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)

Tamoxifen (TXF), a triphenylethylene antiestrogen, is the major therapeutic agent for breast cancer. In rare cases, TXF treatment appears to increase incidence of endometrial cancer. Also in rats, TXF was found to induce hepatocellular carcinoma. Previous studies suggested that metabolism of TXF may contribute to its antiestrogenic and anticancer activity. The current study demonstrates a novel route of TXF metabolism. TXF is metabolized by rat and human liver microsomes into a reactive intermediate (txf*) which binds irreversibly to microsomal proteins. The binding requires NADPH and O2 and is inhibited by CO, inhibitors of P-450, and antibodies to rat NADPH-P450 reductase, indicating catalysis by P450. Phenobarbital treatment of rats markedly increases binding, suggesting the involvement of induced P450s. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of proteins from incubation of [14C] TXF with phenobarbital-treated microsomes exhibits a major radiolabeled zone which corresponds to a molecular weight of approximately 54,000, suggesting binding to a P-450. Cysteine and glutathione inhibited the binding of TXF without significantly affecting P-450-mediated metabolism of TXF, possibly by reacting with txf* or by competing for the same binding sites. Exposure of phenobarbital-treated microsomes and control-microsomes to 50 degrees C for 90 s, which inactivates the flavin-containing monooxygenase (FMO), diminished binding and pH 8.6 enhanced binding. Also, alternate FMO substrates inhibited binding. These findings indicate that P-450 and possibly FMO catalyze the reactions leading to the formation of txf*. However, incubations with single-labeled and dual-radiolabeled tamoxifen or with [14C]TXF-N-oxide demonstrated that monodesmethyl-TXF and TXF-N-oxide, the principal P-450 and FMO-mediated metabolites, respectively, are not on the major route of txf* formation, indicating that txf* could not be an aldehyde derived from tamoxifen nitrone. Thus, though the structure of txf* was not characterized, certain possibilities were excluded. Speculations on the structure of txf* and on its possible pharmacological and toxicological activity are presented.
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PMID:Cytochrome P-450-mediated activation and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver: possible involvement of flavin-containing monooxygenases in tamoxifen activation. 193 68

Estrogen receptor-negative, 7, 12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinoma (TF1357) grew equally well in ovariectomized females, ovariectomized females with thyroidectomy and ovariectomized females given injections of Tamoxifen (0.1 mg/day), Medroxyprogesterone acetate (8 mg/day) or CB-154 (1 mg/day). However, the growth of TF1357 was inhibited markedly by injections of a very large amount of 17 beta-estradiol (1 mg/2 days) and also by hypophysectomy. The growth of estrogen receptor-positive, DMBA-induced rat mammary carcinoma (8K2401) was also almost completely inhibited by hypophysectomy and injections of high doses of 17 beta-estradiol, while 8K2401 grew well in castrated males. Secretory changes characterized by vacuolation in cytoplasm were observed in 8K2401 cells in castrated males with injections of high doses of estrogen but these changes were not found in 8K2401 cells in castrated males with hypophysectomy or in TF1357 cells in ovariectomized females which had had hypophysectomy or injections of high doses of estrogen. These observations suggest that hypophysectomy and/or injections of high doses of estrogen may be effective treatment for breast cancer unresponsive to ovariectomy or injections of antiestrogen drugs.
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PMID:Hypophysectomy and injections of high doses of estrogens inhibit the growth of ovary-independent rat mammary carcinomas. 196 85

Between 1977 and 1983 100 elderly women (median 76.3 years) with breast cancer were treated with tamoxifen as primary therapy. The median follow-up is 59 months. Sixty-eight responded (40 CR and 28 PR) with median response durations of 47 months and 26 months respectively. Twenty-two patients had disease stabilization for a median of 15.5 months and 10 had progressive disease. The median time to best response was 13.5 weeks for patients achieving CR and 14 weeks for those with PR. Oestrogen receptor values were obtained in 37 patients of which two patients had no ER detectable. Sixty-seven per cent of ER-unknown patients responded compared with 74% of ER-rich. Likelihood of response did not appear to depend upon T-stage or age. Survival was better than that of an unmatched historical group treated with surgery/radiotherapy and compares favourably with recent reports. Although 35% have died of breast cancer, 25% died of other causes and 22% remained free of recurrence at the time of reporting or at death. Only 11% underwent subsequent mastectomy/lumpectomy and the most frequent subsequent treatments were radiotherapy to the breast (32%) and further hormonal therapies (40%). Tamoxifen is a practical primary therapy of breast cancer in elderly and frail women obviating the need for surgery in a high proportion of cases.
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PMID:A 10-year experience of tamoxifen as primary treatment of breast cancer in 100 elderly and frail patients. 199 54

The pharmacology of the antiestrogen tamoxifen is reviewed. The drug is currently used extensively in the treatment of all stages of breast cancer and is being considered as a preventive agent for women at high risk for breast cancer. Extensive laboratory studies demonstrate that tamoxifen is a tumoristatic agent in models of mammary carcinogenesis. Any clinical applications must therefore consider long-term (5-10 years) treatment strategies. Tamoxifen prevents rat mammary carcinogenesis. However, the timing of the carcinogenic insult is unknown among women. Tamoxifen must be considered to be a chemosuppressive agent to prevent the appearance of the primary tumor rather than to prevent the initial carcinogenic insult.
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PMID:Chemosuppression of breast cancer with long-term tamoxifen therapy. 200 27

One hundred and thirteen women aged 70 years or more with locoregional breast cancer were treated with tamoxifen alone as primary treatment. They were followed for a minimum of 5 years. Complete response occurred in 38 women, partial response in 17, no change in 34 and progressive disease in 24. Where progressive disease occurred, or where patients relapsed after an initial response, the most suitable conventional therapy was given. The actuarial 5-year survival rate was 49.4 per cent for all patients and was much higher (92 per cent) in those showing an initial complete response. Seventy patients (61.9 per cent) were not controlled by tamoxifen alone to death or most recent follow-up. Tamoxifen provides an alternative treatment for operable breast cancer in older women in the short term and may be particularly suitable for those with concurrent disease or who are unwilling to undergo surgery. The low morbidity rate from tamoxifen must be balanced against the need to maintain close follow-up. In the medium to long term, sole primary treatment by tamoxifen delays more definitive therapy.
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PMID:Long-term follow-up of elderly patients with locoregional breast cancer treated with tamoxifen only. 201 78

Adjuvant therapy in operable breast cancer (stage I and II) can significantly reduce the risk of recurrences and improve survival. In stage I disease, 20-30% of patients will eventually recur. Several prognostic factors may help in identifying poor prognostic subgroups of stage I patients, including ER and PR status, flow cytometry data, nuclear grade, neu oncogene expression, and perhaps haptoglobin-related protein, Cathepsin-D, and Ki-67 expression. Single-agent chemotherapy and oophorectomy have not resulted in prolongation of survival. Combination chemotherapy regimens are superior to single agents, and doxorubicin-containing regimens may be superior to non-doxorubicin-containing regimens. Tamoxifen is effective in improving survival in patients who are ER positive, particularly those women older than 50 years. It appears that six cycles of an effective regimen is as effective as more prolonged administration of the same drugs, and drugs should be given at the optimal dose rate. Preliminary results of alternating non-cross-resistant chemotherapy regimens show promise, but additional data are needed to determine its impact on survival.
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PMID:Current status of adjuvant therapy of early breast cancer. 202 18

The antiestrogen tamoxifen (Tam or Nolvadex, ICI)-Z-1-[4-[2-(dimethylamino) ethoxy]phenyl]-1,2-diphenyl-1-butene is widely used in treatment of hormone-dependent breast cancer. The drug is extensively metabolized by cytochrome P450 dependent hepatic mixed function oxidase in man, yielding mainly the N-desmethyl metabolite (DMT). This study has been carried out to determine the P450 enzyme involved in the N-oxidative demethylation of Tam in microsomal samples from 25 human livers (23 adults, two children). This metabolic step was inhibited by carbon monoxide up to 75%. Tam was demethylated into DMT with an apparent Km of 98 +/- 10 microM; rates varied between 37 and 446 pmol/min/mg microsomal protein. These metabolic rates were strongly correlated with 6 beta-hydroxylation of testosterone (r = 0.83) and erythromycin N-demethylase (r = 0.75), both activities known to be associated with P450 IIIA enzyme. To further assess whether or not the Tam demethylation pathway is catalysed by the same P450, the inhibitory effect of TST on this reaction was determined. The competitive inhibition had an apparent Ki of 100 +/- 10 microM. Drugs such as erythromycin, cyclosporin, nifedipine and diltiazem were shown to inhibit in vitro the metabolism of tamoxifen. Furthermore the P450 IIIA content of liver microsomal samples, measured by Western blot technique using a monoclonal P450NF (nifedipine) antibody, was strongly correlated with DMT formation (r = 0.87). Tam N-demethylase activity was inhibited by more than 65% with polyclonal anti-human anti-P450NF. All these in vitro observations establish that a P450 enzyme of the IIIA sub-family is involved in the oxidative demethylation of tamoxifen in human liver.
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PMID:Identification of the cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes. 203 44

The antiestrogen tamoxifen is the most widely used hormonal therapy for breast cancer. The drug exerts its antiproliferative effects primarily through estrogen receptor (ER)-mediated mechanisms, although other cellular actions may augment tumor inhibition. Clinically, tamoxifen has been less well studied in premenopausal than in postmenopausal patients. The drug has complex endocrine effects that are dependent on the treatment duration and dose, menopausal status, and target organ. In postmenopausal women receiving tamoxifen, serum estrogen levels remain low, and the normally elevated gonadotropin levels decrease. In contrast, serum estrogen levels are strikingly elevated in many premenopausal women, and gonadotropin concentrations are either unchanged or slightly increased. Large systematic trials in metastatic breast cancer have established tamoxifen as the recommended hormonal therapy for postmenopausal women with ER-positive tumors. Tamoxifen is also an active agent for premenopausal metastatic disease, and response rates are comparable to those reported for oophorectomy. Clinical experience with tamoxifen in this younger age group, however, is more limited. Few premenopausal women (less than 400) have been included in phase II and phase III trials. Two randomized trials (total of 160 patients) comparing oophorectomy with tamoxifen do not definitively establish therapeutic equivalence, and a survival advantage for either treatment cannot be excluded. Many questions remain concerning the appropriate role for tamoxifen in premenopausal patients. Still, tamoxifen has an attractive toxicity profile, and it offers a favorable therapeutic alternative for premenopausal women with ER-positive metastatic breast cancer who wish to avoid surgical or radiation castration.
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PMID:Tamoxifen in premenopausal patients with metastatic breast cancer: a review. 204 68

In 1980, there were 570,000 cases of breast cancer in the world. In Norway, there are an average of 2000 new cases per year, and incidence had increased 50% from 1955 to 1984. About 40% of those afflicted die of the disease. Environmental, age, and reproductive factors seem to be implicated in its genesis. The rate increased almost fivefold in the course of a generation among Polish people who migrated to California from low incidence areas. It doubled among Chinese and Japanese who moved to California. The rate increases sharply up to age 50, then it levels off, thus early menopause is protective. Ovarial hormones (estrogen and progesterone) play a role in the development of preclinical tumors. Younger age at first delivery offers protection, but women who give birth to their first child after age 35 face a higher risk than nulliparas. Women with early menarche, which can be delayed by a lower caloric intake and vigorous physical activity, also face a heightened risk. Before menopause, overweight women are relatively protected, but the reverse is true after age 60. The consumption of animal fat is another risk factor, although a US study that involved 90,000 nurses did not bear this out. The Japanese increased their intake of animal fat from 10-25% from 1955-1975 without a corresponding increase in the rate of breast cancer. A vegetarian diet is nonprotective. Even the moderate consumption of alcohol increases the risk by 40% for women aged 15-30. Long-term use of oral contraceptives before birth of the first child up to age 35 increases the risk. Tamoxifen has protected women with a familial history of breast cancer who face a 3-5 fold higher risk. After menopause, its estrogenic properties promote the risk. Tamoxifen has an antitumor effect that can treat tumors clinically which are not manifested; it also lowers LDL (low density lipoprotein) and increases HDL (high density lipoprotein) cholesterol.
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PMID:[Can breast cancer be prevented?]. 206 86

Tamoxifen is a widely used drug in medical oncology, mainly for treatment of breast cancer, but also for second line treatment of endometrial cancer. We recently reported an increased incidence of endometrial cancer associated with long-term adjuvant tamoxifen. This observation, previous reports of stimulatory effects of tamoxifen in the female genital tract, and experimental data are in accordance with a mainly estrogenic effect of tamoxifen in these tissues. An increased incidence of endometrial cancer may limit the usefulness of tamoxifen for benign indications. For adjuvant treatment of early breast cancer, however, the improvement of both recurrence-free survival and overall survival probably outweighs the increased frequency of uterine tumors. However, the possibility of growth stimulation of tumor subclones should be considered when tamoxifen is used in the treatment of endometrial cancer.
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PMID:Effects of tamoxifen on the female genital tract. 206 3


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