Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.
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PMID:Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor. 164 19

The family of cytochrome P450 enzymes that mediates steroid hydroxylations are distinct but structurally related proteins. Inhibitors of these steroidogenic steps generally exhibit only relative and dose-related specificity. We evaluated an imidazole, cytochrome P450-related inhibitor, CGS 16949A, in postmenopausal patients with metastatic breast cancer. While a relatively specific aromatase inhibitor at daily dosages of 1-2 mg, CGS 16949A significantly blunted cortisol responses to ACTH at a dose of 16 mg daily. To further evaluate other inhibitory effects of this drug, we determined blood levels of aldosterone (ALDO) and 18-hydroxycorticosterone and their respective urinary metabolites, tetrahydroaldosterone and tetrahydro-18-hydroxy-11-dehydrocorticosterone in 16 postmenopausal women receiving CGS 16949A. At a dose of 16 mg/day, CGS 16949A produced significant (P less than 0.001) suppression of both basal and ACTH-stimulated ALDO production. This was accompanied by a significant rise in the blood 18-hydroxycorticosterone/ALDO ratio (11.4 +/- 0.19; normal, less than 2; P less than 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 +/- 1.2; normal, less than 5; P less than 0.001) in the urinary tetrahydro-18-hydroxy-11-dehydrocorticosterone/tetrahydroaldosterone ratio was also observed. These results suggest that CGS 16949A is a potent inhibitor of the corticosterone methyloxidase type II enzyme at a dose of 16 mg daily. At doses of 1-2 mg daily, CGS 16949A blocks aromatase without altering basal aldosterone production and, thus, exhibits dose-related specificity.
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PMID:The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis. 215 89

The factors involved in regeneration of the autotrasplanted adrenal cortex were studied experimentally in dogs. On the basis of a number of conditions necessary for the regeneration of adrenocortical tissue, the dogs were divided into 4 groups according to differences in substitution therapy following autotransplantation. The only group to demonstrate long-term survival received an intermittent substitution of cortisone acetate after the completion of 6 days postoperative replacement therapy. The hormonal functions after adrenocortical autotransplantation were examined in the long-term survivers. The secretory function of adrenocortical tissue after autotransplantation was confirmed by the detection of serum concentrations of aldosterone and cortisol, however, estrogens were not detected in the peripheral blood stream following autotransplantation. The negative response to the synthetic ACTH stimulation test observed in this study was evidence of the functional limitation of regenerated cortical tissue. Clinically, however, the procedure performed in this study will be beneficial for patients with advanced and metastatic breast cancer, not only as a form of surgical hormonal therapy, but also as an effective palliative method of treatment.
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PMID:Autotransplantation of the adrenal cortex into the spleen of dogs. 235 7

Both medroxyprogesterone acetate (MPA) and megestrol acetate (MA) are effective in the treatment of metastatic breast cancer. Although the dose-dependent mode of actions of MPA have been extensively clarified, there is still some uncertainty regarding the mode of actions and dosage of MA. Thirty-three patients with metastatic breast cancer were treated with various dosages of MA under a phase-II study. Eight patients were given 200 mg, 9 X 400 mg, 10 X 600 mg and 6 X 800 mg MA daily per os. The LH, FSH, TBI, T3, T4, TSH, ACTH, aldosterone, testosterone, prolactin and cortisol levels were determined regularly during treatment to enable the investigation of the pharmacodynamics of MA. A complete remission was achieved in two patients, a partial remission in seven patients and there was no change in eight patients (total responder rate 51.5%). The clinical and endocrine changes therefore suggest that the dose-dependent mode of actions of MPA and MA are identical. Equivalent dosages of MPA are 1000-1500 mg per os and of MA 160-200 mg. Furthermore, similar relationships between the endocrine changes and remission behaviour of MA and MPA have been observed. Persisting tumour remissions are inevitable under cortisol suppression and normal prolactin, aldosterone and ACTH levels.
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PMID:[Megestrol acetate in various doses in the treatment of metastatic breast carcinoma--clinical and endocrinologic studies]. 298 1

Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.
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PMID:Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone. 406 49

Based upon preliminary observations that tumor response to MPA was correlated to cortisol suppression 42 patients were treated with MPA at different dose levels. 1500 mg MPA p.o. almost completely suppressed endogenous cortisol production in 23 out of 23 patients. Consequently, 51 patients with advanced stage metastatic breast cancer were treated with Medroxyprogesteroneacetate (HD-MAP) at a dosage of 1500 mg p.o. daily or 500 mg i.m. on 5 days per week. There were 5 complete and 7 partical remissions, 23 patients with no change and 10 with progressive disease. 7 patients were not evaluable. Clinical results correlated to plasma cortisol and prolactin blood levels bot not to LH, FSH, TSH, TBI, T3, T4, ACTH and aldosterone measurements. There was no patient with relapse and suppressed cortisol or normal prolactin measurements. The development of pituituary resistance to MPA is suggested. HD-MPA was equally effective in estrogen and/or progesterone receptor positive as in receptor negative patients. It is proposed that cortisol and prolactin determinations are useful to monitor for effective MPA treatment and the early detection of MPA resistance.
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PMID:[High dose medroxyprogesteroneacetate in metastasizing breast cancer: correlations between course of the disease and hormone profiles]. 622 46

The calcitonin-like immunoreactivity (CT-like immunoreactivity) was measured in blood aspirated from the vascular bed of the anterior pituitary gland during transsphenoidal surgery in 33 patients with PRL-producing microadenomas, 2 patients with Cushing's disease, and 1 patient with metastatic breast cancer with a normal pituitary gland. The mean level of CT-like immunoreactivity in the pituitary vascular bed was 2-3 times higher than in peripheral blood (2.4 +/- 0.9 ng/ml vs. 0.69 +/- 0.19 ng/ml), and the difference was highly significant (P less than 0.001). However, the serum ACTH, hGH, TSH, PRL, and FSH in the pituitary vascular bed was 1000 times or higher than that found in the peripheral blood. The serum CT-like immunoreactivity levels in the pituitary bed in the two patients with Cushing's disease were similar to that found in other patients. Our investigations indicate: 1) CT-like immunoreactivity in man is higher in the blood obtained from the pituitary vascular bed than that found in the peripheral blood; 2) the serum CT-like immunoreactivity level in the pituitary vascular bed is much less than ACTH or the other hormones secreted by the pituitary gland; 3) there is no correlation between CT-like immunoreactivity and ACTH levels.
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PMID:Calcitonin-like immunoreactivity in the pituitary vascular bed of man. 627 Jan 88

In an attempt to delineate the mechanism and the site of action of cyproheptadine and dopaminergic agonists as well as hormones including thyrotropin-releasing hormone (TRH) and hydrocortisone, the effects of these substances on ACTH secretion from corticotroph adenoma cells in culture were examined. Dispersed cells of pituitary adenomas obtained at surgery from four patients with Nelson's syndrome and one subject with Cushing's disease formed a monolayer and actively secreted ACTH into the medium. When TRH (0.1 microM) was added to the medium, a significant increase in ACTH secretion was demonstrated by adenoma cells from two patients who responded to TRH preoperatively. Moreover, a dose-response relationship between TRH concentrations and ACTH secretion was observed. Incubation of cells with cyproheptadine (1 or 0.1 microM) resulted in a significant decrease in ACTH release, and inhibited stimulation produced by TRH in one experiment. This effect of cyproheptadine was blocked when equimolar concentrations of serotonin was coincubated, whereas serotonin by itself did not affect ACTH secretion. Dopamine (0.1 microM) lowered ACTH accumulation in the medium, which was blocked by the addition of haloperidol. When hydrocortisone was added to the culture, dose-dependent suppression of ACTH secretion was demonstrated. TRH at an equimolar concentration reversed this effect, but, failed to overcome the inhibition induced by a higher concentration of hydrocortisone in cells from one adenoma studied. Cultured normal corticotrophs obtained from a patient with metastatic breast cancer, on the other hand, did not show any response to these substances, except for hydrocortisone. We suggest that TRH, cyproheptadine, dopamine affect ACTH secretion in patients with ACTH-producing pituitary adenomas by their direct action on the adenoma.
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PMID:Direct effects of thyrotropin-releasing hormone, cyproheptadine, and dopamine on adrenocorticotropin secretion from human corticotroph adenoma cells in vitro. 627 Jan 92

One of the central effects of MAP is the intrinsic glucocorticoid activity. In the therapy of metastatic breast cancer with high dose MAP the cortisol like effect could be shown even in long term treatment. The cortisol like activity of MAP leads via the suppression of ACTH to a decrease of endogenous cortisol secretion. This cortisol like activity of MAP is sufficient to replace the obligate cortisol substitution in the therapy of metastatic breast cancer with aminoglutethimide. Thus within the therapy of metastatic breast cancer the combination of two endocrine acting drugs is possible.
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PMID:[Medroxyprogesterone acetate as glucocorticoid in combination with aminoglutethimide in the treatment of metastatic breast cancer]. 629 Sep 55

Hormonal therapy for breast cancer began more than a century ago with the observation that bilateral oophorectomy caused tumor regression in selected premenopausal patients. In the first half of this century, besides extending ablation of ovarian function to photon irradiation, surgical adrenalectomy and hyophysectomy were introduced, and hormonal additive therapy was established. Regression rates for advanced breast cancer with all types of endocrine therapy at this point did not exceed 35%. The demonstration that adjuvant systemic therapy can prolong the disease-free interval and improve overall survival has been a major advance in the management of breast cancer, the rationale was to control or eliminate micrometastases before tumor recurrence. The nonsteroidal antiestrogen tamoxifen was chosen for the majority of studies since the mid-1970s. Since the first report of successful treatment of metastatic breast cancer, the number of treated women worldwide has reached over 3,000,000. Objective response rate (CR+PR following UICC) in unselected patients is 34%. Tamoxifen has been used successfully to treat both pre- and postmenopausal women with all stages of the disease. In an overview analysis of 30,000 patients from 40 trials of adjuvant tamoxifen, a significant increase was found in both disease-free and overall survival. When patients were separated by nodal status, statistically significant increases were observed in disease-free and overall survival for both node-positive and node-negative patients. Women over 50 appear to benefit most from tamoxifen treatment experiencing highly significant increases in disease-free and overall survival regardless of nodal status. However, since tamoxifen primarily acts as a cytostatic and not cytotoxic agent, most patients ultimately experience disease recurrence or progression during or after therapy. Newer antiestrogens include trioxifene, toremifene, and droloxifene (3-OH-tamoxifen). Randomized, prospective studies are still under way to establish their clinical superiority (or lack of it). Progestins exert direct antiproliferative effects on human breast cancer cell lines. They may also exert direct antiestrogenic action by increasing the oxidative activity of 17 beta-hydroxy-steroid-dehydrogenase, thereby facilitating the conversion of estradiol to estrone. Progestins may exert additional antiestrogenic effects by suppressing estrogen receptor levels. As they also cause estrogen deprivation indirectly through suppression of pituitary ACTH secretion, resulting in reduced production of adrenal androgen precursors, both low- and high-dose regimens have been studied. Aromatase inhibition in premenopausal women interrupts estrogen biosynthesis; the reflex rise in FSH then stimulates production of new aromatase enzyme, and the LH increment results in enhanced ovarian steroidogenesis, counteracting the inhibitory action of aromatase-blocking drugs on the ovary.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endocrine management of breast cancer. 787 88


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