Response to endocrine manipulation and oestrogen receptor concentration in large operable primary breast cancer.
(65/183)
Forty-three patients with large (greater than or equal to 4 cm) but operable carcinoma of the breast have been treated by endocrine manipulation before definitive local surgery. This has allowed the study of the relationship between response to therapy and pretreatment oestrogen receptor (ER) concentration, as measured by a dextran-coated charcoal adsorption method. Premenopausal patients (17) were treated by surgical (4) or medical (13) oophorectomy. Post-menopausal patients (26) received either tamoxifen (10) or an aromatase inhibitor (16). Response was assessed from statistical analysis of the changes in tumour size. On completion of 12 weeks of endocrine therapy, there was significant regression of tumour size in 18 of the 43 patients. All 18 patients had tumours with ER concentrations of greater than or equal to 20 fmol mg-1 cytosol protein. Conversely all patients except one progressing on treatment had tumours with ER concentrations of less than 20 fmol mg-1 cytosol protein. This relationship applied for both premenopausal and post-menopausal patients. The overall response rate of patients with tumours of ER concentration greater than or equal to 20 fmol mg-1 cytosol protein was 60%. (+info)
Rat adrenal uptake and metabolism of high density lipoprotein cholesteryl ester.
(66/183)
Metabolism of high density lipoprotein (HDL) cholesteryl ester (CE) by cultured rat adrenal cells was studied. Addition of [3H]CE-HDL to cells pretreated with adrenocorticotrophin in lipoprotein poor media resulted in a time- and concentration-dependent accumulation of [3H]cholesteryl ester and production of [3H]cholesterol and [3H]corticosterone. HDL-CE metabolism could be described as the sum of a high affinity ([ HDL-cholesterol]1/2 max = 16 micrograms/ml) and low affinity ([ HDL-cholesterol]1/2 max greater than 70 micrograms/ml) process. [3H]Cholesterol was found both intracellularly and in the media. Accumulation of [3H]cholesteryl ester could not be attributed to uptake and re-esterification of unesterified cholesterol since addition of Sandoz 58-035, an inhibitor of acyl coenzyme A:cholesterol acyltransferase, did not prevent ester accumulation. Moreover, addition of chloroquine did not inhibit cholesteryl ester hydrolysis indicating that hydrolysis was not lysosomally mediated. Aminoglutethimide prevented conversion of [3H]CE-HDL to steroid hormones but did not inhibit [3H]cholesteryl ester uptake. Cellular accumulation of [3H] cholesteryl ester exceeded accumulation of 125I-apoproteins 5-fold at 1 h and 35-fold at 24 h indicating selective uptake of cholesteryl ester moiety. We conclude that rat adrenal cells possess a mechanism for selective uptake of HDL cholesteryl esters which provides substrate for steroidogenesis. These results constitute the first direct demonstration that cholesteryl esters in HDL can be used as steroidogenic substrate by the rat adrenal cortex. (+info)
Alterations in the production rate and the metabolism of oestrone and oestrone sulphate in breast cancer patients treated with aminoglutethimide.
(67/183)
Plasma level, plasma clearance, production rate and interconversions of oestrone and oestrone sulphate were measured in six breast cancer patients receiving aminoglutethimide therapy. Three additional patients had the production rate of oestrone sulphate investigated. Plasma oestrone and oestrone sulphate levels were reduced by a mean of 46% (P less than 0.05) and 71% (P less than 0.005) respectively. These alterations were due to a combined action of aminoglutethimide inhibiting oestrogen production but also increasing oestrogen metabolism. While oestrone and oestrone sulphate production rate was reduced by a mean of 31% (P less than 0.05) and 41% (P less than 0.005) respectively, the plasma clearance rate of oestrone was found to be increased by a mean of 30% (P less than 0.05), and the plasma clearance rate of oestrone sulphate was increased by a mean of 112% during aminoglutethimide treatment. The fraction of oestrone sulphate converted into plasma oestrone was reduced by 52% (P less than 0.05), the transfer of circulating oestrone into sulphate was non-significantly reduced by a mean of 16%. The findings in this investigation show that aminoglutethimide treatment influences oestrogen disposition by mechanisms unrelated to aromatase inhibition. The possibility that such effects might be partly responsible for the mechanism of action of aminoglutethimide in advanced breast cancer should be considered. (+info)
Effects of aminoglutethimide on hypothalamic-pituitary-adrenal functions.
(68/183)
This study was performed on four groups of subjects, including 10 patients with Cushing's disease, 10 patients with simple obesity, 8 patients with hypopituitarism and 13 normal subjects. The study was conducted by measuring the sequential changes of plasma ACTH, serum cortisol, 24-h UFC, 24-h 17 KS and 24-h 17 KGS following aminoglutethimide (AG) administration. The results suggest that normal subjects showed sequential changes of hypothalamic-pituitary-adrenal hormone concentrations with normal feedback regulation of the axis following AG administration. Patients with Cushing's disease had obvious autonomy in the production of ACTH from the pituitary. Patients with simple obesity might display abnormality to some degree in the production from the pituitary. Patients with hypopituitarism lost the capacity of ACTH production in various degrees because of pituitary lesions. (+info)
Rat granulosa cell apolipoprotein E secretion. Regulation by cell cholesterol.
(69/183)
We have demonstrated previously that cultured rat ovarian granulosa cells synthesize and secrete apoE, and this production of apoE is increased by agents that stimulate protein kinase A (cyclic AMP-dependent enzyme) (for example, cholera toxin) and protein kinase C (Ca2+/phospholipid-dependent enzyme) (for example, 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester). In the studies presented in this report, we have examined the effect of changes in cell cholesterol synthesis on the production of apoE by rat ovarian granulosa cells. Mevinolin, an inhibitor of hydroxymethylglutaryl (HMG)-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), and 4,4,10 beta-trimethyl-trans-decal-3 beta-ol, an inhibitor of squalene cyclization, both attenuate the cholera toxin or 12-O-tetradecanoylphorbol-13-acetate stimulation of granulosa cell apoE secretion and apoE mRNA content in a dose-responsive manner. The inhibitory effect of mevinolin is reversed by the concomitant administration of mevalolactone, which provides the cells with the product of the reaction catalyzed by HMG-CoA reductase. Steroidogenesis per se has no effect on apoE production. Aminoglutethimide, which blocks the rate-limiting step in steroidogenesis, has no effect on apoE or apoE mRNA. The data indicate that products of HMG-CoA reductase (isoprenes, cholesterol and/or cholesterol metabolites) are required along with stimulators of protein kinases A and C, to regulate ovarian granulosa cell apoE production. (+info)
Effects of ACTH and aminoglutethimide administration on the morphological and functional responses of rat adrenal zona fasciculata to a prolonged treatment with 4-aminopyrazolo-pyrimidine.
(70/183)
The prolonged administration of the hypocholesterolaemic drug 4-APP induced morphological changes in rat zona fasciculata cells (AER hypertrophy, peroxisome proliferation and lipid droplet depletion), enabling them to synthesise their own cholesterol and to maintain an adequate level of corticosterone output. Chronic ACTH administration provoked, in zona fasciculata cells of 4-APP-treated rats, a further increase in the AER and the volume of peroxisome compartment, coupled with a significant rise in the volume of the mitochondrial compartment and in the surface area per cell of mitochondrial cristae; the volume of the lipid droplet compartment did not change, whereas the plasma level of corticosterone significantly increased. These findings indicate that the modified adrenocortical cells of 4-APP-treated rats possess a good functional reserve, being still able to enhance their growth and steroidogenic capacity in response to ACTH. Aminoglutethimide, a drug blocking cholesterol utilisation in steroid synthesis, lowered the blood level of corticosterone in 4-APP/ACTH-administered rats; it increased the intra-adrenal concentration of cholesterol, but did not provoke lipid droplet accumulation in zona fasciculata cells. This result may suggest that in adrenal lipid droplets is stored only exogenous cholesterol taken up from plasma lipoproteins. (+info)
A comparison of the endocrine effects of low dose aminoglutethimide with and without hydrocortisone in postmenopausal breast cancer patients.
(71/183)
The endocrine effects of 125 mg (low dose) aminoglutethimide (AG) twice daily (b.d.) were compared with those of 125 mg AG + 20 mg hydrocortisone (HC) b.d. in 23 and 45 postmenopausal patients with advanced breast cancer, respectively. The patients in each group were drawn from two separate populations, but the mean age and weight of the groups were similar and there were no significant differences between the pretreatment serum levels of the hormones investigated. Serum oestrone and oestradiol levels were suppressed by both treatments, but there was a significantly greater suppression by AG + HC. This greater suppression is probably due to the observed increase in serum androstenedione (i.e. precursor) levels with AG alone, whilst with AG + HC these levels were found to be reduced. In terms of suppression of serum oestrogen levels it is of benefit to combine low dose AG with HC. (+info)
CGS 16949A, a new nonsteroidal aromatase inhibitor: effects on hormone-dependent and -independent tumors in vivo.
(72/183)
CGS 16949A is a very potent and highly selective inhibitor of the aromatase enzyme system in vitro and of estrogen biosynthesis in vivo. These characteristics are reflected in the marked efficacy with which it affects growth of estrogen-dependent 7,12-dimethylbenz(a)antracene-induced mammary carcinomas in intact female Sprague-Dawley rats. Daily p.o. treatment of tumor-bearing rats for 42 days with CGS 16949A at doses of 1.0 to 8.0 mg/kg caused almost complete regression of palpable tumors and almost totally suppressed the appearance of new tumors. A dose of about 0.1 mg/kg corresponded to the 50% effective dose, and a fully effective dose was estimated to be about 2.0 mg/kg. Eight to 10 days after cessation of treatment, tumor regrowth was observed. No unexpected side-effects were noted during the course of treatment. Tumors, which were allowed to regrow after a first treatment with CGS 16949A, were similarly efficaciously suppressed with a second treatment with CGS 16949A. Continuous long-term treatment with 2.0 mg/kg for 27 wk caused complete regression of tumors, suppressed the appearance of new tumors completely, and significantly prolonged the survival time of the tumor-bearing rats. This treatment schedule caused no major hematological or blood chemistry changes and was very well tolerated. CGS 16949A was ineffective against transplantable hormone-independent tumors such as R-3230AC mammary carcinoma, 11095 prostate carcinoma, leukemia L1210, and B16 melanoma. (+info)