Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.
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PMID:Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer. 868 41

The development of ovulation-inducing drugs has enabled clinicians to more effectively treat the hypothalamic, pituitary, and ovarian abnormalities resulting in infertility. Pregnancy rates have been improved with the use of agents such as clomiphene citrate (CC), human menopausal gonadotropin [hMG or follicle-stimulating hormone (FSH) preparations], with gonadotropin-releasing hormone (GnRH) and its analogs, stimulating the development of multiple ovarian follicles and increasing the number of fertilizable oocytes. The use of these drugs is not without certain detrimental or "toxic" consequences. The negative effects from superovulation can occur during follicle development, decreasing the number of healthy oocytes and embryos capable of leading to viable pregnancy. Ovulation induction can lead not only to higher incidences of spontaneous abortions, and multiple and ectopic pregnancies, but also to poor pregnancy rates, due, in part, to asynchrony between embryonic development and the uterine environment. Diseases such as ovarian hyperstimulation syndrome (OHSS), resulting in the secretion of supraphysiologic levels of estradiol, can lend to severe health complications, possibly requiring hospitalization. Most drugs used for ovulation induction can lead to OHSS. Although incidences of OHSS following CC use are less frequent, CC has been associated with hot flushes, multiple gestations, visual disturbances, cervical mucus abnormalities, and luteal phase deficiency. Finally, there are reports that link any or all of the ovulation-inducing drugs with a higher incidence of ovarian and breast cancer, however, a cause-effect relationship has yet to be proven.
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PMID:Reproductive toxicity of ovulation induction. 898 29

This review focuses on etiologic factors and hormonal correlates of the three major gynecologic cancers-uterine cervix, uterine corpus and ovary- and breast cancer. The incidence rate of the three gynecologic cancers combined is only 40 percent of the breast cancer rate (43.6 vs 109.5 per 100,000), whereas the combined mortality rate is half that for breast cancer (14.3 vs 27.3 per 100,000). Cervical cancer is distinctive in that it's hormonal correlates are few; it exhibits the epidemiologic characteristics of a sexually transmitted disease. Integration of Human Papilloma Virus DNA types 16, 18 (or other) within the cellular genome has been identified in more than 80% of high grade cervical intraepithelial neoplasias and invasive carcinomas. Epithelial ovarian cancers occur most commonly in nulliparous, infertile women and familial carriers of BRCA1. Oral contraceptive (OC) use reduces ovarian cancer risk by at least one-half, a benefit which increases with increasing duration of use and persists for at least 15 years after discontinuation. Pregnancy and OCs suppress gonadotropin secretion, whereas fertility drugs enhance follicle-stimulating hormone production. These indicators of alterations in the hypothalmic-pituitary-ovarian axis provide some support for both the excess gonadotropin and the incessant ovulation theories of ovarian carcinogenesis. Endometrial carcinoma is the prototype hormonally-determined disease. Increased estrogen from either endogenous or exogenous sources increases risk. Lowering the estrogen load or adding progestin reduces risk. This explains the marked protection achieved by combined estrogen/progestin OC's and the dramatic increased risk uncurred by long-term estrogen replacement therapy (ERT). Breast tissue, also a target for sex steroid hormones, displays a more complex risk profile. Current ERT use increases breast cancer risk by about 30%; adding a progestin to the estrogen does not improve the situation (40% increased risk). Furthermore, OCs do not reduce breast cancer risk, but may increase it for current OC users under age 45. The magnitude of these hormonal effects is much smaller than that exhibited with endometrial cancer.
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PMID:Epidemiologic analysis of breast and gynecologic cancers. 910 87

Toremifene (Fareston) is a triphenylethylene derivative structurally similar to tamoxifen (Nolvadex) that was selected for development based on its in vitro activity against breast cancer and its lesser uterotrophic effect than tamoxifen in rat models. In phase I and II studies conducted in several countries, toremifene was well tolerated over a wide range of doses (10 to 680 mg/d). The major side effects were hot flashes, nausea, and vomiting. Toremifene's excretion half-life is 5 days. It produces a modest decline in serum levels of luteinizing hormone, follicle-stimulating hormone, and antithrombin III, as well as an increase in sex hormone-binding globulin levels. In studies in which toremifene was used as first-line therapy in patients with estrogen receptor (ER)-positive or ER-unknown tumors, response rates to doses of 40 to 60 mg/day ranged from 30% to 54%. In two larger studies of patients who had proved refractory to tamoxifen therapy, toremifene produced an objective response rate of 4% to 5%. When patients with stable disease were added to those with objective responses, 27% to 28% of patients were considered to derive clinical benefit from toremifene. The dose range chosen for further study was 40 to 60 mg/d.
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PMID:Phase I and II studies of toremifene. 916 2

As part of a breast cancer case-control study of serum hormones conducted in Columbia, MO, we included several replicate quality control samples to monitor the consistency of laboratory assays. Sera were obtained from three postmenopausal women; from each woman, three samples were placed randomly in each of nine batches with the laboratory unaware of which sample corresponded to whom. Laboratory assays for estrone (E1), estradiol (E2), testosterone, androstenedione (Adione), E1SO4, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG), and percentages of free and albumin-bound E2 were done at a single academic facility. ANOVA results showed that hormone values varied considerably from one batch to the next. The overall coefficients of variation (CVs) estimated for E2, percentage of unbound E2, and percentage of albumin-bound E2 were higher than 15%, but of these, only percentage of unbound E2 had both inter- and intra-assay CVs greater than 10%. Intraclass correlations (ICC) for FSH, SHBG, and DHEAS were high, suggesting that these assays are suitable for population-based studies attempting to link hormone levels to disease risk. The ICC estimated for E1SO4 was quite low due to aberrant values reported in a single batch. For the remaining hormones, the ICCs were fair (ranging from 47% for albumin-bound E2 to 67% for Adione), and studies using these assays would require a substantial increase in the sample size to detect small case-control differences.
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PMID:Assay reproducibility of hormone measurements in postmenopausal women. 918 76

We are conducting a long-term randomized controlled trial to determine if intervention with a low-fat high-carbohydrate diet reduces breast cancer risk. The present study examines the effects of 2 years of dietary intervention on serum sex hormone levels in premenopausal women. Subjects with extensive mammographic densities were enrolled in a dietary intervention trial. The intervention involved intensive individual counselling aimed at reducing total dietary fat to 15% of calories. Control subjects received general advice about diet but were not counselled to change their fat intake. Serum sex hormone levels were measured in 220 premenopausal subjects at entry and 2 years after randomization. Two years after randomization oestradiol levels were 20% (70 pmol l(-1)) lower (P = 0.04) and progesterone levels were 35% (1.0 nmol l(-1)) lower (P = 0.004) and follicle-stimulating hormone (FSH) levels were 7% (1 IU) higher (P = 0.38) in the intervention group than in the control group. The FSH-oestradiol ratio was 13% higher in the intervention group (P = 0.18). Samples analysed accounting for the timing of the blood sample in relation to the menstrual cycle showed that, in the intervention group, oestradiol and progesterone levels were lower and FSH levels higher in subjects with blood samples taken more than 30 days after the last menstrual period. Because of the strong evidence linking ovarian hormonal activity to breast cancer risk, these results suggest that a low-fat high-carbohydrate diet may reduce risk of breast cancer by reducing exposure to ovarian hormones that are a stimulus to cell division in the breast.
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PMID:Effects of a low-fat high-carbohydrate diet on plasma sex hormones in premenopausal women: results from a randomized controlled trial. Canadian Diet and Breast Cancer Prevention Study Group. 982 Jan 90

Toremifene is a chlorinated tamoxifen analogue that is indicated for the treatment of postmenopausal hormone-dependent breast cancer. It competes with estradiol for estrogen receptors and has growth-inhibitory effects on MCF-7 breast cancer cells. At concentrations < 10(-6) mol/L, this growth inhibition can be reversed by estradiol, but at higher concentrations toremifene is cytotoxic. In dimethylbenzanthracene (DMBA)-induced mammary cancer in rats, toremifene has been shown to decrease the number of new tumours and to inhibit the growth of existing tumours. Toremifene causes growth inhibition by suppressing mitosis and inducing apoptosis. The mechanism by which these events occur may involve the induction of transforming growth factor-beta 1 and inhibition of insulin-like growth factor-1 (mecasermin). Toremifene is primarily an antiestrogen, but it has some estrogen agonist properties in postmenopausal women. The latter are reflected by the fall in luteinising hormone and follicle-stimulating hormone levels and the rise in sex hormone-binding globulin levels that are associated with its use in most women. After estrogen priming, toremifene 68mg administered orally has been found to exert a similar antiestrogenic effect on the vaginal epithelium in postmenopausal women as tamoxifen 60mg. The half-life of toremifene in plasma is 5 days, and the drug is > 99% bound to plasma proteins. The main metabolites of toremifene are N-demethyl-toremifene and deaminohydroxy-toremifene. Altered liver, but not kidney, function affects the pharmacokinetics of toremifene. Toremifene 60mg daily is as effective as tamoxifen 20mg daily in the treatment of postmenopausal hormone-dependent breast cancer, producing a response in about 50% of patients. Soft tissue and visceral metastases respond better to toremifene than bone metastases. Most of the adverse effects of toremifene are related to its activity at estrogen receptors and include hot flashes, vaginal discharge and nausea. Although toremifene decreases antithrombin III levels slightly, the incidence of thromboembolic complications is low. Thus far, no carcinogenic effects have been noted in humans, and preclinical data are mostly reassuring. Toremifene has favourable effects on serum lipids, and thus has potential in preventing coronary heart disease. Although toremifene is somewhat more expensive to use than tamoxifen, toremifene is an effective and well tolerated alternative to tamoxifen in the treatment of postmenopausal women with hormone-dependent breast cancer. No formal pharmacoeconomic comparisons of toremifene and tamoxifen have yet been published. Toremifene is potentially safer than tamoxifen in relation to carcinogenic effects and effects on serum lipids.
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PMID:Toremifene in postmenopausal breast cancer. Efficacy, safety and cost. 934 56

Prostate-specific antigen (PSA) is produced by the female breast. Prior in vitro evidence suggests that PSA expression in breast epithelial cells is regulated by androgens and progestins but not estrogens. The purpose of this study was to determine whether (a) PSA expression in breast nipple aspirate fluid (NAF) and in serum is influenced by progesterone (PG); (b) the ability to obtain NAF decreases with repeated breast aspirations; and (c) PSA in NAF correlates with abnormal NAF cytology. Eight pre- and three postmenopausal women with no breast cancer risk factors were enrolled in a pilot study and had NAF and serum collected every 3-4 days for a month to evaluate the influence of serum PG, luteinizing hormone, estradiol, and follicle-stimulating hormone on PSA in serum and in NAF. NAF was obtained in 99% (112 of 113) of aspiration visits. Median, mean, and peak NAF but not serum PSA levels were higher in pre- than in postmenopausal subjects. NAF PSA levels were associated with the rise or peak in serum PG in seven of eight premenopausal women (seven of seven with a PG surge) and in zero of three postmenopausal women. Considering all 11 women, there was an association between NAF PSA and PG (P = 0.005) but not luteinizing hormone, estradiol, or follicle-stimulating hormone. NAF volume did not significantly change over time. Atypical hyperplasia (9%) and hyperplasia without atypia (36%) were identified in the NAF of a subset of the subjects. Median, mean, and peak levels of NAF PSA (P = 0.05, 0.05, and 0.10, respectively) were higher in subjects with normal versus hyperplastic cytology. PSA production in the breast increases in association with PG. With aspiration every 3-4 days, NAF volume does not significantly decrease over time. NAF cytology and PSA levels in NAF may help identify women at increased breast cancer risk. Changes in biomarkers of breast cancer risk in NAF (including PSA and cytology) may predate mammographic abnormalities. NAF may, therefore, be useful as a breast cancer screening tool for young women who are not recommended to undergo mammography and as an adjunct to screen women who have mammograms performed.
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PMID:Prostate-specific antigen production in the female breast: association with progesterone. 956 87

Many studies have addressed the clinical value of pS2 as a marker of hormone responsiveness and of cathepsin D (Cath D) as a prognostic factor in breast cancer. Because pS2 and Cath D are both oestrogen induced in human breast cancer cell lines, we studied the influence of the menstrual cycle phase and menopausal status at the time of surgery on the levels of these proteins in breast cancer. A population of 1750 patients with breast cancer, including 339 women in menstrual cycle, was analysed. Tumoral Cath D and pS2 were measured by radioimmunoassay. Serum oestradiol (E2), progesterone (Pg), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at the day of surgery were used to define the hormonal phase in premenopausal women. There was a trend towards a higher mean pS2 level in the follicular phase compared with the luteal phase (17 ng mg(-1) and 11 ng mg(-1) respectively, P = 0.09). Mean pS2 was lower in menopausal patients than in women with cycle (8 ng mg(-1) and 14 ng mg(-1) respectively, P = 0.0001). No differences in mean Cath D level were observed between the different phases of the menstrual cycle, or between pre- and post-menopausal women. In the overall population, pS2 was slightly positively associated with E2 and Pg levels and negatively associated with FSH and LH, probably reflecting the link between pS2 and menopausal status. In premenopausal women, no association was found between pS2 and E2, Pg, FSH or LH levels. There were no correlations between Cath D level and circulating hormone levels in the overall population. However, in the subgroup of premenopausal women with ER-positive (ER+) tumours, E2 was slightly associated with both pS2 and Cath D, consistent with oestrogen induction of these proteins in ER+ breast cancer cell lines. There are changes in pS2 level in breast cancer throughout the menstrual cycle and menopause. This suggests that the choice of the pS2 cut-off level should take the hormonal status at the time of surgery into account. In contrast, the level of Cath D is unrelated to the menstrual cycle and menopausal status.
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PMID:Time at surgery during menstrual cycle and menopause affects pS2 but not cathepsin D levels in breast cancer. 1007 Aug 89

We report the design, construction, and use of the first very large non-immunized phage antibody library in Fab format, which allows the rapid isolation and affinity analysis of antigen-specific human antibody fragments. Individually cloned heavy and light chain variable region libraries were combined in an efficient two-step cloning procedure, permitting the cloning of a total of 3.7 x 10(10) independent Fab clones. The performance of the library was determined by the successful selection of on average 14 different Fabs against 6 antigens tested. These include tetanus toxoid, the hapten phenyl-oxazolone, the breast cancer-associated MUC1 antigen, and three highly related glycoprotein hormones: human chorionic gonadotropin, human luteinizing hormone, and human follicle-stimulating hormone. In the latter category, a panel of either homone-specific or cross-reactive antibodies were identified. The design of the library permits the monitoring of selections with polyclonal phage preparations and to carry out large scale screening of antibody off-rates with unpurified Fab fragments on BIAcore. Antibodies with off-rates in the order of 10(-2) to 10(-4) s-1 and affinities up to 2.7 nM were recovered. The kinetics of these phage antibodies are of the same order of magnitude as antibodies associated with a secondary immune response. This new phage antibody library is set to become a valuable source of antibodies to many different targets, and to play a vital role in target discovery and validation in the area of functional genomics.
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PMID:A large non-immunized human Fab fragment phage library that permits rapid isolation and kinetic analysis of high affinity antibodies. 1037 23


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