Cell culture supports for slam-frozen and molecular distillation dried procedures.
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Animals↗
Biomedical subjects
D M Hoover
Publications and source records attributed to D M Hoover.
Endocrine and antiprostatic effects of raloxifene (LY156758) in the male rat.
The benzothiophene anti-estrogen, raloxifene [LY156758; (6-hydroxy-2-(4-hydroxyphenyl) benzo(b)thien-3-yl)(4-(2-1-piperidinyl)ethoxy)phenyl methanone hydrochloride] has selective estrogen pharmacological antagonist activity in female rats. The present studies were done in the male rat to assess activity of raloxifene related to inhibition of prostatic growth and effects on the hypothalamic-pituitary-gonadal axis. Raloxifene did not compete for binding of the androgen, [3H]-methyltrienolone (R1881) in cytosolic extracts of ventral prostate. Similarly, the compound did not inhibit prostatic 5 alpha-reductase or testicular 17 alpha-hydroxy/C17,20-lyase activities. Raloxifene had no effect on the ventral prostatic uptake of [3H]-R1881 in vivo. Administration of estradiol to castrated male rats stimulated fourfold increases of in vitro ventral prostatic binding of [3H]-R1881. Raloxifene was devoid of agonist activity in castrated animals, because the compound had no stimulatory effect on prostatic androgen receptor binding activity. When raloxifene was coadministered with estradiol, the compound markedly antagonized the estrogen-induced increase of prostatic [3H]-R1881 binding, confirming its antiestrogenic properties in male rats. Serum prolactin was also elevated significantly (P < 0.05) with a single injection of raloxifene (20.0 mg/kg). In these same animals, serum FSH was significantly (P < 0.05) decreased by one dose (10.0 mg/kg) of the compound. Luteinizing hormone levels in castrated male rats were unaffected by raloxifene administration. Raloxifene treatment of castrated males significantly (P < 0.05) antagonized the stimulatory response of the ventral prostate (VP) to exogenous androgens in a dose-dependent manner. Raloxifene treatment of intact male rats for 14 and 28 days produced significant (P < 0.05) dose-dependent regression of the VP and seminal vesicles (SV). The VP regressive responses to raloxifene were associated with a decline in serum testosterone levels. Histological analysis of the VPs in raloxifene-treated rats was consistent with an androgen-deprived state. These findings support the contention that raloxifene is a pure estrogen antagonist and a physiological antagonist of androgen action in male rats. These pharmacological properties provide support for further structure-activity and mechanistic investigations with benzothiophenes in the medical management of prostatic neoplasia.
Aldehyde-Lyases↗
Comparative antitumor effects of hormonal ablation, estrogen agonist, estrogen cytotoxic derivative, and antiestrogen in the PAIII rat prostatic adenocarcinoma.
The effects of hormonal ablation, estrogen, estrogen-derived cytotoxic agent, and estrogen antagonist therapies used clinically were evaluated on in vitro colony formation, in vivo growth, and lymphatic and pulmonary metastasis of the PAIII tumor. Ventral prostatic and seminal vesicle weights were evaluated in the same animals to assess androgen-related responses. Estradiol, estramustine phosphate, and testosterone had no effects on PAIII colony formation in vitro. Castration, hypophysectomy, estradiol benzoate, and estramustine phosphate treatment of PAIII-bearing Lobund Wistar rats produced significant (P less than 0.05) regression of male accessory sex organs. Of these treatments, only hypophysectomy had significant (P less than 0.05) inhibitory effects on primary PAIII growth and lymphatic and pulmonary metastasis. LY117018 [6-hydroxy-2-(p-hydroxyphenyl)benzo(b)thien-3-yl-p-2-(l-pyrrolidin yl)ethoxy phenyl ketone] has antiestrogenic activity but produces no significant agonist responses. LY117018 had no effect upon PAIII colony formation in vitro. Following s.c. implantation of PAIII cells, LY117018 (2.0, 10.0, or 20.0 mg/kg s.c.) had no effect on primary tumor growth in the tail. In vitro LY117018 administration produced marked antimetastatic effects. In a dose-dependent manner, LY117018 inhibited PAIII metastasis to the gluteal (97%) and iliac lymph nodes (88%) (P less than 0.05 for both). LY117018 also maximally inhibited pulmonary metastasis by 86% (P less than 0.05). Maximal regression of 42% for ventral prostatic and 35% for seminal vesicle weights were also seen after LY117018 administration (P less than 0.05 for both). Co-administration of estradiol benzoate had no antagonistic effect upon the antitumor responses produced by LY117018. The mechanism of action of LY117018 is not known. The failure of estradiol benzoate to affect PAIII growth and metastasis supports the contention that the responses to LY117018 are not attributable to simple antagonism of estrogen action. LY117018 may be exerting its antitumor effects through autocrine, paracrine, or endocrine mechanisms. LY117018 represents a class of agents with potential utility in treating metastatic cancer of the prostate.
Adenocarcinoma↗
Effect of the peroxisome proliferator LY171883 on hepatocellular replication in female B6C3F1 mice.
LY171883 was shown to increase the incidence of hepatocellular carcinomas and other proliferative lesions in female B6C3F1 mice. This appeared to be unrelated to the induction of peroxisomal beta-oxidation. Experiments were conducted to determine the effect of dietary LY171883 for 7 or 94 days on hepatocellular replication using continuous 7-day infusion of bromodeoxyuridine. LY171883 caused a dose-related increase in hepatocyte replication during the first 7 days, with statistical significance in the two higher dose groups. There was no effect on hepatocyte replication after 94 days of treatment. Liver weight and peroxisomal beta-oxidation were increased in the two higher dose groups after 7 and 94 days, indicating there was not a general loss of hepatic responsiveness to LY171883. The data indicate that the hepatocarcinogenesis of LY171883 in female B6C3F1 mice is not associated with sustained replication in the general population of hepatocytes. It is possible that a mitogenic effect of LY171883 exerted on spontaneously initiated cells is involved in the development of the proliferative lesions; however, further work is needed to determine this.
Acetophenones↗
Perception of loudness and musical preference: comparison of musicians and nonmusicians.
To estimate the relationship between musical preference and perceived loudness, 25 subjects, musicians and nonmusicians, were asked to match the loudness of a neutral stimulus to a given musical selection. Ten different types of music were used; each was rated for likability by the subject. Over-all analysis of loudness ratings indicated that nonmusicians were more accurate in matching loudness of a neutral stimulus with the musical selections. This finding suggests differences in loudness perception between musicians and nonmusicians. Both groups were most accurate on the selection which could be inferred as most familiar.
Adult↗
Vancomycin-induced release of histamine from rat peritoneal mast cells and a rat basophil cell line (RBL-1).
Rapid intravenous administration of the glycopeptide antibiotic, vancomycin, may cause a hypotensive reaction which can usually be prevented by infusing vancomycin in dilute solutions. The release of histamine from circulating cells such as basophils and tissue mast cells has been implicated in hypotensive reactions since the effects can be prevented by antihistamine pretreatment. The direct effects of vancomycin on histamine release were therefore investigated in rat peritoneal mast cells and rat leukemic basophils (RBL-1 cells). Suspension cultures of mast cells or RBL-1 cells were exposed to vancomycin for 30-60 minutes at concentrations comparable to those infused clinically (2.28 or 4.56 mg/ml). Vancomycin induced a time- and dose-dependent release of histamine into the culture media from both cell types. The reference degranulating agent, Compound 48/80 (CP 48/80), was also shown to induce histamine release from mast cells and RBL-1 cells. Mast cells were significantly more sensitive to vancomycin and CP 48/80 than RBL-1 cells and, unlike RBL-1 cells, were responsive to the inhibitory effects of cromolyn sodium on histamine release. Cromolyn sodium did not inhibit vancomycin-induced histamine release in RBL-1 or mast cells. Morphologically, mast cells exposed to either vancomycin or CP 48/80 exhibited dose-related degranulation. On the other hand, treatment-related degranulation effects of either vancomycin or CP 48/80 on RBL-1 cells could not be reliably distinguished from controls by qualitative evaluation. Based upon these findings it is concluded that mast cells may represent a more useful model to evaluate the potential of investigational agents to release histamine and to study mechanisms of histamine release than RBL-1 cells.
Animals↗
Comparative effects of disulfiram and N-methyltetrazolethiol on spermatogenic development in young CD rats.
N-Methyltetrazolethiol (NMTT) and NMTT-containing cephalosporin antibiotics cause characteristic testicular lesions in young but not adult rats. In addition, NMTT-containing cephalosporins inhibit aldehyde dehydrogenase and have been associated with a disulfiram-like reaction in humans and animals. Therefore, the potential testicular toxicity of disulfiram (10, 30, or 100 mg/kg) was evaluated in 37-day-old rats given oral doses on Postpartum Days 6 through 36, and was compared to the toxicity induced by NMTT (100 mg/kg). NMTT and each dose of disulfiram caused a decrease in testes weight. By DNA flow cytometry, testicular cell suspensions from rats given 100 mg/kg of NMTT had a 40% reduction in spermatids while those from rats given 10, 30, or 100 mg/kg of disulfiram had reductions of 52, 61, or 89%, respectively. Microscopically, the testes of rats given either NMTT or disulfiram had qualitatively similar changes, characterized by delayed maturity of the leading waves of germinal cells which had reached early maturation phase in control animals. Moderate to severe reduction occurred in the total number of spermatids with complete absence of acrosome phase and maturation phase spermatids. There was also a prominent reduction in the number of spermatocytes. Reduction in number of spermatogonia was minimal. While the mechanism of toxicity is not known for either compound, it is possible that the toxicity was related to the enzyme-inhibitory effects which both compounds possess. By defining the mechanism of testicular toxicity for compounds which cause a NMTT-like testicular toxicity in rats, biological differences in the spermatogenic process between the young and adult rat may be further understood. Direct extrapolation of the testicular effects in neonatal rats to man is not possible because of the substantial differences in initiation of spermatogenesis between rodents and humans.
Aldehyde Dehydrogenase↗
A retrospective survey of endocardial proliferative lesions in rats.
Sixty, proliferative, endocardial lesions were diagnosed in 19,304 rats, for an overall incidence of 0.3%. This population consisted of 10,127 Fischer 344, 8,737 Wistar, 200 Sprague-Dawley, and 240 Long Evans rats from chronic/oncogenicity studies reported at Lilly Research Laboratories from 1976 to 1988. Of the 60 proliferative lesions, 44 were classified as endocardial hyperplasia, 15 as endocardial schwannomas, and one as an endocardial sarcoma for prevalence rates of 0.2%, 0.08%, and 0.005%, respectively. Affected rats ranged in age from 42 to 110 weeks. There were no sex or treatment-related differences in the prevalence of the rat endocardial proliferative lesions. A review of endocardial lesions in 18 of 233 Wistar rats treated with carbamate derivatives revealed endocardial hyperplasia in 12 rats, schwannomas in five rats, and a sarcoma in one rat. One of the 12 rats with endocardial hyperplasia also had an intramural schwannoma. Of 200 Wistar rats given N-nitroso-N-methylurea, two had endocardial hyperplasia, and one had an endocardial schwannoma. Morphologic features were similar in either spontaneous or treatment-associated hyperplasia or neoplasia of the rat endocardium. Probable Schwann cell origin of the endocardial proliferative lesions was indicated by positive immunohistochemical staining for S-100 antigen in 10/12 spontaneous and 11/14 carcinogen-associated endocardial hyperplastic lesions. Further, 15/16 spontaneous and 6/7 carcinogen-associated neoplasms were immunoreactive to S-100. No tumor metastasis was recorded in either the spontaneously affected or carcinogen-treated rats.
Animals↗
Experimental induction of neoplasia in the accessory sex organs of male Lobund-Wistar rats.
Experimental induction of neoplasia in the urogenital tract was studied in male Lobund-Wistar rats. Animals were given single 30.0-mg/kg i.v. injections of N-nitroso-N-methylurea (NMU) followed 7 days later by s.c. implantation of a 2.0-cm Silastic capsule containing testosterone propionate (TP). Additional rats were given the NMU or TP treatments individually. Control animals were given a single i.v. injection of saline followed by implantation of an empty Silastic capsule. The Silastic implants for each group were replaced every 2 months. This hormone treatment regimen produced significantly (P less than 0.05) elevated serum testosterone concentrations relative to control for 42 days following implantation. Animals were killed at 92, 177, 259, 361, or 427 days post-NMU injection. A high treatment-related incidence of adenocarcinoma occurred in the dorsal and lateral prostatic lobes of animals given the combined NMU-TP treatment. In addition, a few animals had adenocarcinomas of the coagulating gland or the seminal vesicle. The estimated probability of neoplasia in the accessory sex organs by 427 days after initiation of the NMU-TP treatment was 68%, with no occurrence before 9 months. The NMU-TP treatment was also associated with an incidence of focal dysplasia in the accessory sex organs, particularly in the coagulating gland. These findings indicate that NMU-TP treatment of Lobund-Wistar rats can provide a useful experimental system to study the biochemical and molecular events involved in the induction of accessory sex organ neoplasia.
Adenocarcinoma↗
In vitro correlation of ultrastructural morphology and creatine phosphokinase release in L6 skeletal muscle cells after exposure to parenteral antibiotics.
Morphologic changes in a rat skeletal muscle cell line (L6) exposed for 1 h to the parenteral antibiotics amphotericin B (AMP), tetracycline-HCl (TET), erythromycin lactobionate (ERY), and cephaloridine (CEP) were characterized by transmission and scanning electron microscopy and compared to cellular release of creatine phosphokinase (CPK). AMP (0.05, 0.1, 0.5 mg/ml) caused a concentration-related swelling of nuclei, endoplasmic reticulum, and mitochondria. Loss of membrane integrity associated with AMP exposure was evident at the middle concentration and extensive at the high concentration, which correlated well with the 43 and 90% depletion of CPK from the muscle cells, respectively. TET (0.25, 1.0, 2.5 mg/ml) caused dilation of endoplasmic reticulum and cytoplasmic blebbing at the low concentration but had no effect on the cytoplasmic membrane or CPK. Cells exposed to the high concentration of TET had extensive damage to the cytoplasmic membrane, and CPK was completely depleted. ERY (2.5, 5.0, 25 mg/ml) caused a pattern of morphologic changes and CPK depletion similar to TET. CEP (4.0, 20, 50 mg/ml) had no effect on membrane integrity or CPK; however, membranous whorls were prominent in the cytoplasm. A good correlation between CPK release and cytoplasmic membrane integrity was evident and the ability of these agents to release CPK from muscle cells in culture correlated with the known irritancy potential of these parenteral antibiotics. Furthermore, CPK depletion seems to be a reliable indicator of muscle cell damage after cytoplasmic membrane perturbation and is therefore an appropriate index of toxicity in this in vitro muscle irritation model.
Amphotericin B↗
Effect of ciprofibrate, bezafibrate, and LY171883 on peroxisomal beta-oxidation in cultured rat, dog, and rhesus monkey hepatocytes.
Cultured rat hepatocytes have been used extensively to study the mechanisms of chemically induced peroxisome proliferation. Hepatocytes from nonrodent species have been used on a limited scale to study interspecies differences in the response. Because of their importance in pharmaceutical safety assessment, we have developed a model to study the response of beagle dog and rhesus monkey hepatocytes to peroxisome proliferators. Treatment of the hepatocytes with peroxisome proliferators was begun after 20 hr in culture and continued for 72 hr. Untreated rat, dog, and monkey hepatocytes retained 62, 42, and 43% of their initial (20 hr) peroxisomal beta-oxidation activity throughout 92 hr of culture. Ciprofibrate, bezafibrate, and LY171883 caused a dose-related increase in beta-oxidation in rat hepatocytes to a maximum of 10-, 8-, and 5-fold, respectively. In dog and monkey hepatocytes the increases in beta-oxidation were less than 2-fold. Peroxisome morphology in dog and monkey hepatocytes appeared to be unchanged by the drugs. Morphometric analysis in monkey hepatocytes showed no increase in peroxisome volume fraction in response to the chemicals. Treatment of dog and monkey hepatocytes with dexamethasone and glucagon during the final 24 hr in culture caused a 4- to 6-fold increase in tyrosine aminotransferase activity. This induction is characteristic of the in vivo response. The small increase in beta-oxidation reflects the relative insensitivity of the dog and monkey liver to peroxisome proliferators in vivo rather than a loss of sensitivity during culture. Cultured hepatocytes from beagle dog and rhesus monkey may provide a model for studying the mechanisms underlying the interspecies differences. Such information would help clarify the relevance of rodent data in human risk assessment.
Acetophenones↗
Changes in hepatic lipid metabolism associated with lipid accumulation and its reversal in rats given the peroxisome proliferator LY171883.
Dietary administration of 0.05, 0.1, and 0.3% LY171883 to rats for 1 day caused a dose-related increase in hepatic triglycerides. When added to rat liver mitochondria in vitro, LY171883 caused competitive inhibition of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme for mitochondrial fatty acid oxidation. This effect appears to be involved in the lipid accumulation. The hepatic triglycerides in rats given 0.1% LY171883 increased progressively through 3 months of treatment. In contrast, hepatic triglycerides in high-dose rats returned to control levels by Day 3 and remained there throughout the study. The regression of the lipid corresponded with increases in hepatic peroxisomal beta-oxidation, mitochondrial beta-oxidation, and CPT-1 activity of up to 13-, 7-, and 3.2-fold, respectively. The 0.1% dose increased these parameters modestly compared to those of high-dose rats (2-, 3-, and 1.6-fold, respectively). Addition of LY171883 to mitochondria from rats given dietary treatment for 2 weeks inhibited CPT-I by the same percentage as in control mitochondria. In mid-dose rats, the induction of CPT-I was largely negated by LY171883 in vitro. Even with the inhibition, CPT-I activity in mitochondria from high-dose rats remained 2-fold higher than that in untreated controls. The data suggest that the induction of CPT-I in high-dose rats was sufficient to overcome the inhibitory action of LY171883. The increased oxidative capacity in peroxisomes and mitochondria led to the regression of the lipid in high-dose rats. The more modest increases in fatty acid oxidation in rats given 0.1% LY171883 were not sufficient to reverse the lipid accumulation.
Acetophenones↗
Effects of chronic treatment with the leukotriene D4-antagonist compound LY171883 on B6C3F1 mice.
A 2-year toxicity/oncogenicity study was done to evaluate the potential effects of the leukotriene antagonist LY171883 in B6C3F1 mice. Dietary concentrations of LY171883 during the initial 7 months of the study were 0.0, 0.005, 0.015, or 0.05% but were increased to 0.0, 0.0075, 0.0225, or 0.075% during Months 7 through 24. The estimated average daily compound intake was 0.0, 7.3, 22.5, or 80.5 mg/kg for males and 0.0, 9.2, 27.5, or 95.9 mg/kg for females. Survival was not adversely affected by treatment, however, body weight of males and females in the high dose group was significantly lower than that of controls. The chronic toxicity was localized primarily to the liver. Liver weights were increased in males in the high dose group and in females in the mid and high dose groups. Microsomal p-nitroanisole-O-demethylase activity was increased in mid and high dose females. Hepatic peroxisomal beta-oxidation was increased approximately twofold in both sexes in the high dose group only. Centrilobular eosinophilic granular change of hepatocytes was a common histopathologic finding in male and female mice in the high dose group, with the incidence and severity being greater in females. An increased incidence of hepatocellular carcinomas was observed in female mice in the mid and high dose groups. The number of male mice in the high dose group with hepatocellular carcinomas was higher than that of controls but the change was not statistically significant. Hepatocellular adenomas were increased in females in the high dose group but not in males. All groups of treated females had increased nodular hepatocellular hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetophenones↗
Effects of chronic treatment with the leukotriene D4 antagonist compound LY171883 on Fischer 344 rats and rhesus monkeys.
One-year toxicity studies were done to evaluate potential toxic effects associated with chronic exposure of rats and monkeys to the leukotriene antagonist LY171883. Rats were fed dietary doses of 0.0, 0.01, 0.03, or 0.1%, equivalent to approximately 0, 5, 15, or 50 mg/kg of body weight/day. Monkeys were given daily nasogastric gavage doses of 0, 30, 75, or 175 mg/kg of body weight. No treatment-related effects occurred in physical, behavioral, ocular, food consumption, or urinalysis parameters in either species. Mild dose-related hepatotoxicity occurred in rats given approximately 15 or 50 mg/kg of LY171883. The hepatotoxicity was characterized by liver enlargement associated with induction of hepatic peroxisomal beta-oxidation and microsomal drug metabolism. Male rats also had hepatocellular fatty change, centrilobular hypertrophy of hepatocytes, and increased levels of serum alanine transaminase and total bilirubin. Other effects in rats included minimal decreases in hematocrit values, decreases in serum triglycerides and cholesterol, and increased kidney weight. The monkeys tolerated daily oral doses of LY171883 up to 175 mg/kg with only minor increases in hepatic microsomal enzyme activity and slightly increased liver and kidney weights in males. No effects occurred in monkeys given 30 mg/kg. There was no induction of hepatic peroxisomal enzymes or pathologic abnormalities in monkeys treated with LY171883. The peroxisomal inductive effect was apparently a species-related effect separate from the pharmacologic activity of leukotriene antagonism.
Acetophenones↗
Comparison of in vitro and in vivo models to assess venous irritation of parenteral antibiotics.
The venous irritation potential of four parenteral antibiotics, tetracycline hydrochloride (TET), erythromycin lactobionate (ERY), amphotericin B (AMP), and cephaloridine (CEP), was evaluated in an in vivo model using the rabbit ear vein. Lateral ear veins of New Zealand White rabbits were infused for 1 hr with test solutions containing TET (0.25,2.5, or 10 mg/ml), ERY (2.5, 5, or 25 mg/ml), AMP (0.05, 0.1, or 0.5 mg/ml), or CEP (4 or 20 mg/ml). Control rabbits received comparable volumes of 0.9% NaCl or 5% dextrose. Approximately 24 hr postinfusion, the rabbits were evaluated for visually evident changes in the treated ears. Pathologic evaluation of the veins was performed using histologic sections and scanning electron microscopy. TET, ERY, and AMP caused concentration-dependent changes in veins characterized primarily by loss of endothelium with associated inflammation and thrombus formation, consistent with the known clinical irritancy of these antibiotics. CEP, on the other hand, was well tolerated in the rabbit ear vein, paralleling its low irritancy potential in man. Test solutions identical to those used in vivo in rabbits were also evaluated in established in vitro assays for hemolytic potential when mixed with whole blood from monkeys and for damage to L6 muscle cells as determined by loss of creatine phosphokinase. Results of the in vitro test systems paralleled those of the rabbit ear model, with TET, ERY, and AMP exhibiting dose-dependent hemolysis and muscle cell toxicity, while CEP was comparatively nontoxic. Of the three models, the rabbit ear vein had the greatest sensitivity when histopathologic evaluation was employed.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Long term effects of gastrocystoplasty in rats.
Twenty prepubescent rats underwent microsurgical gastrocystoplasty by a technique which is described. An equal number of control rats had their bladders opened and closed. Rats were sacrificed at 16 to 18 months postoperatively. There were no differences in final weight, serum electrolytes, or renal function between the two groups. Prominent histopathologic changes of the bladder occurred in the gastrocystoplasty group. These changes included papillomas present in five of the 15 rats surviving long term. No significant changes occurred in the bladders of the control group of rats. Possible etiologies and the significance of the rats. Possible etiologies and the significance of the gastrocystoplasty related lesions are discussed.
Animals↗
Comparative contractile responses among ventral, dorsal, and lateral lobes of the rat prostate.
Prostatic zonal heterogeneity as a factor influencing urogenital smooth muscle contractile mechanisms was evaluated in the dorsal, lateral, and ventral lobes of the sexually mature rat. Additionally, using the ventral lobe, we assessed the role of the prostatic capsule to determine its contribution to tissue contractility. Smooth muscle contractile responses were determined for the alpha-adrenergic agonists norepinephrine and methoxamine; the cholinergic agonist carbamylcholine; the alpha 2-adrenergic agonist UK-14,304; serotonin; and potassium chloride. The dorsal, lateral, and ventral lobes contracted in response to all agonists. In the three lobes, norepinephrine was the most potent contractile agent; alpha 2 receptor activation with UK-14,304 resulted in the lowest maximum response. Carbamylcholine and serotonin were only weak contractile agonists in all three lobes. Maximum contractile responses to alpha agonists were greatest in the ventral prostate relative to the other two lobes, based on contractile responses to norepinephrine and methoxamine relative to KCl. The contractions of the ventral lobe in the presence and absence of the capsule were similar; thus the observed responses were not enhanced by the capsule but were attributable primarily to the presence of prostatic smooth muscle. Insofar as these studies with anatomically distinct lobes in the rat may reflect zonal homology in other species, these results support the contention that all zones may contribute to prostatic contractility.
Animals↗
Antagonism of androgen and estrogen effects in guinea pig seminal vesicle epithelium and fibromuscular stroma by keoxifene (LY156758).
Using separated epithelium (SVE) and fibromuscular stroma (SVM) of guinea pig seminal vesicle, the antihormonal effects of daily subcutaneous administration (14 and 28 days) of the benzothiophene keoxifene (LY156758; [6-hydroxy-2-(4-hydroxyphenyl)benzo(b) thien-3-yl] [4-(2-1-piperidinyl) ethoxyl] phenyl) methanone hydrochloride) in intact, castrate, and androgen/estrogen-maintained castrate animals was evaluated. The compound was devoid of agonist activity in castrated males, in that the compound had no stimulatory effect on SVM wet weight or DNA content. In vitro cytosolic binding of [3H]estradiol (E2) in the SVM was decreased in a concentration-dependent manner by keoxifene, but the compound did not perturb the binding of [3H]dihydrotestosterone (DHT) in the SVM or SVE. Likewise, keoxifene administration to castrated males treated with exogenous steroids antagonized the estrogen-induced hyperplastic response of the SVM, whereas no interference with androgen-induced growth of the SVM or SVE was observed. Keoxifene treatment of intact male guinea pigs produced regression of the androgen-sensitive SVE as well as the androgen/estrogen-sensitive SVM. Keoxifene-induced decreases in guinea pig serum testosterone levels were associated with this activity. Histological analysis of the seminal vesicle under these conditions suggests androgen deprivation. These findings indicate that keoxifene is a physiological antagonist of androgen action in the intact male guinea pig. The pure estrogen antagonist properties of keoxifene and its ability to decrease accessory sex organ epithelium and fibromuscular stroma in vivo suggest potential applications of the benzothiophenes in the medical management of prostatic neoplasia.
Androgen Antagonists↗