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Biomedical subjects

F Labrie

Publications and source records attributed to F Labrie.

At least 361 records · Page 20Linked to original sources
PubMed1989

Additive inhibitory effects of bromocryptine (CB-154) and medroxyprogesterone acetate (MPA) on dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in the rat.

Treatment for 18 days of rats bearing dimethylbenz[a]anthracene-induced mammary tumors with the synthetic medroxyprogesterone acetate (MPA) or the inhibitor of prolactin secretion 2 alpha-bromocryptine (CB-154) inhibited total tumor area to 30 +/- 7% of the original volume. Combination of the two drugs, on the other hand, caused further inhibition to 10 +/- 5% of the pretreatment tumor area. The most striking effect of combination of the two drugs is a doubling of complete responses (no detectable tumor) from 30% when either drug was used alone to 60% in animals treated with the combination therapy. Both estradiol and progesterone receptors were further decreased when MPA was added to CB-154. The present data demonstrate that combination of the synthetic progestin MPA and the inhibitor of prolactin secrection CB-154 exerts maximal inhibitory effects on the growth of the DMBA-induced mammary tumor, the most widely used in vivo model of human breast cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Effect of 2-week combination therapy with the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide and the antiandrogen flutamide on prostate structure and steroid levels in the dog.

Treatment of adult dogs for 15 days with the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (50 micrograms daily, s.c.) causes a 41.6% inhibition of prostatic weight while a 55% inhibition is achieved when the antiandrogen flutamide (250 mg, twice daily) is given in association with the LHRH agonist (p less than 0.01). At histology, the glandular acini in the prostate of animals treated with the combination therapy are more atrophied than with either treatment used alone. A 2-week treatment with the LHRH agonist is characterized by two distinct phases, namely a stimulation of testicular androgen secretion between days 0 and 8 followed by an inhibition between days 9 and 15. During the inhibitory phase, the concentration of all testicular steroids progressively decreased to castration levels, thus indicating that the differences observed at the prostatic level at 2 weeks are due to the inhibition of androgen action by the antiandrogen flutamide during the period which precedes complete chemical castration by the LHRH agonist. Flutamide administered alone had no effect on plasma or prostatic steroid levels measured after 2 weeks and it did not interfere with the potent and generalized inhibitory effect of the LHRH agonist on the serum and prostatic concentration of all steroids measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1989

Ontogeny of prolactin mRNA in the rat pituitary gland as evaluated by in situ hybridization.

We have studied the ontogeny of prolactin (PRL) messenger RNA (mRNA) in male and female rats. Quantitative in situ hybridization was performed on sections of fixed pituitaries using a 32S-labeled PRL cDNA probe. With this technique, hybridization signal was first detected on day 19 of gestation. The PRL mRNA levels were very low in foetuses and newborn animals. Higher PRL mRNA levels were found in 5-day-old animals. Thereafter, mRNA concentrations regularly increased to reach a plateau at 60 and 90 days of age in males and females, respectively. Sexual dimorphism was first observed in 20-day-old animals, the PRL mRNA levels being higher in the female than in the male. This difference in PRL mRNA became more marked after puberty such that in 90-day-old animals the amounts of PRL mRNA in females were 2.7 times those observed in males. Since sexual dimorphism in PRL mRNA levels occurs well before sexual dimorphism in PRL secretion, which takes place first during puberty, it is suggested that during sexual maturation PRL secretion is regulated translationally as well as transcriptionally.

Animals↗
PubMed1989

Anti-hormone treatment for prostate cancer relapsing after treatment with flutamide and castration. Addition of aminoglutethimide and low dose hydrocortisone to combination therapy.

The effect of further adrenal androgen blockade with aminoglutethimide (AG) plus low dose hydrocortisone (HC) was studied in 119 patients with clinical stage D2 prostate cancer who previously progressed after standard hormone therapy and were under progression while receiving the combination therapy with Flutamide and castration. Using the objective criteria of the US NPCP, 1 complete, 2 partial and 14 stable responses were obtained for a total response rate of 14.3%, while 102 patients continued to progress. The 50% probability of survival was 21.0 months for the responders and 9.2 months for the non-responders. The present data indicate that further androgen blockade with AG + low dose HC is well tolerated and can be of benefit to a significant proportion of patients in progression at a very late stage of the disease.

Aminoglutethimide↗
PubMed1989

Assignment of the human 3 beta-hydroxysteroid dehydrogenase gene (HSDB3) to the p13 band of chromosome 1.

Three-beta-hydroxysteroid dehydrogenase (HSDB3) is the enzyme which catalyses the oxidative conversion of delta 5-3 beta-hydroxy steroids to the delta 4-3-keto configuration and is therefore involved in the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. Deficiency of the enzyme is associated with congenital adrenal hyperplasia and is usually lethal in early life. Despite its crucial role, chromosome assignment of the gene for this enzyme has not been reported. Using in situ hybridization, we report that hybridization with labeled human HSDB3-specific cDNA yielded 27% of silver grains associated with chromosome 1 with a maximal concentration in the p13 band.

3-Hydroxysteroid Dehydrogenases↗
PubMed1989

Electron microscopic autoradiographic localization of prolactin mRNA in rat pituitary.

Recent immunoelectron microscopic studies have shown that immunoreactive prolactin (PRL) in rat pituitary can be detected not only in typical PRL cells, characterized by large secretory granules, but also in another type of cell, which contains small secretory granules. To determine whether or not these two cell types are involved in PRL biosynthesis, we developed a procedure to investigate PRL gene expression by using in situ hybridization at the ultrastructural level. Rat pituitary was fixed and vibratome sections were incubated with a PRL [35S]-cDNA probe and subsequently flat-embedded in Araldite. Semi-thin and ultra-thin sections were processed for autoradiography. The results indicate that only the two PRL cell types were labeled. When immunolabeling for PRL was applied to ultra-thin sections, only immunopositive cells were seen to contain silver grains. In these cells the silver grains were associated with the rough endoplasmic reticulum and nucleus. When a growth hormone (GH) [35S]-cDNA probe was used as a control, only GH-secreting cells were labeled. This study confirms that the two PRL cell types are involved in biosynthesis of PRL. Moreover, this simple in situ hybridization technique provides a new approach to accurately localize mRNA in complex tissue and to investigate the subcellular distribution of mRNA under differing experimental conditions.

Animals↗
PubMed1989

Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate.

Androgens play a major role in the development, growth, and function of accessory sexual organs, especially the prostate. However, the testis is not the sole source of circulating androgens in man, since the adrenal gland secretes dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (delta 4-dione) in large quantities. The aim of the present study was to investigate the effect of plasma concentrations of DHEA and delta 4-dione similar to those found in adult man on sensitive and specific markers of androgen action in the rat ventral prostate. In addition to ventral prostate weight, we have measured the steady state levels of the mRNAs encoding the C1 component of rat prostatic binding protein (PBP-C1) and spermine-binding protein (SBP) using 35S-labeled cDNA probes for in situ hybridization. One week after castration, ventral prostate weight fell 84%, while prostatic 5 alpha-dihydrotestosterone (DHT) and androgen-dependent mRNAs were undetectable. When administered via Silastic implants to castrated adult rats for 1 week, plasma concentrations of 1.37 +/- 0.06 ng/ml DHEA or 0.43 +/- 0.08 ng/ml delta 4-dione independently caused increases in ventral prostate weight to 33% and 65% of normal values, respectively. The same plasma levels of DHEA and delta 4-dione resulted in high intraprostatic levels of DHT to 1.19 +/- 0.34 and 3.66 +/- 0.89 ng/g tissue, respectively. Furthermore, DHEA caused an increase in the steady state levels of PBP-C1 and SBP mRNAs to 50% and 57% of the normal state, respectively, while delta 4-dione caused increases corresponding to 80% and 119% of control values, respectively. Castrated adult rats receiving testosterone at a concentration of 1.66 +/- 0.37 ng/ml plasma maintained normal ventral prostate weight and gene expression levels. The present results demonstrate that circulating levels of the adrenal steroids DHEA and delta 4-dione comparable to those found in man cause an important stimulation of androgen-dependent gene expression in the rat, probably after their conversion to DHT in the prostatic tissue itself.

Adrenal Glands↗
PubMed1989

Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line.

Much clinical evidence indicates that androgens have beneficial effects in the treatment of breast cancer in women. Physiological concentrations of androgens strongly inhibit both basal and estrogen-induced cell proliferation in the human breast cancer cell line ZR-75-1 through their interaction with the androgen receptor. The present study shows that androgens strongly suppress estrogen receptor (ER) and progesterone receptor contents in this model, as measured by radioligand binding and anti-ER monoclonal antibodies. Similar inhibitory effects are observed on the levels of ER messenger RNA (mRNA) measured by ribonuclease protection assay. The androgenic effect is observed at subnanomolar concentrations of the nonaromatizable androgen 5 alpha-dihydrotestosterone, regardless of the presence of estrogens, and is competitively reversed by the antiandrogen hydroxyflutamide. Such data on ER expression provide an explanation for at least part of the antiestrogenic effects of androgens on breast cancer cell growth and moreover suggest that the specific inhibitory effects of androgen therapy could be additive to the standard treatment limited to blockade of estrogens by antiestrogens.

Androgens↗
PubMed1989

Inhibitory effect of androgen on estrogen-induced prolactin messenger ribonucleic acid accumulation in the male rat anterior pituitary gland.

Estrogens are known to exert specific stimulatory effects on basal and dopamine-inhibited PRL secretion and synthesis as well as on PRL gene expression. However, dihydrotestosterone (DHT) and progesterone (P), although inactive alone, can reverse the effect of 17 beta-estradiol (E2) on PRL release both in vivo and in vitro. Using castrated male rats, we have studied the effect of E2 (0.25 micrograms), P (2 mg), or DHT (100 micrograms) administered twice daily for 14 days alone or in combination on pituitary PRL mRNA levels measured by quantitative in situ hybridization. Treatment with E2 increased the accumulation of PRL mRNA by about 2.6-fold. Administration of P or DHT alone failed to modify PRL mRNA concentrations. However, DHT could prevent by 80% the stimulatory effect of E2 on PRL mRNA levels. Similar results were obtained by dot blot hybridization assay. The effects of sex steroids on PRL mRNA were closely paralleled to pituitary PRL content measured by RIA. The present data demonstrate that the effect of sex steroids on immunodetectable PRL result from a modulation of PRL mRNA accumulation. The sexual dimorphism observed in pituitary PRL content results from a 3.5-fold greater accumulation of PRL mRNA in intact females than in male rats. These results also clearly show that quantitative in situ hybridization is a powerful tool in the investigation of the regulation of gene expression in addition to providing valuable information on the localization of specific mRNA.

Androgens↗
PubMed1989

Regulation of pro-gonadotropin-releasing hormone gene expression by sex steroids in the brain of male and female rats.

The fine modulation of gonadotropin gene expression and secretion is well recognized to be regulated by sex steroids through their direct action both at the anterior pituitary level and on the pulsatile pattern of GnRH secretion at the hypothalamic level. Since the influence of sex steroids on hypothalamic GnRH mRNA levels remains to be elucidated, quantitative in situ hybridization was used to study the effect of sex steroids on cellular levels of pro-GnRH mRNA in adult rats of both sexes. The effects of 14-day gonadectomy as well as administration of 17 beta-estradiol (E2, 0.25 micrograms) or dihydrotestosterone (DHT, 100 micrograms) twice a day during 14 days to gonadectomized animals were evaluated. In addition, the effect of progesterone (P, 2 mg, twice daily) alone or in the presence of E2 was also studied in ovariectomized animals. Hybridization was performed using a 35S-labeled cDNA probe encoding rat pro-GnRH and the corresponding mRNA levels were assessed by counting the number of silver grains overlying labeled neurons. In male rats, castration induced a highly significant 65% increase (compared to intact rats) in the mean number of grains per neuron. Administration of E2 or DHT to castrated animals completely prevented the post castration rise in pro-GnRH mRNA levels. In female animals, the effect of ovariectomy was less striking than in the male, a 25% increase (P less than 0.001) being observed. Treatment with E2 or DHT also completely prevented the increase in pro-GnRH mRNA levels induced by ovariectomy. Moreover, treatment with P in ovariectomized animals markedly potentiated the inhibitory effect of E2 on pro-GnRH mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Inhibitory effect of estrogens on GCDFP-15 mRNA levels and secretion in ZR-75-1 human breast cancer cells.

In order to better understand the mechanisms responsible for the antagonism between steroids in human breast cancer cells, we have studied the effect of 17 beta-estradiol (E2), dihydrotestosterone (DHT), and dexamethasone (DEX) alone or in combination on the expression of the breast gross cystic disease fluid protein-15 (GCDFP-15) in ZR-75-1 cells. Incubation with E2 markedly decreased basal GCDFP-15 mRNA levels accompanied by a parallel inhibition of the secretion of this tumor marker, the estrogenic effect being exerted at a half-maximal concentration of about 44 pM E2. The inhibitory effect of E2 on GCDFP-15 expression was competitively reversed by the antiestrogen LY156758. In addition, 1 nM E2 inhibited the marked stimulation induced by 1 nM DHT or 300 nM DEX on GCDFP-15 mRNA accumulation and on the secretion of the glycoprotein. However, at the concentration used, E2 reversed by only 65% the stimulation achieved by the combination of DHT and DEX on GCDFP-15 mRNA levels. It is of interest to mention that the effect of DHT, DEX, and E2 on GCDFP-15 expression is opposite to the respective effect of each steroid on ZR-75-1 cell proliferation. The present data on the regulation of GCDFP-15 mRNA demonstrate an estrogen-induced inhibition of mRNA levels under physiological conditions, thus offering a unique opportunity to study the mechanisms involved in the down-regulation of gene expression by estrogens and to achieve a better understanding of the antagonism between estrogens, androgens, glucocorticoids, and progestins in breast cancer cells. Furthermore, GCDFP-15 could well be a good marker for monitoring the response to androgens and antiestrogens during the course of breast cancer therapy.

Apolipoproteins↗
PubMed1989

Full length cDNA structure and deduced amino acid sequence of human 3 beta-hydroxy-5-ene steroid dehydrogenase.

Polyclonal antibodies raised against 3 beta-hydroxysteroid dehydrogenase isolated from human placenta were used to screen a lambda gt11 expression cDNA library from the same tissue. The protein deduced from cDNA sequences contains 372 amino acids with a calculated mol wt of 42,216. Since 3 beta-hydroxysteroid dehydrogenase is the enzyme catalyzing the formation of all classes of hormonal steroids, the availability of the cDNA encoding this enzyme opens new possibilities for a detailed investigation of the factors regulating the expression and activity of this crucial enzyme in adrenal, gonadal as well as peripheral tissues.

3-Hydroxysteroid Dehydrogenases↗
PubMed1988

Low androgen levels induce the development of androgen-hypersensitive cell clones in Shionogi mouse mammary carcinoma cells in culture.

The influence of the concentration of androgen present on the development of heterogeneous growth responsiveness to androgens was studied in an androgen-sensitive clone (SEM-1) of the Shionogi mammary carcinoma cell line incubated for up to 6 months in the presence of 0, 0.01, 0.3, or 100 nM dihydrotestosterone (DHT). In the absence of added androgen, there was a rapid increase in spontaneous cell growth, the increase being delayed by 2, 4, and 6 months when the cells were incubated with 0.01, 0.3, and 100 nM DHT, respectively. Conversely, the mitogenic effect of DHT decreased rapidly when originally androgen-sensitive cells were incubated with less than maximal concentrations of DHT. The most significant finding was the marked heterogeneity in the androgen sensitivity of the clones obtained after incubation for 2 months in the presence of less than maximal concentrations of DHT. In cells exposed to a maximal concentration of DHT (100 nM), only 2 of 22 clones were more sensitive to DHT (lower Km value) than the original clone, while 8 subclones were hyposensitive to DHT. On the other hand, when the cells were incubated for 2 months with a low (0.3 nM) concentration of DHT, 29% (7 of 24) of the clones were hypersensitive to DHT. Clones derived from cells treated with 0 or 0.1 nM DHT lost most of their responsiveness to DHT during the same time interval, with a simultaneous increase in spontaneous growth rate. The present data show that incubation of a clone of androgen-sensitive Shionogi carcinoma cells in the presence of a low DHT concentration, comparable to the circulating levels of DHT in castrated men, induces the development of androgen-hypersensitive cell clones that are able to grow on minute amounts of androgens. Such androgen-hypersensitive cells are likely to be unresponsive or resistant to antihormonal therapy. The present data emphasize the major importance of the hormonal environment on the maintenance, loss, and increase of tumor cell responsiveness to androgens.

Androgen Antagonists↗
PubMed1988

Maintenance of androgen responsiveness by glucocorticoids in Shionogi mammary carcinoma cells in culture.

The possibility that glucocorticoids can delay or prevent loss of responsiveness to androgens in androgen-deprived cells was investigated. While a complete loss of responsiveness to dihydrotestosterone (DHT) was observed within 60 days of androgen deprivation, addition of the synthetic glucocorticoid dexamethasone (DEX) delayed both the loss of growth responsiveness to DHT and the increase in spontaneous growth rate by approximately equal to 60 days. When the growth response to DEX was studied, the changes found were similar to those described above for DHT, namely loss of response following steroid deprivation and preservation of response in cells preincubated with DHT or DEX. In addition, long-term incubation in the presence of DEX was accompanied by low-amplitude stimulation of cell growth at extremely low concentrations of DHT and DEX, suggesting that androgen- and glucocorticoid-hypersensitive cell clones developed during androgen deprivation. The present data show that long-term incubation of androgen-sensitive Shionogi cells leads not only to an increase in the spontaneous growth rate, but also to the appearance of androgen- and glucocorticoid-hypersensitive cells, which may well play an important role in the development of resistance to endocrine therapy in human hormone-sensitive cancers. Although it is not as efficient as DHT, the glucocorticoid DEX can delay the loss of androgen sensitivity in this cell line.

Androgens↗
PubMed1988

Plasma levels of hydroxy-flutamide in patients with prostatic cancer receiving the combined hormonal therapy: an LHRH agonist and flutamide.

The present study describes a method for the measurement of the plasma levels of hydroxy-flutamide (Flu-OH), the biologically active and main circulating metabolite of flutamide. We have observed that two to four hours after oral administration of 250 mg of flutamide to healthy young men, as well as to patients with prostate cancer, the plasma concentration of Flu-OH reaches a peak at approximately 1.7 microM. The plasma concentration of Flu-OH measured at months 6, 12, and 18 of treatment shows a minimal basal level of 3.4 microM with a maximal increase at 6.8 to 8.5 microM at 2 to 4 hours. Since the serum levels of testosterone in these patients are approximately 1 nM, the levels of the active antiandrogen are at a 5000- to 10000-fold excess. However, due to the low affinity of the antiandrogen for the androgen receptor, it is extremely important to maintain this concentration of the antiandrogen in plasma constant.

Adult↗
PubMed1988

Sexuality changes in prostate cancer patients receiving antihormonal therapy combining the antiandrogen flutamide with medical (LHRH agonist) or surgical castration.

The results of a written questionnaire with 44 patients (pilot study) indicated that before the beginning of treatment for advanced prostatic cancer, most subjects had an active sexual life, as illustrated by a normal erotic imagery, an adequate sexual desire and a normal frequency of intercourse. More than three-quarters (80%) of subjects had at least one coitus a week. Slightly more than 50% were able to easily achieve an erection by erotic imagery or by a preferred sexual fantasy; 50% never experienced erectile problems. When compared with their previous sexual functioning, 70% of subjects noticed during the antiandrogenic treatment a major reduction in their interest for sexual intercourse which was maintained in only 18% of patients. It became impossible for 57% to induce an erection by erotic imagery. However, 19% claimed an ability to maintain an erection during sexual activity, as compared to 56% before treatment, but erections usually lacked full rigidity. Twenty-two percent of patients mentioned having nocturnal or morning erections. Despite this dramatic decrease in sexual activity in most patients, complete antiandrogen blockade left sexual activity in approximately 20% of patients. Due to the treatment's excellent tolerance, the findings suggest that such combined androgen blockade could be beneficial for the treatment of sex offenders.

Aged↗
PubMed1988

Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line.

This study describes the inhibitory effect of 5 alpha-dihydrotestosterone (5 alpha-DHT) and its precursors testosterone (T) and androst-4-ene-3,17-dione (delta 4-DIONE) on the growth of the estrogen-sensitive human breast cancer cell line ZR-75-1. In the absence of estrogens, cell proliferation measured after a 12-day incubation period was 50-60% inhibited by maximal concentrations of 5 alpha-DHT, T, or delta 4-DIONE with half-maximal effects (IC50 values) observed at 0.10, 0.15 and 15 nM, respectively. This growth inhibition by androgens was due to an increase in generation time and a lowering of the saturation density of cell cultures. The antiestrogen LY156758 (300 nM) induced 25-30% inhibition of basal cell growth, its effect being additive to that of 5 alpha-DHT. The mitogenic effect of 1 nM estradiol (E2) was completely inhibited by increasing concentrations of 5 alpha-DHT with a potency (IC50 = 0.10 nM) similar to that measured when the androgen was used alone. E2 had a more rapid effect on cell proliferation than 5 alpha-DHT, the latter requiring at least 5 to 6 days to exert significant growth inhibition. As found in the absence of estrogens, maximal inhibition of cell proliferation in the presence of E2 was achieved by the combination of the antiestrogen and 5 alpha-DHT. Supraphysiological concentrations of E2 (up to 1 microM) were needed to completely reverse the growth inhibitory effect of a submaximal concentration of 5 alpha-DHT (1 nM). The antiproliferative effect of androgens was competitively reversed by the antiandrogen hydroxyflutamide, thus indicating an androgen receptor-mediated mechanism. The present data suggest the potential benefits of an androgen-antiestrogen combination therapy in the endocrine management of breast cancer.

Androgen Antagonists↗