were sacrificed by by 50% at a concentration of about 3 nmol/liter in rat ovarian decapitation between 1 and 3 p.m., about 6 h after the final drug administration. Trunk blood was collected on heparin and centrifuged, homogenates (8), rat and human ovarian granulosa cells (9), and plasma was stored at -20Â°C. In the second experiment, body human stromal cells from adipose tissue (10), and human weight and weight of tumors were also recorded. HistolÃ³gica! exami placenta microsomes (11). It also lowered serum estradici levels nation of the tumors revealed the presence of acinar and mainly by more than 90% after a single p.o. administration of 0.05 mg/kg in pregnant mare's serum gonadotropin-primed female papillary cystic adenocarcinomas. The number of tumors was recorded for each animal on the first and last day of treatment. rats (9). In male cynomolgus monkeys as well as in postmeno- To more specifically investigate the endocrine effects of (+)-vorozole pausal women, peripheral conversion of labeled androstenedi- on the pituitary-ovarian axis, 32 female Sprague-Dawley rats bearing one into estrone was decreased by 85% after i.v. administration DMBA-induced mammary tumors were included in a separate study. of 0.003 mg/kg and by 93% after a single p.o. administration Twenty-two rats were ovariectomized on day 1. The animals were of 1 mg, respectively (12, 13). randomized in 4 groups: vehicle; (+)-vorozole (R 83842) (2.5 mg/kg In vitro and in vivo, vorozole, at doses at least 500-fold higher twice a day); ovariectomy; and ovariectomy plus (+)-vorozole (2.5 mg/ kg twice a day). After 2 weeks of treatment, the rats were sacrificed and than that needed for aromatase inhibition, is devoid of any plasma was collected as described before. Received 9/12/91; accepted 12/13/91. Hormonal Determinations. Plasma progesterone and testosterone The costs of publication of this article were defrayed in part by the payment levels were measured using direct radioimmunoassay kits, using anti- of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2The abbreviations used are: DMBA, 7,12-dimethylbenz(a)anthracene; LH, ' To whom requests for reprints should be addressed. luteinizing hormone, lutropin; FSH, follicle stimulating hormone, fnllitropin. 1240

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1992 American Association for Cancer Research. ANTITUMORAL AND ENDOCRINE EFFECTS OF VOROZOLE body-coated tubes and iodinated tracers (Coat-a-Count; Diagnostic Table 1 Effect of ovariectomy or voro:ole treatment on the multiplicity of DMBA-induced mammary carcinoma infernale rats Products Corporation, Dilbeek, Belgium). Plasma estradiol was assayed by a direct radioimmunoassay kit, using a double antibody procedure Ovariectomy was performed and treatment was started on day 64 after DMBA and 125I-estradiol (Coat-a-Count). administration (day 0 of treatment). Plasma androstenedione was measured after extraction into pentane No. of tumors/rat (median using |1,2 'H]:uHlrosteiieilioiK- (NEN, Dreieich, Germany, with a spe and range) (mean Â±SEM) cific activity of 1.5 TBq/mmol) and an antibody raised in rabbit against androstenedione hemisuccinate coupled to bovine serum albumin (La 424(1-7)4.39 boratoire d'Hormonologie, Marloie, Belgium). The main cross-reacting Control18)Ovariectomized rats (n = Â±0.201 Â±0.400(0-1)Â°0.25 steroids were androstanedione 4.6%, dehydroepiandrostanedione, and 16)Vorozole, rats (n = (1-2)1.56 testosterone 1.4%. Activated charcoal was used to separate bound and Â±0.181 Â±0.113 free steroids. Serum LH and FSH concentrations were determined 1)Vorozole,0.2 mg/kg b.i.d.* (n = 1 (1-2)1.27 (0-6)2.90 using the National Institute of Arthritis, Diabetes, and Digestive and Â±0.141 Â±0.491 18)Vorozole,1 mg/kg b.i.d. (n = (1-3)1.44 (0-6)"2.0 Kidney Diseases rat LH and FSH kits (National Hormone and Pituitary Â±0.171 Â±0.400 Program, Baltimore, MD) and iodinated tracers obtained from Chem- 5 mg/kg b.i.d. (n = 19)DayO1(1-4)1.56(1-5)2.0 (0-6)Â°0.79 icon International Inc. (Temecuta, CA) (specific activity, 4218 and Â±0.26Day Â±0.33 4588 kBq/Vg, respectively). The results are expressed as ng/ml in terms ' PÂ£ 0.001 versus control. of National Institute of Arthritis, Diabetes, and Digestive and Kidney * b.i.d., twice a day. Diseases rat LH-RP2 and rat FSH-RP2 Statistical Analysis. Data from tumor volumes and weights (when Table 2 Effects of ovariectomy, vorozole. (-)-vorozole, and (+)-vorozole determined) as well as the number of tumors on days 64 and 106 and treatment on the multiplicity of DMBA-induced mammary carcinoma hormonal levels at the end of the experiment were analyzed for signif infernale rats icance by the Mann-Whitney U test (two-tailed) using the StatView II Ovariectomy was performed and treatment was started on day 64 after DMBA software (Abacus Concepts, Inc.) with all references to statistical sig administration (day 0 of treatment). nificance being at least at the <0.05 level. No. of tumors/rat (median and range) (mean Â±SEM) RESULTS 423(1-13)4.75 Antitumoral Effects of Various Doses of Vorozole (R 76713, Control32)Ovariectomized rats (n = the Racemate). In a dose-finding study, randomized groups of Â±0.131 Â±0.420 30)Vorozole, rats (n = (1-2)1.07 (0-2)"0.37 animals received vorozole p.o. at daily doses of 0.2, 1, and 5 Â±0.051 Â±0.100 mg/kg twice a day. From day 8 of treatment onwards, either 1)(-)-vorozole,2.5 mg/kg b.i.d.* (n = 1 (1-3)1.45 (0-2)"0.36 Â±0.211 Â±0.202(1-5)2.50 ovariectomy or vorozole administration with both 1 and 5 mg/ 10)(+)-vorozole,2.5 mg/kg b.i.d. (n = (1-3)1.30 kg twice a day induced a highly significant regression of tumor Â±0.211 Â±0.450(0-1)Â°0.19 growth (P < 0.01 at least, at any time point) as compared to 16)(+)-vorozole,2.5 mg/kg b.i.d. (n = (1-5)1.56 Â±0.301 Â±0.101 control (Fig. 1). Median tumor volume became undetectable 25 20)(+)-vorozole,0.63 mg/kg b.i.d. (n = (1-3)1.20Â±0.121(0-5)Â°1.40 days after ovariectomy or treatment with 5 mg/kg twice a day Â±0.374(1-8)3.79 and 32 days after treatment with 1 mg/kg twice a day. Twice 0.16 mg/kg b.i.d. (n = 14)DayO1(1-4)1.50(1-2)1.57 Â±0.14Day Â±0.59 daily administration of 0.2 mg/kg of vorozole did not signifi ' P < 0.0001 versus control. cantly modify the growth of the tumors (Fig. 1). * b.i.d., twice a day. The reduction of tumor growth measured after 1 and 5 mg/ kg twice a day was not significantly different from that observed after ovariectomy. by ovariectomy and treatment with 1 and 5 mg/kg, whereas no The multiplicity of the tumors was also significantly reduced significant difference could be detected between the number of tumors in the animals receiving vehicle or 0.2 mg/kg (Table 1). After ovariectomy or treatment with 5 mg/kg, the number of 100i tumors remaining after 6 weeks of treatment did not differ significantly, whereas treatment with 1 mg/kg reduced tumor multiplicity to a lesser extent than ovariectomy Comparative Antitumoral Effects of Vorozoleand of Its Enan- 10: Vehicle (n.18) tiomers. The antitumoral effects of the racemate and of both Ovex(n-16) enantiomers were compared in a second experiment. A daily 0.2mg/Vg(n=11) 1 mg/kg (n-18) p.o. dose of 2.5 mg/kg twice a day was chosen, which is one- 5 mg/Kg (n=19) half the dose producing an antitumoral effect similar to ovar iectomy when the racemate was used in the first experiment. In the second experiment, both vorozole (R 76713) and (+)- vorozole (R 83 842) and ovariectomy reduced the growth and weights (Figs. 2 and 3) of the tumors as well as their multiplic 0.1 -5 15 20 25 30 35 40 45 ity, when compared to control animals (Table 2; P < 0.0001). Days No statistical difference was detected among ovariectomy, vo Fig. 1. Effect of ovariectomy (Ovex) and treatment with vorozole (R 76713, rozole, and (+)-vorozole treatment, (-)-vorozole (R 83839) did the racemate) on the growth of DMBA-induced rat mammary carcinoma. Ovar iectomy was performed and treatment was started on day 64 after DMBA not show any significant antitumoral effects, at least at this administration. Due to ulcÃ©rationofsome of the tumors in animals receiving the dosage (Figs. 2 and 3; Table 2). vehicle, only 7 animals were included in this group on days 32, 38, and 42. From At 0.63 mg/kg twice a day, (-l-)-vorozolealso significantly day 6 until day 42, tumor growth measured after ovariectomy, 1 and 5 mg/kg twice a day, was significantly reduced as compared to vehicle-treated rats (at least reduced tumor growth (P < 0.0001 from day 14 onwards), as well as tumor weight and number (P Â£0.0001; Figs. 2 and 3; 1241

Vehicle(n=32) (*)-vorozole Table 2). However, the number of tumors on day 42 was 1001 Ovex(n=30) - 2.5 mg/kg(n=16) - 0.63 mg/kg(n=20) significantly higher than that measured after ovariectomy or vorozole(racemate)(n=11) 2.5 mg/kg (+)-vorozole twice a day. (-)-vorozole (nÂ»10) â€”¿0.16mg/kg(n=14) At 0.16 mg/kg twice a day (+)-vorozole still significantly reduced tumor volume (P < 0.05, from day 7 to 35) but did not significantly alter the weight and number of tumors on day 42 (Fig. 3; Table 2). Effects on Body Weight. Ovariectomy and (-f-)-vorozole treat ment (down to 0.63 mg/kg twice a day) significantly increased body weight of the rats (Fig. 4). This is likely to be a conse quence of estrogen deprivation. The inactive enantiomer (-)- vorozole did not alter the body weight. The drug was well tolerated and no overt side effects were observed. Endocrine Effects of Vorozole Treatment. Vorozole (R 76713, 10 15 20 25 30 35 40 45 Days the racemate) reduced serum estradici to the levels measured in ovariectomized animals at all doses (P < 0.01) (Fig. 5). Fig. 2. Effect of ovariectomy (Ovex) and treatment with 2.5 mg/kg of vorozole twice a day (R 76713, the racemate) and both its enantiomers, (â€”)-vorozole(R Serum progesterone levels were lowered, but not significantly 83839) and (+)-vorozole (R 83842) (2.5, 0.63, and 0.16 mg/kg twice a day), on and to a much lesser extent than after ovariectomy while serum the growth of DMBA-induced rat mammary carcinoma. Ovariectomy was per formed and treatment was started on day 64 after DMBA administration. From LH and FSH concentrations increased, but also much less than day 6 until day 42 after ovariectomy, both vorozole and (+)-vorozole significantly after ovariectomy (P < 0.01 at 1, 5, and 5 mg/kg only) (Fig. 5). reduced tumor growth as compared to vehicle-treated rats (at least /' < 0.01). On the other hand, the androgen levels, which remained unde-

Estradici nmol/l 50-40-30-20-10-Tt

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s- ff n Y/ /Ã€TiTt VehicleOVEX 5 i 02 VehicleOVEX 5 l 02 Vorozole (mg/kg) Vorozole (mg/kg) Vehicie Ovex Vorozole i ) volatole 2.5 0.63 016 (racemate) (+)-vorozole (mg/kg) FSH Fig. 3. Effect of ovariectomy (Ovex) and treatment with 2.5 mg/kg of vorozole ng/ml twice a day (R 76713, the racemate) and both its enantiomers. (-)-vorozole (R 30-1 83839) and (+)-vorozole (R 83842) (2.5, 0.63, and 0.16 mg/kg twice a day), on tumor weight, measured on day 42 after the onset of treatment or ovariectomy (*,/>< 0.01). 20 I 10

4001

VehicleOVEX 5 i 02 VehicleOVEX 5 1 02 Vorozole (mg/kg) Vorozole (mg/kg) 300- Androstenedione Testosterone nmol/l nmol/l 7 200 T 6- 5- i 4- 100- 3- 2- 1- Vorozole (-)-vorozole PT7] V77\ i (racemate) m (+)-vorozole(mg/kg) Vehicle OVEX 5 1 02 VehicleOVEX 5 1 02 Vorozole (mg/kg) Vorozole (mg kg) Fig. 4. Effect of ovariectomy (Orr.v) and treatment with 2.5 mg/kg of vorozole twice a day (R 76713, the racemate) and both its enantiomers, (â€”)-vorozole(R Fig. 5. Effects of ovariectomy (Ovex) and vorozole (R 76713. the racemate) 83839) and (-H)-vorozole (R 83842) (2.5, 0.63, and 0.16 mg/kg twice a day), on treatment (2.5 mg/kg twice a day) on serum estradiol, progesterone, testosterone, body weight, measured on day 42 after the onset of treatment or ovariectomy (*, androstenedione, LH, and FSH levels in female Sprague-Dawley rats bearing DMBA-induced mammary adenocarcinomas. *, P Â«0.01 versus vehicle. 1242

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1992 American Association for Cancer Research. ANTITUMORAL AND ENDOCRINE EFFECTS OF VOROZOLE Table 3 Effects of ovariectomy (Ovex) alone or combined with a 2-weeks (+)-vorozole treatment on serum estradiol, progesterone, testosterone, androstenedione, LH, andFSH levels infernale Sprague-Dawley rats bearing DMBA-induced mammary adenocarcinomas (ng/ (pmol/liter)41 (nmol/liter)42 (nmol/liter)<0.7 (nmol/liter)0.5 (ng/ml)0.75 ml)5.5 Control (n = 9) Â±12 Â±17 Â±0.1 Â±0.42 Â±0.3 Ovex(n = 11) 15Â±3 4Â±1Â° <0.7 0.3 Â±0.1 3.28 Â±0.40" 36.0 Â±1.8Â° (+)- Vorozole (n = 11) 16 Â±3 18 Â±6* 7.4 Â±1.3Â°-' 10.5 Â±1.7"-' 2.0 Â±0.2Â°-* 8.1 Â±1.7* Ovex + (+)-vorozole (n = 11)Estradiol <10rProgesterone 4Â±1Â°Testosterone <0.7Androstenedione0.4 Â±0.1LH 2.5 Â±0.3Â°FSH 36.0 Â±2.1Â° ' P Â£0.01 versus control. * P < 0.01 versus ovariectomy. c P < 0.05 versus control. tectable or decreased after ovariectomy, markedly rose after dose of 2 mg/kg of fadrozole has been reported to be the vorozole treatment (P < 0.01 at all doses) (Fig. 5). maximally effective dose, compared to vehicle (20), which is in To determine the ovarian or pituitary origin of these changes, good agreement with the dose of 1 mg of vorozole twice a day the hormonal levels were determined in female Sprague-Dawley reported in this paper. Pharmacological studies have indeed rats bearing DMBA-induced mammary tumors, receiving a 2- demonstrated that both these nonsteroidal aromatase inhibitors week treatment of (+)-vorozole, alone or combined with ovar show a similar potency for aromatase inhibition (7-9, 11, 14, iectomy. After (+)-vorozole administration, the endocrine 24, 25). changes observed in intact rats (increased androgens, small Since both drugs were well tolerated in DMBA-treated rats, increase of gonadotropins) were not detected in ovariectomized their pharmacokinetic and pharmacological profiles (i.e., their animals, in which all hormone levels measured were similar to selectivity for other P450-dependent reactions such as those of those determined in ovariectomized rats receiving vehicle only adrenal steroid biosynthesis) will be important for their clinical (Table 3). These data demonstrate the ovarian origin of the evaluation. In this respect, (+)-vorozole shows a very high endocrine changes induced by vorozole. specificity (7, 9-11, 14). The effects of vorozole treatment on serum estradiol levels DISCUSSION are in keeping with a specific inhibition of ovarian aromatase (19-23). Similarly, the decrease in progesterone levels can be The DMBA-mammary tumor model resembles human breast explained by interference with the active luteal phase. After cancer in its histology (17) and response to estrogen ablative treatment with nonsteroidal aromatase inhibitors, serum go- therapy (18), is widely used for evaluation of antitumoral activ nadotropin levels increase (22, 23) whereas 4-hydroxyandros ity of aromatase inhibitors, and is commonly accepted as one tenedione lowers LH levels. This latter effect appears to be of the most suitable animal models for estrogen-dependent related to the androgenic activity of the compound (19). After mammary carcinoma (19-23). The present study clearly dem vorozole treatment, the rise in gonadotropins, however, was onstrates the potency of vorozole to induce almost complete less pronounced than after ovariectomy. This is likely to be regression of existing mammary carcinomas. Furthermore, the related to the increase of ovarian androgen which may exert a appearance of new tumors during the treatment period was negative feedback on the pituitary. The experiments performed totally inhibited while multiplicity of the existing tumors was in ovariectomized rats clearly demonstrate the ovarian origin drastically reduced. The second experiment confirms that the of the androgen as well as the lack of direct antigonadotropic antitumoral activity of vorozole completely resides in its dextro effects of the drug. The physiological importance of this in enantiomer (+)-vorozole (R 83842). This is in conformity with creased androgen production is less pronounced than the an the potency for inhibition of aromatase activity which also drogenic activity of 4-hydroxyandrostenedione, since uterine mainly resides in this dextro enantiomer (11, 14). weight decreases similarly after ovariectomy and vorozole treat At doses of 2.5 and 5 mg/kg twice a day of the racemate and ment (26) whereas 4-hydroxyandrostenedione does not cause of 2.5 mg/kg (+)-vorozole, this new aromatase inhibitor showed regression of uterine weight and lowers serum LH concentra antitumoral effects identical to those measured after ovariec tion (19). tomy, for all tumoral parameters measured. At a dose of 0.2 Furthermore, the accumulation of ovarian androgen is not mg/kg twice a day, tumor growth was not significantly inhibited relevant for the therapeutic use of nonsteroidal aromatase in whereas serum estradiol levels, measured 6 h after treatment hibitors in postmenopausal women, in whom ovarian function were comparable to those seen in ovariectomized animals. This has stopped. Therefore, these results strongly warrant clinical discrepancy probably results for the shorter duration of aro evaluation of this compound in the treatment of metastatic matase inhibition at this dosage, allowing some escape of estra breast carcinoma in postmenopausal woman. diol after 12 h (9). (-t-)-Vorozole also seems to be more potent than steroidal aromatase inhibitors currently under development; a 75% re ACKNOWLEDGMENTS duction of tumor growth was obtained after daily s.c. adminis The authors wish to thank Leen Geentjens, Lambert Leijssen, and tration of 10 to 50 mg/kg of 4-hydroxyandrostenedione (17), his colleagues for their help in preparing the manuscript. MDL 18962, and atamestane (21, 22). Even if a direct compar ison of these results with those reported here is not possible, a reduction of mean tumor volume of more than 90% was ob REFERENCES tained after 6 weeks of treatment with both vorozole and (+)- 1. Santen, R. J., Manni, A., Harvey, H., and Redmond, C. Endocrine treatment vorozole at p.o. doses of 5 and 2.5 mg/kg twice a day. of breast cancer in women. Endocrino!. Rev., ///.- 221-265, 1990. Direct comparison of the antitumoral effects of (+)-vorozole 2. Barone, R. M.. Slamonki, 1. S., Siiteri, P. K., and Judd, H. L. 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Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1992 American Association for Cancer Research. Antitumoral and Endocrine Effects of (+)-Vorozole in Rats Bearing Dimethylbenzanthracene-induced Mammary Tumors

Roland De Coster, Robert F. Van Finckel, Myriam J. L. Callens, et al.

Cancer Res 1992;52:1240-1244.

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