Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.01 seconds)

A study was started in 1976 whereby patients with Stage II and operable Stage III MBC were given adjuvant Tamoxifen for 1 year, increasing to 2 years from 1988. All patients had axillary nodal involvement. Primary treatment consisted of a radical mastectomy or simple mastectomy with radiotherapy. The rarity of the disease precluded a randomised trial. Thirty-nine patients are available for analysis at a median follow-up of 49 months. The actuarial survival of the Tamoxifen treated patients is 61% (range 42-80%) at 5 years compared to 44% (range 35-53%) for historical controls (P = 0.006). Disease-free survival was 56% (37-75%) vs 28% (17-33%) at 5 years (P = 0.005). There were no serious side-effects recorded. The conclusion from this, the first reported series on adjuvant Tamoxifen therapy for MBC, is that significant improvement in disease-free survival can be achieved with minimal upset to the patients. Recruitment to the study continues.
Br J Cancer 1992 Feb
PMID:Adjuvant tamoxifen for male breast cancer (MBC). 173 25

We investigated the ability of high concentrations of oestradiol to reverse the growth inhibitory action of tamoxifen on MCF-7 breast cancer cells in vivo. Tamoxifen inhibits the oestradiol stimulated growth of MCF-7 cells in athymic mice. Using a sustained release preparation of tamoxifen we consistently achieved serum concentrations of the drug in the 40 to 50 ng ml-1 range and much higher levels in tissues. These serum levels are sufficient to inhibit the oestrogen stimulated growth of MCF-7 tumours exposed to physiologic (i.e. 300-600 pg ml-1 serum oestradiol concentrations). However, by administering dosages that increase serum oestradiol concentrations to 900-2000 pg ml-1, mimicking the increase often observed clinically in premenopausal women taking tamoxifen, we show that the growth inhibitory action of tamoxifen can be partially reversed. Serum tamoxifen levels were elevated to nearly 400 ng ml-1 by injecting 1 mg day-1 tamoxifen (IP 3 x weekly); this dosage was more effective at inhibiting oestradiol stimulated tumour growth than subcutaneous tamoxifen capsules alone. Our data suggest that at low serum levels tamoxifen may not act optimally. There may be a need to monitor tamoxifen levels in premenopausal patients to ensure that they are high enough not to be overcome by a tamoxifen induced increase in ovarian steroidogenesis.
Br J Cancer 1991 Dec
PMID:Reversible control of oestradiol-stimulated growth of MCF-7 tumours by tamoxifen in the athymic mouse. 176 61

We compared the initial treatment of 383 patients with breast cancer in two central London teaching hospitals during 1986 with the guidelines of the King's Fund Consensus Conference for breast cancer treatment held in London the same year. The majority of patients (68%) received lumpectomy and 18% received mastectomy. Lumpectomy was followed by radiotherapy for 95% of cases but 30% of mastectomy patients also received radiotherapy. Only 42% of the patients had surgical sampling of the axillary nodes. Cytotoxic chemotherapy was recorded for 27% women under 50, but also for 16% women age 50 or more. Tamoxifen was given to 58% of women aged 50 or more, but also to 26% of women under 50. We conclude that there are discrepancies between consensus guidelines and clinical practice. Further study is needed to determine whether these variations are clinically important, and whether similar variations exist elsewhere in Europe.
Eur J Cancer 1991
PMID:Treatment of breast cancer in two teaching hospitals: a comparison with consensus guidelines. 182 65

The authors report a case of endometriosis (adenomyosis + endometrioma) which occurred in a female patient aged 69 years, who had undergone the menopause 15 years previously and who had been taking Tamoxifen for 7 years as an adjuvant treatment for cancer of the breast. Tamoxifen, a non-steroidal anti-estrogen derived from diethylstilbestrol, has a variable antagonist/agonist so that estrogenic stimulation of the female genital tract may occur, particularly of the endometrial mucosa. The reactivation of the endometriosic foci which had become quiescent under the impact of the natural menopause, which, by iatrogenic analogy is included in the series of paradoxical uterine effects of tamoxifen.
 ...
PMID:[Post-menopausal endometriosis developed during tamoxifen treatment]. 187 4

Two hundred and fifty evaluable patients with breast cancer entered a protocol combining neoadjuvant and consolidation therapy by vinblastine (V), thiotepa (T), methotrexate (m) and 5-fluorouracil (f) (VTMF) with or without Adriamycin (A) (Doxorubicin; Adria Laboratories, Colombus, OH USA), and radiation therapy as exclusive locoregional treatment. Tamoxifen was given to 195 patients, 130 post menopausal and 65 pre-menopausal, and was omitted in 55 patients (31 postmenopausal and 24 pre-menopausal). There were 19 stage I, 86 IIa, 51 IIB, 36 IIIA and 58 IIIB. Primary chemotherapy induced tumor volume regression of more than 75% in 41% of the patients and complete clinical regression in 30% of the patients. The 5 years DFS rates were 100% for stage I, 82% for stage IIA, 61% for stage IIB, 46% for stage IIIA and 52% for stage IIIB patients. Among the 72 primary relapses there were 39 distant metastases, 6 locoregional and distant metastasis and 27 isolated locoregional metastases. The actuarial rate of locoregional recurrence is 13% for T2, 18% for T3, 19% for T4. At 5 years the rate of breast preservation was 94%. Cosmetic results are excellent or good for most patients. The 5 years overall survival (OS) were 95% for stage I, 94% for stage IA, 80% for stage IIB, 60% for stage IIIA and 58% for stage IIIB. In multivariate analysis tumor regression appears as an independent and significant factor. This parameter should be preserved in many patients with infiltrative breast cancer.
Bull Cancer 1991
PMID:[Tumor regression as a prognostic factor in breast cancer]. 187 5

A procedure for the extraction of tamoxifen and metabolites from various rat and human tissues was developed and verified. With this method, we determined the drug and metabolite concentrations during one dosing interval in various tissues (brain, fat, liver, heart, lung, kidney, uterus, and testes) of rats given tamoxifen once daily for 3 or 14 days, and in various normal and malignant tissues obtained during surgery or at autopsy from patients with breast cancer treated with tamoxifen. In the rat, the concentrations of tamoxifen and metabolites in most tissues were 8- to 70-fold higher than in serum. The highest levels were observed in lung and liver; substantial amounts were also recovered from kidney and fat. Fluctuations of metabolites and tamoxifen content in most tissues were observed during one dosing interval, corresponding to a ratio of 4:8 between Cmax and Cmin, except in fat and testicular tissues, where the drug concentrations were relatively stable. In addition to tamoxifen, N-desmethyltamoxifen, followed by 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, and N-desdimethyltamoxifen, were abundant in most tissues. In contrast, adipose tissue contained only small amounts of these metabolites. The concentrations of tamoxifen and metabolites found in human normal and malignant tissues confirmed and extended the conclusions made in the experiments with rats. In humans, levels were 10- to 60-fold higher in tissues than in serum, and relatively high concentrations were detected in liver and lung. Additionally, pancreas, pancreatic tumor, and brain metastases from breast cancer and primary breast cancer retained large amounts of drug. Again, the amounts of demethylated and hydroxylated metabolites were high in most tissues, except in fat. Tamoxifen and some metabolites were also present in specimens of skin and bone tissue. In one patient, significant amounts of drugs could be detected in lung, heart, ovary, and intestinal wall 14 months after withdrawal of tamoxifen, demonstrating efficient retention and slow washout of these compounds in human tissue.
Cancer Res 1991 Sep 15
PMID:Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. 189 76

Immunohistochemical assays have been employed to study the expression of ER, PgR, EGFR and Ki67 immunostaining in normal breast tissue (n = 76). The expression of ER and PgR was highly variable in both pre and postmenopausal women and was characterised by large numbers of apparently negative cells. This was most evident for ER-ICA staining in tissues removed from premenopausal women. PgR levels were highest in the ducts of premenopausal women, while EGFR expression was elevated in both ducts and lobules. Ki67 expression was observed in less than 10% of all normal cells and was suppressed by the menopause in lobular tissue. Tamoxifen therapy (40 mg d-1) did not influence the expression of PgR, EGFR or Ki67 immunostaining in cancer associated normal tissue (n = 17). A significant increase, however, was observed in the mean percentage ER positivity in ductal tissue. No effect of duration of tamoxifen therapy was observed on the expression of the antigens studied.
Br J Cancer 1991 Oct
PMID:Influence of the antioestrogen tamoxifen on normal breast tissue. 191 Dec 27

Acquired tamoxifen resistance represents a major cause of treatment failure in breast cancer. We implanted estrogen receptor-positive MCF-7 human breast cancer cells in athymic nude BALB/c mice as a model to study in vivo acquired tamoxifen resistance. After 4-6 months of tumor growth suppression by trans-tamoxifen, tumor progression was observed despite continued tamoxifen administration. Acquired resistance was not due to loss of estrogen receptors, to alterations in serum or tumor estrogen levels, or to changes in tamoxifen or its major metabolites in serum. Tamoxifen-resistant tumors remained estrogen dependent in vivo. However, resistance was also associated with the ability of tamoxifen to stimulate tumor growth. Resistant tumors were characterized by markedly lower intracellular tamoxifen levels and by isomerization of the potent antiestrogenic metabolite trans-4-hydroxy-tamoxifen to the less potent cis isomer. Metabolic tolerance, as manifested by alterations in cellular concentrations of tamoxifen and its metabolites, may thus be one mechanism for acquired tamoxifen resistance in breast cancer.
J Natl Cancer Inst 1991 Oct 16
PMID:Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. 192 Apr 88

Tamoxifen is used to treat selected patients at each stage of breast cancer. Although most clinical experience has been obtained with postmenopausal women, increasing numbers of premenopausal women will be treated with 5 or more years of adjuvant tamoxifen therapy following surgery. Indeed, the proposed use of tamoxifen to prevent breast cancer in high-risk women could result in its extended use during the childbearing years. We have monitored the changes in circulating hormone levels from the ovary and pituitary gland in premenopausal (41-47 years old) women with stage I or II breast cancer during adjuvant therapy with tamoxifen as the single agent for 4-72 months following a mastectomy. Each patient (total eight) continued to menstruate, and ovulation occurred. Circulating levels of luteinizing hormone and follicle-stimulating hormone (except in one woman) remained in the normal range (determined in 12 regularly menstruating women in a control group). The levels of estradiol, estrone, and progesterone were elevated onefold to threefold. Prolactin levels decreased by 30%-40%, but the levels of sex hormone binding-globulin were unaffected. These data demonstrate that premenopausal women taking tamoxifen are potentially at risk for pregnancy and must be counseled about barrier contraception. Furthermore, the impact of many years of ovarian stimulation by tamoxifen must be evaluated, especially in women with node-negative disease or in healthy women in whom tamoxifen is used to prevent breast cancer.
J Natl Cancer Inst 1991 Oct 16
PMID:Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. 192 Apr 95

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.
Cancer Res 1991 Nov 15
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


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>