Differential Effects of Tranylcypromine and Imidazole on Mammary Carcinogenesis in Rats Fed Low and High Fat Diets1

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[CANCER RESEARCH 49, 3168-3172, June 15, 1989] Differential Effects of Tranylcypromine and Imidazole on Mammary Carcinogenesis in Rats Fed Low and High Fat Diets1

David L. McCormick,2 Ann M. Spicer, and Jacqueline L. Hollister

Life Sciences Department, IIT Research Institute, Chicago, Illinois 60616

ABSTRACT studies with this class of compounds used inhibitors of the cyclooxygenase pathway of arachidonic acid catabolism; exper Neoplastic development in the rat mammary gland can be suppressed iments performed in our laboratory and by Ip and coworkers by inhibition of the activity of several enzymes involved in eicosanoid biosynthesis. In order to investigate the potential utility of prostacyclin demonstrated that the postcarcinogen phase of rat mammary and thromboxane synthetases as targets for mammary cancer chemopre- carcinogenesis can be suppressed by dietary administration of vention, experiments were conducted to determine the influence of tran- indomethacin (7, 8) or flurbiprofen (9). However, although the ylcypromine (TCP), an inhibitor of prostacyclin synthetase, and Â¡mida/ole anticarcinogenic activity of indomethacin is similar to that of (IMI), an inhibitor of thromboxane synthetase, on mammary carcinogen- more widely studied inhibitors of mammary carcinogenesis such esis induced in rats by 7V-methyl-/V-nitrosourea. Fifty-day-old female as retinyl acetate (10) and selenium (11), the dose levels of Sprague-Dawley |Hsd:SD(BR)l rats received a single s.c. dose of 0 or 40 indomethacin required for chemopreventive efficacy in rats are mg of .V-mcth>l-.Y-nitrosoiirea per kg of body weight. Beginning 7 days close to the threshold of lethal toxicity (12). For this reason, after carcinogen administration, groups of rats were fed isoenergetic, studies are ongoing to identify additional modifiers of arachi casein-based diets containing 3 or 20% corn oil (w/w), supplemented with donic acid metabolism whose administration provides an effec (per kg of diet) 10 mg of TCP, 1000 mg of IMI, or sucrose carrier only. TCP reduced mammary carcinoma multiplicity in rats fed the 20% corn tive means for the suppression of mammary cancer induction, yet which possess improved therapeutic ratios, i.e., greater oil diet, but had no effect in rats fed the diet containing 3% fat. By "margins of safety" between the dose levels required for anti- contrast, supplementation with IMI increased mammary cancer incidence in the group fed the 20% fat diet and increased carcinoma multiplicity in carcinogenic efficacy and those which induce significant toxic the 3% fat group to the levels seen in rats fed the 20% fat diet. These ity. data suggest that inhibition of prostacyclin synthetase, but not thrombox The oxidation of arachidonic acid by cyclooxygenase is an ane synthetase, may present a useful mechanism for mammary cancer early step in the biosynthesis of a number of eicosanoids, chemoprevention in animals consuming a diet high in fat. Furthermore, including PGA2,3 PGD2, PGE2, PGF2o, PGI2, and TXB2. Be the differential effects of TCP and IMI in rats fed low and high fat diets cause cyclooxygenase is involved in the synthesis of a large suggest that the action of dietary fat in mammary cancer induction may number of biologically active compounds, the possibility exists involve influences on the arachidonic acid cascade. that the chemopreventive and toxic effects of cyclooxygenase inhibition are a result of alterations in the synthesis of different INTRODUCTION eicosanoids. In such a circumstance, the chemopreventive effi Chemical carcinogenesis in the rat mammary gland is subject cacy and toxicity of cyclooxygenase inhibition might be disso to modulation through a variety of endocrine, pharmacological, ciable through the use of a more narrowly targeted approach and nutritional manipulations (1). Because of the close biolog designed to influence levels of fewer eicosanoids. The enzymes ical and histopathological correspondence between mammary prostacyclin synthetase and TX synthetase utilize a common substrate in the post-cyclooxygenase portion of the arachidonic neoplasia in rats and in humans, modification of mammary cancer response in the rat model may provide useful insights acid cascade; a negative interaction between the products of into the regulation of neoplastic development in the human these two enzymes has been proposed (13, 14). The present breast. For example, the identification of factors which enhance study was designed to determine the efficacy of TCP, an inhib mammary cancer induction in rats [e.g., dietary fat (2, 3)] can itor of prostacyclin synthetase (15, 16), and IMI, an inhibitor aid in the elucidation of risk factors for human breast cancer. of TX synthetase (17, 18), as chemopreventive agents in the rat Conversely, a number of factors which suppress neoplastic mammary gland, and to determine if the activity of these development in the rat mammary gland [e.g., early full-term compounds as modifiers of mammary cancer induction is influ pregnancy (4, 5)] appear to play a similar role in reducing the enced by dietary fat intake. risk of breast cancer in humans (6). Finally, the experimental use of modifiers of carcinogenesis can provide data concerning MATERIALS AND METHODS the mechanisms through which neoplastic development in the mammary gland is regulated; such data can be applied to both Experimental Animals. Virgin female Sprague-Dawley [Hsd:SD(BR)J cancer risk assessment and the identification of appropriate rats were received at 28 days of age from Harlan/Sprague-Dawley, targets for the design of anticarcinogenic drugs. Indianapolis, IN. Rats were housed in groups of three in polycarbonate Modifiers of arachidonic acid metabolism are one class of cages on hardwood bedding, and they were held in a temperature- and agents with significant activity as inhibitors of rat mammary humidity-controlled room maintained on a daily cycle of 14 h of light carcinogenesis. The initial mammary cancer chemoprevention and 10 h of dark. During the quarantine period, rats were allowed free access to a standard laboratory chow diet (Wayne Lab Chow; Allied Received 12/5/88; revised 2/16/89; accepted 3/17/89. Mills, Chicago, IL) and drinking water; 5 days prior to the initiation The costs of publication of this article were defrayed in part by the payment of the study, the chow diet was replaced with a semipurified, casein- of page charges. This article must therefore be hereby marked advertisement in based diet containing 3% fat. All food and bedding materials were accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ' Supported by Grant R01-CA-40874 from the National Cancer Institute, changed twice weekly. Department of Health and Human Services. Presented in part at the Annual Experimental Diets. Basal diets used in the experiment were isoener- Meeting of the American Association for Cancer Research, New Orleans, LA, May 25-28, 1988. 3The abbreviations used are: PG, prostaglandin(s); TX, thromboxane(s); TCP, 2To whom requests for reprints should be addressed, at Life Sciences Depart tranylcypromine; IMI, imidazole; MNU, A'-methyl-iV-nitrosourea; T50, time to ment, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616. 50% cancer incidence (median cancer induction time). 3168

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1989 American Association for Cancer Research. TRANYLCYPROMINE AND IM1DAZOLE EFFECTS ON RAT MAMMARY CARCINOGENESIS getic, semipurified, casein-based diets containing either 3% or 20% fat mammary cancer incidence at 180 days post-MNU were compared (w/w), as added corn oil. Diets were manufactured to our specifications using x2 analysis; comparisons of T$owere made using the median test by Teklad Test Diets, Madison, WI. The composition of the basal diets (21). Group body weights were compared using analysis of variance. is provided in Table 1. As required by the protocol, diets were supplemented with either 10 mg of TCP (99% purity; Sigma Chemical Co., St. Louis, MO) or 1000 RESULTS mg of IMI (99+% purity; Sigma) per kg; dietary levels of TCP and IMI were selected on the basis of preliminary subchronic toxicity studies. TCP and IMI had opposite effects on mammary cancer To facilitate homogeneous distribution of these agents in the diets, induction by MNU. Significant differences between these two TCP and IMI were mixed into diets using a sucrose carrier (10 g/kg of agents were found in comparisons of their influence on mam diet). Dietary controls received the 3% or 20% fat diets supplemented mary carcinoma multiplicity and tumor latency and in the with sucrose carrier only. effects of dietary fat on their activity as modifiers of mammary Experimental Protocol. MNU was purchased from Ash-Stevens (De carcinogenesis. troit, MI) and was dissolved in sterile saline (pH 5.0) immediately prior Administration of a supplement of 10 mg of TCP per kg of to administration. At 50 days of age, all rats received a single s.c. injection of 0 or 40 mg of MNU per kg of body weight. Seven days diet conferred significant protection against mammary carci after carcinogen administration, rats were randomized by weight into nogenesis in rats fed the diet containing 20% corn oil (Table groups according to the protocol (Table 2), and administration of 2). As illustrated in Fig. 1, TCP decreased the mean number of experimental diets was begun. mammary cancers per rat by approximately 40%, from 2.67 in Beginning 4 wk after MNU administration, rats were palpated twice controls to 1.64 (P < 0.01). The compound also increased T5o weekly to monitor mammary tumor appearance; the location and date from 98 days in the 20% fat control group to 130 days and of appearance of all palpable lesions were recorded. Animals were decreased tumor-related mortality from 12% in controls to 0% observed twice daily throughout the study to monitor their overall (0.05 < P < 0.10). However, although exposure to TCP in health status, and they were weighed weekly. All animals found dead creased the median time to mammary cancer appearance, the during the experiment or killed at its termination were subjected to a compound had no effect on cancer incidence at the termination complete necropsy. Sections of all mammary tumors and any other grossly abnormal tissues were fixed in 10% buffered formalin and of the study. processed by routine methods for histopathological classification. In contrast to its chemopreventive activity in rats fed the 20% Mammary tumor pathology was defined according to the criteria of fat diet, TCP had no effect on mammary carcinogenesis in rats Young and Hallowes (19). Because benign mammary tumors were fed an isoenergetic diet containing 3% corn oil (Table 2). infrequent (<0.2 tumors/rat in all groups), only histologically con Terminal cancer incidence, tumor-related mortality, and me firmed mammary cancers were used in the data analysis. dian tumor induction time did not differ between the control Statistical Analysis. Values for mammary cancer incidence and mul and TCP groups fed the 3% fat diet; carcinoma multiplicity tiplicity were calculated using life table analysis, and thus include curves for the two groups were comparable throughout the corrections for intercurrent mortality. Comparisons of cancer latency experiment (Fig. 2). curves were made using the logrank test (20). Animal survival and The effects of dietary supplementation with 1000 mg of IMI per kg were generally opposite those of TCP. Whereas a signif Table 1 Composition of experimental diets icant reduction in carcinoma multiplicity was observed in rats Corn Corn oil oil diet (g/ fed the 20% fat diet supplemented with TCP, IMI had no effect DietarycomponentCasein, diet(g/kg)200.03.030.0360.0323.032.035.05.010.02.020%kg)200.03.0200.0150.0140.0255.035.05.010.02.0on mammary cancer number in rats fed this level of fat. As proteinDL-MethionineCornhigh indicated in Fig. 1, mammary cancer multiplicity in the IMI group fed the high fat diet was within 1% of control levels at oilExpanded the termination of the study. Similarly, comparisons of tumor- maltodextrinSucroseCelluloseMineral related mortality and median tumor latency demonstrated no differences between dietary control and IMI groups fed the 20% AIN-76Calciummix, carbonateVitamin fat diet. However, primarily as a result of a late burst in AIN-76ACholinemix, carcinoma appearance, IMI did increase terminal cancer inci bitartrate3% dence to 96% from 78% in controls (P < 0.05). Total available energy" 3.7 kcal/g 3.7 kcal/g In rats fed the 3% fat diet, administration of IMI increased " Calculated using the following nutrient values: protein, 4 kcal/g; carbohy mammary cancer number by approximately 30% from control drate, 4 kcal/g; fat. 9 kcal/g. levels (Fig. 2). This increase was not statistically significant

Table 2 Influence of tranylcypromine and imidaiole on mammary carcinogenesis induced by N-methyl-N-nitrosourea dose of (mg/kg fat agent (mg/kg incidence wt(g)298 Group123456789101112No.rats201010201010502525502525MNUbodywt)000000404040404040Dietarylevel(%)333202020333202020Chemopreventivediet)(0)TCP (%)000000788392788896*T*,(days)120112999813075Cancers/rat0000002.162.202.772.671.64C2.69Body Â±10Â°293 (10)IMI Â±6295 (1000)(0)TCP Â±6297 Â±10284 (10)IMI Â±6280 (1000)(0)TCP Â±7292 Â±5282 (10)IMI Â±4277 (1000)(0)TCP Â±5*287 Â±5282 (10)IMI Â±4269 (1000)Cancer Â±4C Â°Mean Â±SE. * P < 0.05 versus appropriate control group. ' P < 0.01 versus appropriate control group.

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60 80 100 120 140 180 60 80 100 120 140 160 DAYS POST-CARCINOGEN DAYS POST-CARCINOGEN Fig. 1. Influence of tranylcypromine and imidazole on mammary carcinogen- Fig. 3. Mammary cancer response in rats fed isoenergetic diets containing 3% esis in rats fed a semipurified diet containing 20% corn oil. D, control; â€¢¿, or 20% corn oil (w/w). D, 3% corn oil; â€¢¿20%corn oil. tranylcypromine (10 mg/kg of diet); A, imidazole (1000 mg/kg of diet). DISCUSSION

Inhibitors of the generation of arachidonic acid, as well as its catabolism by cyclooxygenase and lipoxygenase, can all confer protection against cancer induction when administered to rats following exposure to an organotropic mammary gland carcin ogen (7,8, 22,23). The results of the present study demonstrate that two compounds with activity as inhibitors of enzymes in the post-cyclooxygenase portion of the arachidonic acid cascade can also modify mammary cancer induction. However, only one of the two agents suppressed mammary carcinogenesis, while the other increased cancer induction. Dietary administration of TCP at a level of 10 mg per kg of diet (approximately 0.7 mg/kg of body weight/day) resulted in a significant suppression of mammary carcinogenesis in rats fed a 20% fat diet, but conferred no protection in rats fed a diet 60 80 100 120 140 160 180 containing 3% fat. No systemic or organ-specific toxicity was observed in TCP-treated rats at any point during the experi DAYS POST-CARCINOGEN Fig. 2. Influence of tranylcypromine and imidazole on mammary carcinogen- ment. Furthermore, the preliminary subchronic toxicity study esis in rats fed a semipurified diet containing 3% corn oil. D, control; â€¢¿. indicated that the only adverse effect of exposure to TCP at tranylcypromine (10 mg/kg of diet); A, imidazole (1000 mg/kg of diet). doses up to 10 times higher than that used in the carcinogenesis study was a 15% suppression of body weight (data not shown). (0.05 < P < 0.10). However, Â¡tis of interest to note that the The wide range between anticarcinogenic and toxic doses of magnitude of the increase in mammary carcinoma multiplicity TCP differs significantly from the results of our previous studies seen in the 3% fat group fed IMI (2.77 cancers per rat versus with indomethacin (8, 12). These data indicate that TCP, an 2.16 in controls) is similar to the increased mammary cancer agent which inhibits prostacyclin synthetase in several experi multiplicity seen in the dietary control group fed 20% fat (2.67 mental systems (15, 16), can confer significant protection cancers per rat). Statistical comparisons of cancer response in against mammary carcinogenesis in animals consuming a high the control groups fed 3% and 20% fat (with 50 rats per group) fat diet. Furthermore, these data suggest that the toxicity of did indicate a significant enhancement of mammary cancer cyclooxygenase inhibition may be dissociable from its chemo induction in rats fed the high fat diet (Fig. 3). These data preventive activity through the use of agents which modify the suggest that a similar level of statistical significance may have activity of enzymes lower in the arachidonic acid cascade. been attained with the IMI group had it contained 50, rather By contrast to the effects of TCP, dietary supplementation than 25, rats. with IMI at a level of 1000 mg per kg of diet (approximately Neither TCP nor IMI induced any significant toxicity during 70 mg/kg/day) did not suppress mammary cancer induction; in the course of the experiment. The general health status of rats fact, exposure to IMI was associated with increased tumor fed TCP or IMI was not different from controls, and no organ- response in several groups. We are aware of no other studies specific toxicity attributable to drug exposure was observed at which have examined the influence of a thromboxane synthesis necropsy. Mean body weights in groups fed TCP were within inhibitor on carcinogenesis; however, the results of the present 5% of control levels at all points in the study (P > 0.10). study with IMI are similar to several recent reports which noted Exposure to IMI did suppress mean body weight by 5 to 7% in either no effect or increased growth of transplantable tumors rats treated with MNU (P < 0.05). However, this suppression in mice treated with the thromboxane synthesis inhibitor, daz- of body weight gain was not associated with chemopreventive magrel (UK-38485; 24-26). activity. An antagonism between the products of the prostacyclin and 3170

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1989 American Association for Cancer Research. TRANYLCYPROMINE AND IMIDAZOLE EFFECTS ON RAT MAMMARY CARCINOGENESIS thromboxane pathways of arachidonic acid metabolism has limit mammary carcinogenesis. However, when the dietary fat been proposed (13, 14). The opposing effects of TCP and IMI level is increased to 20%, synthesis of the limiting eicosanoid(s) on mammary cancer induction could be interpreted as support is increased, thereby stimulating neoplastic growth. A parallel ive of this hypothetical negative interaction. In view of the mechanism would be operative when IMI is administered to technical problems inherent in quantitating the effects of phar rats fed the low fat diet; through its reorientation of arachidonic macological agents on tissue-specific eicosanoid biosynthesis in acid metabolism away from TX production and into other vivo, it is not possible at the present time either to confirm or pathways, the biosynthesis of the eicosanoid(s) which stimulates to deny the relevance of this hypothesis to the whole animal mammary carcinogenesis is increased. Although these stimu mammary carcinogenesis data generated in this study. How latory compounds remain undefined, the data from the present ever, the differential effects of TCP and IMI are clearly sugges study exclude TX from this role. tive. A converse mechanism could explain the influence of dietary A negative interaction between these pathways of eicosanoid fat level on the anticarcinogenic activity of TCP. Because the metabolism has also been proposed in the regulation of tumor low level of eicosanoid production in rats fed the low fat diet is metastasis (27). However, prostacyclin and thromboxanes ap already limiting, further decreases in the production of stimu pear to have much different effects on metastasis than on latory eicosanoids through administration of TCP would pro carcinogenesis and tumor growth. The data from the present vide no additional protection against mammary cancer induc study and from studies investigating the influence of thrombox tion. By contrast, administration of TCP would be protective ane synthetase inhibitors on the growth of transplantable tu in rats fed the high fat diet, as the drug would inhibit biosyn mors (24-26) suggest that inhibition of prostacyclin synthesis thesis of stimulatory or permissive factors which serve to en is protective, while inhibition of thromboxane synthetase stim hance mammary cancer induction. Investigations of the anti- ulates tumor growth. By contrast, Honn et al. (27) have reported carcinogenic activity of modifiers of arachidonic acid metabo protection against tumor metastasis by inhibition of thrombox lism coupled with in vitro studies of eicosanoid biosynthesis in ane synthetase and by administration of PGI2. mammary epithelial cells will be required to determine whether The specificity and mechanisms of action of the agents used PGh, PGE2, or other products of the arachidonic acid cascade in these studies should be addressed. IMI has been demon serve as specific regulators of mammary neoplasia. strated to be a highly selective inhibitor of TX synthetase in several experimental systems (28-30), suggesting that the en ACKNOWLEDGMENTS hancement of mammary carcinogenesis observed in groups exposed to IMI was mediated by suppression of TX synthetase The authors thank Bryan J. Bagg for computer graphics and Dorothy- activity and its concomitant effects on eicosanoid biosynthesis. Davis for histolÃ³gica!processing of tumor tissues. Although it is likely that TCP suppresses mammary cancer induction through its activity as an inhibitor of prostacyclin synthetase (15, 16), other possible mechanisms cannot be ex REFERENCES cluded at the present time. TCP inhibits monoamine oxidase 1. Welsch, C.W. Host factors affecting the growth of carcinogen-induced rat activity (31, 32), and like most monoamine oxidase inhibitors, mammary carcinomas: a review and tribute to Charles Brenton Muggins. it can alter the activity of a number of hepatic enzymes involved Cancer Res.. 45: 3415-3443, 1985. 2. Carroll. K. K.. and Khor, H. T. Effects of level and type of dietary fat on in xenobiotic metabolism (33). 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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1989 American Association for Cancer Research. Differential Effects of Tranylcypromine and Imidazole on Mammary Carcinogenesis in Rats Fed Low and High Fat Diets

David L. McCormick, Ann M. Spicer and Jacqueline L. Hollister

Cancer Res 1989;49:3168-3172.

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