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F Labrie

Publications and source records attributed to F Labrie.

At least 217 records · Page 12Linked to original sources
PubMed1993

Structure and tissue-specific expression of a novel member of the rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) family. The exclusive 3 beta-HSD gene expression in the skin.

Structures of cDNA clones encoding three members of the rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) family were characterized. To search for potential new types of 3 beta-HSD, rat types I and II 3 beta-HSD cDNAs were used as probes to screen a rat genomic DNA library. Among the clones isolated, one encodes a novel predicted rat 3 beta-HSD isoenzyme, chronologically designated type IV. The corresponding full-length cDNA was thereafter isolated by selective polymerase chain reaction amplification from rat ovary and day-15 placenta cDNA libraries. The rat type IV 3 beta-HSD cDNA encodes a predicted 372-amino acid protein of 41,854 daltons, which shares 90.9, 87.9, and 78.8% sequence identity with rat types I, II, and III proteins, respectively. Ribonuclease protection assay reveals that type IV 3 beta-HSD is the sole 3 beta-HSD mRNA species detectable in the skin and represents the predominant species in the placenta while being also detectable in the ovary and, to a lower degree, in the adrenal gland. Transient expression of type IV cDNA in SW-13 cells indicates 3 beta-HSD activity similar to that of rat type I 3 beta-HSD. The presence of multiple 3 beta-HSD genes should permit differential and tissue-specific regulation of this rate-limiting enzymatic activity essential in the biosynthesis of all classes of steroid hormones in both classical steroidogenic and intracrine peripheral tissues.

Amino Acid Sequence↗
PubMed1993

Combination therapy for prostate cancer. Endocrine and biologic basis of its choice as new standard first-line therapy.

RESULTS. All double-blind randomized and prospective clinical trials in advanced prostate cancer have shown that combination therapy using a nonsteroidal antiandrogen in association with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy has significant benefits according to all the subjective and objective parameters used, the most important being a prolongation of survival ranging from 5.4-15.0 months compared with LHRH agonists or orchiectomy alone (standard therapy). The benefits observed are probably the result of the blockade by the antiandrogenic agents of the androgens of adrenal origin, which represent, on average, 40% of the total androgens in men and which, otherwise, are left free to continue to stimulate prostate cancer after castration. These data are supported well by the demonstration of the expression of the genes encoding all enzymes required for the formation of active androgens in prostatic tissue from the inactive adrenal steroid precursors; this new specialty is called intracrinology. Both fundamental and clinical data indicate that low androgen levels cause changes in the cancer cells that lead to no or a poor response to antihormonal therapy. CONCLUSIONS. It is thus imperative that combination therapy be used as first treatment in all patients in whom endocrine therapy is indicated. Prior exposure to monotherapy shortens the patient's life by many months and produces a poor quality of life.

Adrenal Cortex Hormones↗
PubMed1993

Ontogeny of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) in rat testis as studied by immunocytochemistry.

The enzymatic complex 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) is a step essential in the biosynthesis of all biologically active steroids, including androgens. In order to obtain information about the expression of 3 beta-HSD during testis development, we have localized this enzyme by light microscope immunocytochemistry during fetal and postnatal periods of development in the rat. In fetal testis, the enzyme was first detected in a few Leydig cells on the 17th day of gestation. The number of labeled cells and intensity of labeling increased with fetal development. From days 19 to 21 of gestation, strongly immunoreactive Leydig cells were arranged in clusters between seminiferous tubules. During the first days following birth, the number and size of positive cells rapidly decreased so that on postnatal days 5 and 10 only small, poorly stained cells could be seen. Fifteen days after birth, positive Leydig cells appeared more numerous and localized in peri- and intertubular spaces. At the onset of puberty, the intensity of labeling markedly increased. After puberty, and during adulthood, both strongly and weakly stained Leydig cells were mainly localized in intertubular spaces. Since the fluctuations in 3 beta-HSD content revealed in the present study by immunocytochemistry appear similar to those already observed for androgen secretion, such data suggest that regulation of 3 beta-HSD by trophic hormones might play an important role in regulating testicular androgen production during fetal as well as postnatal development.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Controlled release low dose medroxyprogesterone acetate (MPA) inhibits the development of mammary tumors induced by dimethyl-benz(a) anthracene in the rat.

Medroxyprogesterone acetate (MPA) is well recognized to have beneficial effects for the treatment of advanced breast cancer which are comparable to those achieved with other forms of endocrine therapy. Using mammary tumors induced in the rat by dimethylbenz(a)anthracene (DMBA) as a model, we have studied the possibility that low dose MPA could prevent the development of these tumors. Single subcutaneous injection of Depo-Provera (crystalline suspension of MPA) or MPA encapsulated in biodegradable microspheres of 50:50 poly[DL-lactide-co-glycolide] was given 7 days before oral DMBA. While 63% of intact animals developed palpable mammary tumors within 85 days after DMBA administration, tumor incidence decreased to 28% and 23% in animals who had received 30 mg and 100 mg of Depo-Provera, respectively. The same amounts of MPA delivered in microspheres caused a further decrease in tumor incidence to respective values of 7% and 6%. Average tumor area, on the other hand, decreased from 4.89 cm2 in intact rats to about 0.75 (0.57-0.88) cm2 and approximately 0.20 (0.14-0.22) cm2 in the Depo-Provera and microsphere-treated groups, respectively. Using the 50:50 formulation of poly[DL-lactide-co-glycolide] designed to release MPA at a constant rate for a 4-month period, the serum MPA concentration at 3 months was measured at 4.99 +/- 0.43 ng/ml. Such data suggest that administration of a low dose controlled-release formulation of MPA in 50:50 poly[DL-lactide-co-glycolide] microspheres could well be an efficient and well tolerated approach for the prevention of breast cancer in women.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Blockade of androstenedione-induced stimulation of androgen-sensitive parameters in the rat prostate by combination of Flutamide and 4-MA.

In order to mimic the human situation in which adrenal steroid precursors are converted to the active androgen dihydrotestosterone (DHT) in prostatic tissue, we have used castrated rats supplemented with the precursor steroid androstenedione (delta 4-dione) released from Silastic implants. While it is well known that the action of DHT can be partially neutralized by antiandrogens which compete for binding to the androgen receptor, we have used 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone into DHT, in order to decrease intraprostatic DHT levels and thus facilitate the action of the antiandrogen. Animals were treated for 7 days with Flutamide (FLU, 2 mg) or 4-MA (4 mg) injected subcutaneously, twice daily, alone or in combination. 4-MA administered alone caused a 54% inhibition of delta 4-dione-stimulated ventral prostate weight while FLU exerted a 74% inhibitory effect and 4-MA+FLU further improved inhibition to 81%. We then measured, by in situ hybridization, the levels of prostatic mRNAs encoding the C1 and C3 components of the prostatic binding protein (PBP) which are highly specific and sensitive markers of androgen action. PBP-C3 mRNA levels fell by 95% following castration while treatment with delta 4-dione completely reversed the effect of castration. Administration of FLU or 4-MA independently caused 33% and 10% decreases, respectively, of PBP-C3 mRNA levels stimulated by delta 4-dione while the combination of both compounds further inhibited PBP-C3 mRNA levels to reach a 55% inhibition. Similar effects were observed on PBP-C1 mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗
PubMed1993

Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy.

The effect of flutamide withdrawal was studied in 40 patients with stage D2 prostate cancer showing progression of the disease after an initial and long (average 3.9 years) period of positive response to combination therapy with flutamide associated with medical (luteinizing hormone-releasing hormone agonist) or surgical castration. Using the criteria of response of the United States National Prostatic Cancer Project, 1 complete, 3 partial and 26 stable responses were observed, while 10 patients continued to have progression after discontinuation of flutamide. The average durations of previous treatment with combination therapy were 1,794 days for the 30 responders (complete, partial and stable responses), compared to 1,726 days for the 10 nonresponders. The average duration of response after the arrest of flutamide was 440 days. Serum prostate specific antigen, which was elevated in all patients, decreased by 90% or more in 19 of the 30 responders (63%) and returned to normal in 17 (57%). The concentration of testosterone binding globulin increased after discontinuation of flutamide, thus also suggesting the suppression of an androgenic influence, while the serum levels of testosterone and dihydrotestosterone, as well as their main metabolites, did not change after withdrawal of flutamide. Alteration of local sensitivity to androgens is a probable explanation for the paradoxical positive response to the arrest of flutamide suggested in the present preliminary study.

Adenocarcinoma↗
PubMed1993

Detection of polymorphisms in the estradiol 17 beta-hydroxysteroid dehydrogenase II gene at the EDH17B2 locus on 17q11-q21.

The human estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II) gene has been assigned by somatic cell hybridization to chromosome 17q11-q21, near the region of assignment of the gene BRCA1, which is involved in hereditary breast-ovarian cancer. The nucleotide sequence of 17 beta-HSD II was completely determined in four unrelated individuals. Direct sequencing of PCR fragments that span the complete 17 beta-HSD II gene revealed a total of 11 allelic variants which were due to single base substitutions. The presence of these variants was then studied in twenty six additional unrelated individuals. There were nine frequent and two rare polymorphisms. Seven of the 11 polymorphisms were in complete linkage disequilibrium. These polymorphisms in the 17 beta-HSD II gene provide markers that can be used for the genetic mapping of this locus, and may be used to establish whether 17 beta-HSD II is a candidate gene for hereditary breast-ovarian cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed1993

Ontogenesis of 3 beta-hydroxysteroid dehydrogenase delta 5-delta 4 isomerase in the rat ovary as studied by immunocytochemistry and in situ hybridization.

The enzyme complex 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5-4-ene isomerase (3 beta-HSD) is involved in the biosynthesis of all classes of active steroids, namely glucocorticoids, mineralocorticoids, and sex steroids. To obtain more information about the age-specific expression and localization of 3 beta-HSD during development in the rat ovary, two complementary cytochemical techniques were used, immunocytochemical localization with antibodies against purified human placental 3 beta-HSD, and 3 beta-HSD mRNA localization achieved by in situ hybridization with a [35S]-labeled cDNA encoding 3 beta-HSD. In the fetal ovary, no significant immunolabeling or hybridization signal could be observed. The first expression of the enzyme was observed 6 days after birth, immunolabeling as well as autoradiographic reaction being found in a few interstitial gland cells. At the 10th day of postnatal life, the theca interna cells of growing follicles appeared to be labeled with both techniques. The granulosa cells of growing follicles also exhibited hybridization signal, whereas no immunostaining could be detected in these cells at any of the time intervals studied. At puberty, 3 beta-HSD was localized in theca interna and granulosa cells of the growing and mature follicles as well as in the interstitial gland and corpus luteum cells. Similar results were obtained in 40-day-old and adult animals. The present data indicate a progressive expression of 3 beta-HSD in different morphological structures during ovarian development in the rat.

Aging↗
PubMed1993

Combination therapy with flutamide and the LHRH agonist [D-Trp6, des-Gly-NH(2)10]LHRH ethylamide in stage C prostatic carcinoma.

A series of 115 previously untreated patients displaying clinical stage C prostatic carcinoma with no evidence of distant metastases received combination therapy using the antiandrogen flutamide and the LHRH agonist [D-Trp6, des-Gly-NH(2)10]LHRH ethylamide; the average follow-up was 3.9 years. Twenty-eight patients showed treatment failure with a probability of disease-free survival of 91.2% at 2 years. Twenty patients died from prostate cancer and 10 from other causes, the survival probability being 93.4% at 2 years. Local control was achieved rapidly in all patients. Urinary obstruction and hydronephrosis were corrected in all cases. When compared with data obtained after single endocrine therapy (orchiectomy or oestrogens) or radiotherapy, the treatment failure rate at 2 years was more than 3.0-fold lower after combination therapy (8.8%) than monotherapy (28.4%). The death rate 2 years after the start of combination therapy was 6.6% and was on average 22.2% (3.6-fold higher) in the studies using monotherapy (orchiectomy or oestrogens) or radiotherapy. The present data suggest that treatment of prostate cancer with combination therapy before clinical evidence of dissemination of disease permits more efficient control of local disease and a decreased rate of progression to metastatic disease.

Aged↗
PubMed1993

Changes in the abundance of mRNA for type-I 3 beta-hydroxysteroid dehydrogenase/delta 5-->delta 4 isomerase in the human placenta and fetal membranes during pregnancy and labor.

A local decrease in progesterone synthesis in the placenta and fetal membranes has long been proposed as a possible mechanism in the control of human labor. We have examined whether changes occur in the abundance of mRNA for 3 beta-hydroxysteroid dehydrogenase/delta 5-->delta 4 isomerase (3 beta-HSD), the enzyme which catalyzes the conversion of pregnenolone to progesterone in human placenta and fetal membranes, by Northern blot analysis using a cDNA probe to human placental type-I 3 beta-HSD, the predominant isoenzyme in the placenta. The abundance of 3 beta-HSD mRNA (1.7-kb transcript) was about 10-fold greater in term placenta than in chorio-decidua, but undetectable in total RNA from amnion. There was no change in the abundance of 3 beta-HSD mRNA in either placenta or chorio-decidua obtained after elective cesarean section at term, after preterm labor, or after term or postterm vaginal delivery. We conclude that the abundance of 3 beta-HSD mRNA does not change in the placenta or fetal membranes with labor, consistent with the view that changes in 3 beta-HSD gene expression and decreased progesterone production are unlikely to effect intrauterine paracrine/autocrine regulatory mechanisms leading to term or preterm labor in women.

Blotting, Northern↗
PubMed1993

Workshop summary: hormonal suppression in the neoadjuvant setting and advanced disease.

For advanced prostate cancer, hormonal suppression has long played an important role in patient management. Furthermore, the concept of combined androgen blockade using a luteinizing hormone-releasing hormone agonist in combination with an antiandrogen such as flutamide is gaining increasing acceptance. The novel regimen of finasteride (a 5-alpha-reductase inhibitor) plus flutamide may also have a role to play in the future. In the neoadjuvant setting, androgen suppression prior to radical prostatectomy is a novel approach. This strategy aims to reduce the size of the tumor as much as possible, hopefully downstaging the disease, and thus increasing the chances of a successful outcome at operation. Data from studies presented at this symposium revealed a clear reduction in tumor size by this method but the effects on both staging of disease and long-term outcome were not so definitive. Questions were put to the audience and the expert panel to assess their opinion of hormonal therapy and staging techniques, both in the neoadjuvant and advanced disease settings.

Androgen Antagonists↗
PubMed1993

Intracrinology: the basis for the rational design of endocrine therapy at all stages of prostate cancer.

Adrenal androgens contribute 40% of total androgens in adult men. The inactive precursor steroids dehydroepiandrosterone (DHEA) and DHEA-sulfate are secreted in large amounts by the adrenals and reach the prostate and other peripheral target tissues, where they are transformed into the potent androgen dihydrotestosterone (DHT). We have cloned and sequenced the cDNAs and/or genes which encode the enzymes responsible for the transformation of DHEA into DHT, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase. Blockade of DHT synthesized by these enzymes, with a pure antiandrogen of the class of flutamide, prolongs life in advanced prostate cancer, the effect being much more important when a small number of metastases is present. Most importantly, 3-month combination therapy reduces cancer-positive margins at radical prostatectomy, from 38.5% in control patients to only 13% in those who received combination therapy. Combined with an efficient strategy for detection of early-stage prostate cancer, the present approach could offer the possibility of a cure to more than 80% of prostate cancer patients, compared with the present situation where a cure can be offered to less than 20% of patients, since the first diagnosis of prostate cancer is usually made at a late stage of the disease.

Adrenal Glands↗
PubMed1993

Androgen receptor-mediated stimulation of 17 beta-hydroxysteroid dehydrogenase activity by dihydrotestosterone and medroxyprogesterone acetate in ZR-75-1 human breast cancer cells.

The estrogen-sensitive human breast cancer cell line ZR-75-1 was used to study the regulation of 17 beta-hydroxysteroid dehydrogenase (17 beta HSD), the enzyme responsible for the interconversion of estrone (E1) and estradiol (E2). We, thus, investigated the effects of a 6-day exposure to various steroids or growth factors on the reductive (E1-->E2) and oxidative (E2-->E1) 17 beta HSD activities in ZR-75-1 cells as measured during a subsequent 16-h incubation with [3H]E1 or [3H]E2. The reductive 17 beta HSD activity was approximately 3-fold higher than the corresponding oxidative (E2-->E1) activity in control cells, thus favoring the predominance of E2 within the cell. Exposure to dihydrotestosterone (DHT) increased by 1.4-fold the reductive 17 beta HSD activity, with the stimulatory effect exerted at an EC50 value of 0.09 nM DHT, while the oxidative pathway was increased by 4.15-fold at an EC50 value of 0.17 nM. Incubation with medroxyprogesterone acetate, on the other hand, enhanced reductive 17 beta HSD activity by 1.87-fold, while the same treatment increased oxidative 17 beta HSD activity by 2.85-fold; the effects were exerted at EC50 values of 0.4 and 5 nM, respectively. The stimulatory effect of both steroids on 17 beta HSD activity was almost completely reversed by simultaneous exposure to the pure antiandrogen hydroxyflutamide (3 microM), thus supporting an action exerted through the androgen receptor. On the other hand, the synthetic estrogen ethynyl estradiol (EE2) inhibited the reductive and oxidative 17 beta HSD activities by 40% and 33%, respectively, whereas dexamethasone (300 nM) increased by 2.5- and 1.9-fold the reductive and oxidative 17 beta HSD activities, respectively. The present data showing that DHT and the androgenic compound medroxyprogesterone acetate favor the degradation of E2 into E1 suggest that the potent antiproliferative activity of these two compounds in E2-stimulated ZR-75-1 human breast cancer cells could be at least partially exerted through changes in 17 beta HSD activity.

17-Hydroxysteroid Dehydrogenases↗
PubMed1993

Characterization and measurement of prostate-specific antigen using monoclonal antibodies.

Monoclonal and polyclonal antibodies were produced using a pure preparation of prostate-specific antigen (PSA) as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). By SDS-PAGE, the apparent molecular weight of PSA was about 33 kD. Eighty-four monoclonal antibodies were produced, 77 of which bind PSA with an affinity higher than 10(9) M-1. Use of these monoclonal antibodies to study the immunological characteristics of PSA revealed the presence of 4 epitopes. Injection of PSA into goats resulted in a production of polyclonal antibodies with high affinity. These polyclonal antibodies were purified by affinity chromatography and adsorbed on plastic tubes. By an immunometric assay, we have also demonstrated that polyclonal antibodies bind PSA at a fifth epitope that is different from those of monoclonal antibodies. Using an iodinated monoclonal antibody and polyclonal antibodies adsorbed on plastic tubes, a sensitive immunoradiometric assay could be developed, and a further increase in sensitivity could be achieved by using a mixture of 2 monoclonal antibodies. The serum PSA levels in 2,250 patients measured with this immunoradiometric assay were identical to the values determined by Tandem-R, although the present assay reached a minimum detectable value of 0.05 ng/ml compared with 0.2 ng/ml by Tandem-R.

Animals↗
PubMed1993

Optimized strategy for detection of early stage, curable prostate cancer: role of prescreening with prostate-specific antigen.

In 1,002 men aged 45-80 y, 81% of the cancers detectable by serum prostate-specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasonography (TRUS) were present in a subpopulation (19% of total) identified by serum PSA above the threshold value of 3.0 micrograms/L. This study was extended to 7,350 men using serum PSA and DRE as first approach, followed by TRUS only when 1 of these 2 tests was abnormal. Because the aim of prostate cancer detection is to find cancers at an early, potentially curable stage, it is of major interest that 71.8% of evaluable cancers were clinical stage B; 8.4% and 10.7% were stages C1 and C2, respectively; only 9.2% were stage D (metastatic) at first visit while none was at stage D at follow-up visits. This study, the first performed in an unselected, unscreened population, shows that serum PSA is the most sensitive technique to identify men at high risk of having prostate cancer and that 12% more cancers can be found at first visit by doing DRE in addition to PSA. Follow-ups can be done every second year using serum PSA alone, as 97% of the cancers detected at annual follow-up by DRE + PSA were PSA+. Cancers are discovered by the present approach at an estimated cost of $2,665 per cancer. Such cancers are potentially curable in at least 80% of cases detected at first visit and in 97% of cases at follow-up. This strategy offers the possibility to improve markedly morbidity and mortality from prostate cancer, presently the second leading cause of cancer death in North American men.

Aged↗
PubMed1993

Science behind total androgen blockade: from gene to combination therapy.

Probably the most important finding in the endocrine therapy of prostate cancer is that the testicles and adrenals contribute approximately equal amounts of dihydrotestosterone (DHT), the active androgen that stimulates normal and cancerous prostatic cell growth and function. Structure of the cDNAs and genes encoding most of the enzymes responsible for the transformation of the adrenal precursor dehydroepiandrosterone (DHEA) into DHT have recently been elucidated, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase, and 5 alpha-reductase. With the action of these enzymes, DHT is then made locally in the prostate from circulating DHEA of adrenal origin. Given such an important role of the adrenals, it is essential to use a pure antiandrogen for maximal blockade of the interaction of DHT with the androgen receptor while the testicles are blocked by orchiectomy or treatment with a luteinizing hormone-releasing hormone (LHRH) super-agonist. This combination therapy was first developed to treat advanced prostate cancer. The multicenter clinical data recently obtained confirm our original data and demonstrate the major importance of the intracrine or in situ formation of androgens in the human prostate from the inactive adrenal steroid precursors. Combination therapy thus permits, for the first time, to prolong life in advanced prostate cancer and, most importantly, offers the possibility of a major improvement in the efficacy of a curative therapy, namely, radical prostatectomy in early stage disease.

Aged↗
PubMed1993

Major advantages of "early" administration of endocrine combination therapy in advanced prostate cancer.

Combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or orchiectomy was administered to 268 patients with previously untreated metastatic stage D2 prostate cancer for an average of 1,191 d (3.26 y). Only 17 of the 268 evaluable patients (6.5%) showed no objective positive response to the combination therapy assessed according to the National Prostatic Cancer Project objective criteria of response. The median duration of the disease-free response was 2.23 y and median overall survival was 3.58 y. The median survival for patients with only 1-5 bone metastases was not yet reached at 8 y, but for patients with 6-10 bone lesions, 11-40 bone lesions, and multiple bone metastases (superscan), median survival was markedly reduced to 3.56, 2.36, and 1.76 y, respectively. Analysis of patients according to general symptomatology, pain, and performance status showed median survivals of 5.47, 2.71, and 2.1 y for minimal, moderate, and severe symptoms, respectively. The present data demonstrate that administration of combination therapy to stage D2 prostate cancer patients having 1-5 bone metastases adds a minimum of 4.4 y of good quality life compared with patients whose disease is slightly more advanced. Our findings clearly demonstrate the major importance of starting combination therapy as soon as possible after diagnosis of metastatic prostatic cancer.

Androgen Antagonists↗