Complete androgen blockade for the treatment of prostate cancer.
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Acid Phosphatase↗
Biomedical subjects
F Labrie
Publications and source records attributed to F Labrie.
Presence of C-19 steroids in mammary Shionogi carcinoma (SC 115) in castrated mice.
Intact and castrated male DD/S mice were inoculated with androgen-dependent cells (SC 115). All intact animals developed tumors after Day 12 of inoculation; however, six of seven castrated animals presented tumors 48 days postinoculation. The levels of steroids in both tumors were then examined. In castrated mice, dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol levels were diminished by 30% and 70%, respectively, while the amounts of testosterone and androstenedione were reduced by more than 90%. Our data also demonstrate that androstane-3 alpha, 17 beta-diol and androstane-3 beta, 17 beta-diol were decreased to 60% and dihydrotestosterone decreased to 6% of their normal value, respectively. This latter level (0.48 nM) was sufficient to still effect a potent androgenic response in the tumor. Besides, a highly significant correlation was found in these tumors between various C-19 steroids (dehydroepiandrosterone and androstane-3 alpha, 17 beta-diol, r = 0.97, P less than 0.01), suggesting a possible conversion of C-19 precursors into potent androgens in the tumors. Determination of the plasma steroid levels in the castrated animals clearly confirmed that potent androgenic steroids and precursors were still in the circulation 3 days after castration. It thus appears that C-19 steroids from adrenal origin may be also involved in "independent" tumor growth.
Animals↗
Combined treatment with LHRH agonist and pure antiandrogen in advanced carcinoma of prostate.
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Androgen Antagonists↗
Dexamethasone is a potent stimulator of growth hormone-releasing factor-induced cyclic AMP accumulation in the adenohypophysis.
The stimulatory effect of maximal concentrations of synthetic human pancreatic growth hormone (GH)-releasing factor (GRF)(1-40)NH on cyclic AMP accumulation in rat anterior pituitary cells in culture is 4.5-fold increased following a 48-h preincubation with the potent glucocorticoid dexamethasone while the sensitivity of GRF action is increased by approximately 4-fold. Dexamethasone pretreatment, on the other hand, has no effect on basal cyclic AMP levels but approximately doubles both basal and GRF-induced GH release. The present data suggest that the potent stimulatory effect of glucocorticoids on GH secretion is exerted on the adenylate cyclase system at a step preceding cyclic AMP formation.
Animals↗
The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review.
The nonsteroidal antiandrogen RU 23908 ( Anandron ) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate. When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth-promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen. In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight. This is due to the property of the pure antiandrogen to neutralize the inhibitory feedback effect of androgens at the pituitary level on the LH responsiveness to LHRH, as illustrated in vitro in rat anterior pituitary cells in culture as well as in vivo in intact and castrated animals. In intact animals, neutralization of the inhibitory feedback action of endogenous androgens leads to an increased LH and testosterone secretion, which partly overcomes the direct action of the antiandrogen at the level of the prostate and seminal vesicles. In fact, the plasma testosterone concentration is more than doubled 6 hr after the administration of 10 mg of RU 23908 while plasma LH and testosterone levels are increased by 7- and 17-fold, respectively, after 14 days of similar daily treatment. Efficient neutralization of the androgenic action at the prostatic level in intact animals thus requires prevention of this escape phenomenon through inhibition of LH secretion. Although inhibition of LH release can be achieved by estrogen and progestins, an optimal inhibitory effect on the prostate is obtained by the combined administration of the antiandrogen with an LHRH agonist that causes a specific blockage of testicular androgen biosynthesis as well as an inhibition of the LH responsiveness to LHRH.
Androgen Antagonists↗
Characteristics of the inhibitory effect of chronic treatment with an LHRH agonist on testicular steroidogenesis in the dog.
Daily subcutaneous administration for 3 months of the potent LHRH agonist (D-Ser(TBU)6, des-Gly-NH2(10] LHRH ethylamide (25 micrograms) to adult dogs having spontaneous benign prostate hyperplasia (BPH) causes a marked inhibition of testicular androstenedione and testosterone secretion. This inhibition of delta 4-androgen secretion is accompanied by a decrease of testicular progestin precursors and 5 alpha-androgen metabolites, thus suggesting that, in dog, the loss of testicular steroidogenic activity, induced by the administration of an LHRH agonist, is due to a total inhibition of testicular steroidogenesis. In plasma, the concentration of both testosterone and dihydrotestosterone is also markedly depressed while androstane-3 alpha, 17 beta-diol levels remain unchanged. Measurement of prostatic steroid content has shown that administration of the LHRH agonist as well as castration is associated with a marked decrease in androstenedione, testosterone, and dihydrotestosterone levels in prostate while there is a small inhibition of androst-5-ene-3 beta, 17 beta-diol, androstane-3 beta, 17 beta-diol, dehydroepiandrosterone, and estrone concentrations in this tissue. The present data show that treatment with an LHRH agonist in the dog causes a marked inhibition of testicular steroid secretion similar to the one observed in adult men, and suggest that steroids from adrenal origin may also be involved in prostatic function.
17-alpha-Hydroxyprogesterone↗
Multiple factors involved in the control of ACTH secretion.
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Adrenocorticotropic Hormone↗
Selective inhibition of spermatogenesis in the presence of normal libido following combined treatment with an LHRH agonist and testosterone in the dog.
In order to maintain libido in dogs treated with an LHRH agonist, animals were administered with testosterone in a gel form for percutaneous adsorption. Histological aspect of testis indicate a complete blockade of spermatogenesis after treatment with the LHRH agonist and the addition of testosterone to these animals did not restore the spermatogenesis. The measurement of testicular steroid levels showed that following LHRH-A administration, the concentration of androgens in testis remained low in the presence or absence of testosterone supplement. However, the prostate weight as well as the volume of ejaculate returned to normal when testosterone was added and this observation can be correlated with the high amount of androgens in prostate. The present study supports the use of LHRH agonist in combination with testosterone as a selective method for inhibition of spermatogenesis in the male.
Animals↗
Modulation of cyclic AMP formation and progesterone secretion by human chorionic gonadotropin, epinephrine, buserelin and prostaglandins in normal or human chorionic gonadotropin desensitized rat immature luteal cells in monolayer culture.
It is now well recognized that hCG-induced luteolysis is associated with hCG-induced desensitization, but the physiological significance of luteal cell GnRH, PGS and beta-receptors is still undefined. Therefore, we intend in this study to observe the effects of prostaglandin F2 alpha and prostaglandin E2 and the interactions between epinephrine, a potent LHRH agonist [(D-Ser-(TBu)6, des-Gly-NH2(10)) LHRH ethylamide: Buserelin] and hCG in normal and in vitro hCG-desensitized rat immature luteal cells in monolayer culture, on basal, hCG or cholera toxin stimulated intracellular and extracellular cyclic AMP and progesterone secretion. The present report shows that incubation of immature rat luteal cells in monolayer culture with Buserelin, led to 25-50% inhibition of the epinephrine--as well as PGE2--induced cyclic AMP and progesterone responses. The LHRH agonist can also reverse the stimulatory effects of cholera toxin in the presence of hCG and led with PGF2 alpha, to additive inhibitory effects on extracellular cyclic AMP accumulation induced by cholera toxin. Both Buserelin and PGF2 alpha can reverse the hCG-induced cyclic AMP and progesterone release but no effect could be observed when the incubation was carried out with either substance in the absence of hCG. Prostaglandin E2, in acute conditions of incubation, seems to share agonist properties with hCG when both were incubated with luteal cells. Buserelin reversed the stimulatory effects of PGE2, hCG, epinephrine, and cholera toxin on cyclic AMP and progesterone responses to these substances. These results suggest that Buserelin and PGF2 alpha have luteolytic-like effects and that there may be a complementary action for the two substances. Preincubation of rat luteal cells in monolayer culture with 1 nM hCG for a 24 h period led to the inhibition of cyclic AMP and progesterone responses after a subsequent exposure to hCG and epinephrine. Luteal cells were no longer responsive to hCG while the presence of epinephrine in hCG-desensitized cells led to a 40% stimulation of cAMP and progesterone production. These observations suggest that there occurred a partial alteration of the N component activity of the adenylyl cyclase system.
Animals↗
Interactions between CRF, epinephrine, vasopressin and glucocorticoids in the control of ACTH secretion.
The secretion of ACTH by corticotrophs in the anterior lobe of the rat pituitary gland is under the stimulatory influence of at least three receptors, namely that for peptidic CRF (corticotropin-releasing factor), vasopressin and alpha 1-adrenergic agents. CRF is a potent stimulator of cyclic AMP accumulation as well as adenylate cyclase activity in the rat adenohypophysis, thus suggesting an important role of cyclic AMP as mediator of CRF action on ACTH secretion. Vasopressin causes a 2-fold increase of the stimulatory effect of CRF on ACTH release in rat anterior pituitary cells in culture. The potentiating effects of vasopressin on CRF-induced ACTH release are accompanied by parallel changes of intracellular cyclic AMP levels. Vasopressin, while having no effect on basal cyclic AMP levels, causes a 2-fold increase in CRF-induced cyclic AMP accumulation without affecting the ED50 value of CRF action. ACTH secretion is also stimulated by a typical alpha 1-adrenergic receptor. Epinephrine causes a marked stimulation of ACTH release which is additive to that of CRF. Epinephrine, in analogy with vasopressin, although having no effect alone on basal cyclic AMP levels, causes a marked potentiation of CRF-induced cyclic AMP accumulation. Glucocorticoids cause a near-complete inhibition of epinephrine-induced ACTH secretion within 4 h with the following order of ED50 values: triamcinolone acetonide (0.2 nM) greater than dexamethasone (1.0 nM) much greater than cortisol (11 nM) greater than corticosterone (22 nM). Similar effects are observed for CRF- and vasopressin-induced ACTH release. Although the activity of the pituitary-adrenocortical axis in the rat is highly dependent upon sex steroids, 17 beta-estradiol, 5 alpha-dihydrotestosterone and the pure progestin R5020 have no detectable effect on basal or epinephrine-induced ACTH release, thus illustrating the high degree of specificity of glucocorticoids in their feedback control of ACTH secretion. Moreover, glucocorticoids have no effect on CRF-induced cyclic AMP accumulation, thus indicating that their inhibitory effect is exerted at a step following cyclic AMP accumulation.
Adenylyl Cyclases↗
Further characterization of the direct inhibitory effect of LHRH agonists at the testicular level in the rat.
To further clarify the relative importance of the pituitary and gonadal sites of LHRH action, intact and hypophysectomized adult male rats were treated with hCG for 7 days, in the presence or absence of simultaneous treatment with increasing doses of the LHRH agonist [D-Ser(TBU)6des-Gly-NH2(10)]LHRH ethylamide, Buserelin (0.025, 0.25, 2.5 or 25 micrograms/rat, twice daily). Daily treatment of intact adult rats with hCG (25 IU) markedly increased ventral prostate and seminal vesicle weight, while a dose-dependent inhibition of the effect was observed following combined administration of Buserelin. In hypophysectomized rats, treatment with hCG resulted in a partial restoration of ventral prostate and seminal vesicle weight, while combined treatment with a high dose of the LHRH agonist (25 micrograms, twice daily) partially (P less than 0.05) inhibited the stimulatory effect of hCG. LH/hCG receptors were almost completely inhibited after hCG injection alone and a further decrease was observed in the presence of simultaneous LHRH agonist treatment. The hCG-induced stimulation of GH/PRL receptors was counteracted by Buserelin treatment in hypophysectomized animals. The present data demonstrate that although LHRH-induced LH release has been shown to play a major role in the loss of testicular functions induced by low doses of LHRH agonists in the rat, a direct inhibitory action of LHRH agonists can be exerted at the testicular level at high doses of the peptide.
Animals↗
Modulation of cyclic AMP formation and progesterone secretion by human chorionic gonadotropin, epinephrine, buserelin and prostaglandins in normal or human chorionic gonadotropin desensitized rat immature luteal cells in monolayer culture.
It is now well recognized that hCG-induced luteolysis is associated with hCG-induced desensitization, but the physiological significance of luteal cell GnRH, PGs and beta-receptors is still undefined. Therefore, we intend in this study to observe the effects of prostaglandin F2 alpha and prostaglandin E2 and the interactions between epinephrine, a potent LHRH agonist [(D-Ser-(TBu)6, des-Gly-NH10(2) LHRH ethylamide: Buserelin] and hCG in normal and in vitro hCG-desensitized rat immature luteal cells in monolayer culture, on basal, hCG or cholera toxin stimulated intracellular and extracellular cAMP and progesterone secretion. The present report shows that incubation of immature rat luteal cells in monolayer culture with Buserelin, led to 25-50% inhibition of the epinephrine-as well as PGE2-induced cAMP and progesterone responses. The LHRH agonist can also reverse the stimulatory effects of cholera toxin in the presence of hCG and led with PGF2 alpha, to additive inhibitory effects on extracellular cAMP accumulation induced by cholera toxin. Both Buserelin and PGF2 alpha can reverse the hCG-induced cAMP and progesterone release but no effect could be observed when the incubation was carried out with either substance in the absence of hCG. Prostaglandin E2, in acute conditions of incubation, seems to share agonist properties with hCG when both were incubated with luteal cells. Buserelin reversed the stimulatory effects of PGE2, hCG, epinephrine and cholera toxin on cAMP and progesterone responses to these substances. These results suggest that Buserelin and PGF2 alpha have luteolytic-like effects and that there may be a complementary action for the two substances. Preincubation of rat luteal cells in monolayer culture with 1 nM hCG for a 24 h period led to the inhibition of cAMP and progesterone responses after a subsequent exposure to hCG and epinephrine. Luteal cells were no longer responsive to hCG while the presence of epinephrine in hCG-desensitized cells led to a 40% stimulation of cAMP and progesterone production. These observations suggest that occurred a partial alteration of the N component activity of the adenylyl cyclase system.
Animals↗
PHI stimulates ACTH release from pituitary tumor cell.
The identification of PHI (the 27-amino acid peptide (P) having an N-terminal histidine (H) and a C-terminal isoleucine amide (I] in median eminence suggested that PHI influences the secretory function of the anterior pituitary. The effects of PHI on ACTH release from clonal mouse pituitary corticotrophs were investigated. The secretory response to PHI was correlated with a prior increase in cyclic AMP accumulation. Both cyclic AMP synthesis and ACTH secretion were increased by PHI in a concentration-dependent manner. PHI was a less effective agonist of cyclic nucleotide synthesis and ACTH secretion than VIP. The secretory response to PHI was blocked by the calcium channel antagonist, nifedipine, and by dexamethasone. Somatostatin and oxotremorine blocked both PHI-stimulated cyclic AMP formation and ACTH secretion. The observation that VIP in high concentrations can elicit ACTH secretion from normal rat anterior pituitary suggested that a VIP-like substance may modulate ACTH secretion. However, the finding that PHI does not elicit ACTH release from primary cultures of dispersed anterior pituitary, coupled to its relatively lower potency compared to VIP, indicate that corticotrophs are not an important target for PHI.
1-Methyl-3-isobutylxanthine↗
LHRH rapidly stimulates phosphatidylinositol metabolism in enriched gonadotrophs.
The effects of luteinizing hormone-releasing hormone (LHRH) and human pancreatic growth hormone-releasing factor (hpGRF(1-40)-NH2) on phospholipid metabolism were studied in rat anterior pituitary cells in primary culture. In a 4-fold enriched population of gonadotrophs, 30 nM LHRH increased 32Pi incorporation into phosphatidic acid (PA) as early as 1 min after its addition. Phosphatidylinositol (PI) labeling was increased 1 min later. The stimulatory action of LHRH was observed in both phospholipids up to 100 min, the last time interval studied. The decapeptide did not affect 32Pi labeling of phosphatidylcholine (PC), lysoPC, phosphatidylethanolamine or phosphatidylserine. Dose-response studies performed after 25 min of incubation showed an ED50 value of LHRH action at approximately 1 nM for PI labeling. In contrast, the addition of 0.1 microM GRF to anterior pituitary cells enhanced 32Pi incorporation only into PC after a 60 min incubation period. The present data suggest that stimulation of acidic phospholipid metabolism, particularly an increase in PA-PI turnover, may represent an early event in the mechanism of action of LHRH but not GRF in the anterior pituitary gland.
Animals↗
Effect of estradiol and haloperidol on hypophysectomized rat brain dopamine receptors.
The effect of chronic haloperidol and estradiol treatments on dopamine receptors independent from the pituitary has been studied in ovariectomized (ovx) and hypophysectomized (hypox) rats. The striatal dopamine receptor density (Bmax) of hypox rats as measured with [3H]spiperone binding was increased after chronic estradiol or haloperidol treatment, while receptor affinity was unchanged. In hypox rats, estradiol given during withdrawal from haloperidol decreased the characteristic increase in dopamine receptor density observed upon withdrawal from this neuroleptic, while the estrogen was ineffective when given concomitantly with haloperidol. These results in hypox rats are similar to those observed in ovx rats, suggesting that haloperidol and estradiol influence striatal dopamine function independently of the pituitary.
Animals↗
Simultaneous administration of pure antiandrogens, a combination necessary for the use of luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer.
Although castration levels of serum androgens are consistently achieved after 2-3 weeks of treatment with luteinizing hormone-releasing hormone (LHRH) agonists, the administration of these peptides alone in adult men is always accompanied by a transient increase in plasma testosterone and dihydrotestosterone levels, which lasts for 5-15 days at the beginning of treatment and is accompanied by disease flare-up in some cases, thus seriously limiting the acceptability of this otherwise efficient and well-tolerated treatment. The present data show that the simultaneous administration of a pure antiandrogen neutralizes the influence of the transient increase in serum androgens on prostate cancer, as indicated by the 60% decrease in serum prostatic acid phosphatase observed within 5 days of combined treatment with an LHRH agonist and a pure antiandrogen. The addition of a pure antiandrogen thus makes fully acceptable the use of LHRH agonists as an advantageous substitute for surgical castration and estrogens in the treatment of prostate cancer.
Acid Phosphatase↗
A new approach in the hormonal treatment of prostate cancer: complete instead of partial blockade of androgens.
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Androgen Antagonists↗
Modulation of gonadotropin secretion by Sertoli cell inhibin, LHRH, and sex steroids.
Sertoli cell culture media (SCM) from 10-, 20-, 30-, 35-, and 40-day-old male Wistar rats were assayed to determine the inhibin activity in anterior pituitary cells in culture. In agreement with previous data, SCM did not affect the luteinizing hormone (LH) spontaneous release at all ages studied, whereas it inhibited specifically follicle-stimulating hormone (FSH) spontaneous release by 40% for the 40-day-old rats. Younger animals (10-, 20-, and 30-day-old) showed a 60% inhibition of the FSH basal release. The inhibin activity was also different at all stages studied, the IC50 being markedly displaced to the right as the age increased, leading to a fivefold difference between 10- and 30- to 40-day-old rats. The same pattern was observed when the LH and FSH responses to 0.3 nM LH-releasing hormone (LHRH) were studied. SCM from 35-day-old rats did not alter total LH, whereas total FSH was markedly reduced, thus suggesting a reduced FSH synthesis in the presence of inhibin. SCM exerts an additive inhibitory effect with dihydrotestosterone on the LH response to LHRH, whereas it reverses the stimulatory effect of the androgen on spontaneous and LHRH-induced FSH release. Moreover, SCM reversed the stimulatory effect of 17 beta-estradiol on both spontaneous and LHRH-induced LH and FSH release, whereas the stimulatory effect of progesterone on FSH release was 50-80% inhibited. The present data show that inhibin activity of Sertoli cell origin can exert marked interactions with sex steroids in the control of gonadotropin secretion. These data also demonstrate that the inhibin component is an important factor in sexual maturation of the rat and that high FSH levels of 10-day-old rats could suggest a modulation by a nonandrogenic factor of gonadotropin secretion in developing rats.
Androgens↗