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R St-Arnaud

Publications and source records attributed to R St-Arnaud.

43 records · Page 3Linked to original sources

Distribution of epidermal growth factor receptors in the rat ovary.

The distribution of epidermal growth factor (EGF) was studied in the ovary using light microscope radioautography which was performed at different time intervals (2-60 min) after intravenous (i.v.) injection of [125I]EGF into adult rat at random stages of the estrous cycle and also after topical localization of iodinated EGF on slide-mounted frozen ovarian sections. After i.v. injection of label, the labeling was mostly observed in the theca interna cells of secondary, preovulatory and atretic follicles and luteal cells of corpus luteum. Primordial and primary follicles did not show any significant labeling. The time-course study performed on luteal cells showed that, 2 min after injection, most silver grains were found at the periphery of the cells. At the 10 min time interval, silver grains were found both at the periphery and over the cytoplasm of these cells. The number of grains was very reduced over the cytoplasm at the 60 min time interval. In the in vitro study, a positive radioautographic reaction was seen in the same cellular elements as found in vivo, with the additional labeling of the granulosa cells of growing and preovulatory follicles. Control experiments indicated that the radioautographic labeling was due to specific interaction of [125I]EGF with its receptor. These results clearly indicate that EGF binding sites are present in luteal, thecal and granulosa cells, and provide support for the inhibitory and stimulatory actions of EGF on different parameters of ovarian cells.

Animals↗

Loss of luteinizing hormone bioactivity in patients with prostatic cancer treated with an LHRH agonist and a pure antiandrogen.

Chronic treatment of adult men with LHRH agonists causes a decrease in serum testosterone and 5 alpha-dihydrotestosterone to castrate levels. In the presence of such low levels of circulating testicular androgens, the concentration of serum LH measured by radioimmunoassay (RIA) sometimes remains normal or is only partially inhibited. In order to assess the biological activity of circulating LH, we have used the mouse interstitial cell assay. Blood samples were obtained from patients with prostatic carcinoma treated with the LHRH agonist [D-Trp6] LHRH ethylamide in combination with the pure antiandrogen Flutamide (Euflex). While serum LH levels measured by RIA were only partially reduced from 2.2 +/- 0.3 (SEM) to 1.1 +/- 0.1 ng/ml after 3 months of therapy, bioactive LH was markedly inhibited from 0.43 +/- 0.04 to 0.030 +/- 0.007 ng/ml, thus causing the ratio of biologically active to radioimmunoassayable LH to drop from 0.26 +/- 0.03 to 0.03 +/- 0.01. In the same patients, serum testosterone levels were decreased from 3.91 +/- 0.51 to 0.14 +/- 0.05 ng/ml after 3 months of treatment. In patients treated for 6 months, the bio/immuno ratio was still reduced at 0.032 +/- 0.005. These data show a marked loss of LH biological activity during treatment of adult men with an LHRH agonist and an antiandrogen. The close parallelism observed between serum testosterone and bioactive LH levels suggests that the loss of biological activity of the gonadotrophin is mainly, if not exclusively, responsible for the inhibition of testicular androgen secretion observed during chronic treatment with LHRH agonists.

Adenocarcinoma↗

Treatment of prostate cancer with gonadotropin-releasing hormone agonists.

It is now well established that chronic treatment with GnRH agonists offers an advantageous alternative to orchiectomy and estrogens for the treatment of prostate cancer. Castration levels of androgens can thus be easily achieved without side effects other than those related to castration levels of serum androgens. However, man is unique among species in having a high secretion rate of precursor adrenal steroids which are converted into active androgens in the normal prostate and prostatic cancer. All the enzymes required for the transformation of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and androst-5-ene-3 beta, 17 beta-diol are present in prostatic tissue. Moreover, as shown in many systems, castration levels of serum testosterone (T) at 0.2-0.4 ng/ml exert significant androgenic activity in target tissues. In order to inhibit the action of androgens of both testicular and adrenal origin, GnRH agonists have been administered in association with the pure antiandrogen Flutamide in patients having clinical stage D2 (bone metastases) prostate cancer. A positive objective response assessed according to the criteria of the United States National Prostatic Cancer Project (USNPCP) has been observed in 84 of the 88 patients who had received no previous treatment (95.4%). After 2 yr of treatment, the probability of continuing response is 70% compared to 0-10% by previous approaches. In addition, the death rate at 2 yr is at 10.9% as compared to approximately 50% after standard hormonal therapy. When the same treatment was applied to patients who had received previous hormonal therapy (orchiectomy, estrogens or GnRH agonists alone) before showing a relapse, the response rate decreased to 62.9% and the death rate at 2 yr was 52%.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen Antagonists↗

Stimulation of the circulating levels of glycoprotein hormone alpha-subunit after combined administration of a luteinizing hormone-releasing hormone (LHRH) agonist and flutamide in patients with cancer of the prostate.

To ascertain whether the immunoreactive luteinizing hormone (LH) levels measured following the combined treatment may represent cross-reaction of the LH antiserum with LH subunits, we have examined the effects of therapy on the serum levels of free alpha- and free LH-beta-subunits in intact, castrated, and estrogen-treated patients. In previously untreated patients receiving the LHRH agonist [D-Trp6,des-Gly-NH2(10)]LHRH ethylamide in association with the pure antiandrogen Flutamide, serum-free alpha-subunit levels were stimulated from 0.09 +/- 0.02 to 3.10 +/- 0.84 ng/ml after 5 days, and declined slowly afterwards to 1.33 +/- 0.20 ng/ml after 3 months of combined treatment. In patients pretreated from 12 to 24 months (17.5 +/- 1.0 months) with diethylstilbestrol (DES) prior to receiving the combined therapy, free serum alpha-subunit concentration followed a similar pattern, rising from 0.22 +/- 0.03 to 1.78 +/- 0.28 ng/ml after 15 days of combined treatment, and declining thereafter to 0.81 +/- 0.10 ng/ml after 3 months. Free LH-beta-subunits were below the detection limit in most previously untreated patients and in all DES-treated patients. After correcting for the cross-reactivity of the alpha-subunit in the LH RIA, immunoassayable LH serum levels in previously untreated patients were only slightly reduced from 0.81 +/- 0.06 ng/ml before the onset of the combined treatment to 0.52 +/- 0.05 ng/ml after 3 months. On the contrary, bioactive serum LH levels were drastically inhibited from 0.43 +/- 0.04 to 0.03 +/- 0.01 ng/ml after the same duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen Antagonists↗

Rat ovarian epidermal growth factor receptors: characterization and hormonal regulation.

Rat ovarian epidermal growth factor (EGF) receptors were characterized in total ovarian homogenate obtained from animals at random stages of the estrous cycle. A single class of specific and high-affinity binding sites with an apparent dissociation constant (KD) of 1.1 +/- 0.2 nM and a total site number of 78 +/- 4 fmoles/mg protein (652 +/- 17 fmoles/100 mg wet tissue) was observed. In 4-day cycling rats, ovarian EGF receptor levels are high (200 fmoles/100 mg ovary) on the morning of estrus as well as in the afternoon of proestrus and are lower by 30, 60 and 55% on the morning of diestrus I, diestrus II and proestrus, respectively. Chronic administration of an LHRH agonist is accompanied by low ovarian EGF receptor levels comparable to those observed on diestrus II. In intact or hypophysectomized female rats pretreated with pregnant mare's serum gonadotropins, administration of ovine follicle-stimulating hormone or human chorionic gonadotropin increases ovarian EGF receptor concentration and content while the administration of ovine prolactin, 17 beta-estradiol or progesterone has no effect. Treatment with dihydrotestosterone or testosterone slightly reduces ovarian EGF binding in intact but not hypophysectomized animals. The variation of ovarian EGF receptor levels observed during the estrous cycle as well as the modulation of these receptors by the administration of exogenous gonadotropins suggest that EGF could well play a physiological role in the regulation of ovarian functions.

Animals↗

[Epidermal growth factor: structure, location, phosphorylation and regulation of its receptor].

Epidermal growth factor (EGF) is a Mr 6045 polypeptide first characterized for its ability to stimulate mitogenesis in epidermal and epithelial cells. The first step in the action of the growth factor is its binding to specific, high affinity membrane receptors. These receptors have been studied in a number of tissues and cell culture lines. The level of EGF receptors is modulated by many agents. EGF down-regulates its receptor. In addition, the number of EGF receptors is decreased by other growth factors (platelet-derived growth factor; transforming growth factor), by many tumor promoters and by viral transformation. Several hormones also can regulate EGF binding in its target tissues.

Animals↗

The 3-epi- and 24-oxo-derivatives of 1alpha,25 dihydroxyvitamin D(3) stimulate transcription through the vitamin D receptor.

Vitamin D is enzymatically modified to more than 35 metabolites. While many of these are thought to represent degradation products, some have been shown to exhibit biological activity. We tested whether 3-epi-1alpha,25-dihydroxyvitamin D(3) (3-epi-1alpha, 25(OH)(2)D(3)), 1alpha,25-dihydroxy-24-oxo-vitamin D(3) (1alpha, 25(OH)(2)-24-oxo-D(3)), and 1alpha,25(OH)(2)D(3)-26,23-lactone can stimulate transcription of vitamin D responsive genes. MC3T3-E1 cells transfected with a 25-hydroxyvitamin D 24-hydroxylase (CYP24) promoter construct displayed a 6 fold response when treated with either 1alpha,25(OH)(2)D(3) or 3-epi-1alpha,25(OH)(2)D(3). Caco-2 cells were transfected with the wild type CYP24 promoter construct, or a Vitamin D Response Element (VDRE)-mutated form. Cells acquiring the wild type reporter responded to 1alpha,25(OH)(2)D(3) and 3-epi-1alpha,25(OH)(2)D(3) but not cells which acquired the mutated reporter. Additionally, VDR-negative COS-7 cells transfected with the wild type promoter responded (approximately 13 fold) to 1alpha, 25(OH)(2)D(3) and 3-epi-1alpha,25(OH)(2)D(3), only when co-transfected with the VDR. These results were confirmed using shorter incubation times and serum-free conditions. This strongly suggested that 3-epi-1alpha,25(OH)(2)D(3) mediates its effects through the VDR and its cognate binding site. Similar results were obtained with 1alpha,25(OH)(2)-24-oxo-D(3) using VDR-negative P19 cells. We could never detect activity from 1alpha,25(OH)(2)D(3)-26, 23-lactone on vitamin D-responsive target promoters. Our results firmly conclude that both 3-epi-1alpha,25(OH)(2)D(3) and the 1alpha, 25(OH)(2)-24-oxo-D(3) elicit their biological effects by acting through the VDR/VDRE.

Animals↗