Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen administered in the diet (420 ppm) to Wistar rats (TOX:P) for only 3 months caused cumulative hepatic DNA damage as assessed by 32P-postlabeling, consistent with the proposal that tamoxifen is a genotoxic carcinogen in this species. Promotion of tumor development with phenobarbital after discontinuation of dietary tamoxifen resulted in the formation of liver carcinomas after 9 months. At 12 and 20 months in this study, the majority of these rats had liver carcinomas. Rats treated with tamoxifen for 3 months but not promoted with phenobarbital also developed liver tumors over a longer period of time. These tumors were predominantly adenomas, with one carcinoma, and occurred at a lower incidence than the tumors produced by promotion with phenobarbital. Rats treated with phenobarbital alone did not develop tumors after 20 months. Tamoxifen-induced DNA adducts were relatively persistent, with only a 38% decrease 3 months after tamoxifen treatment had been discontinued. This demonstrates that, in a susceptible species (the rat), tamoxifen can cause initiation of liver cancer after only 3 months exposure. It is proposed that the persistence of such DNA adducts may account for the ability of phenobarbital to promote a high incidence of liver carcinoma, even after discontinuation of tamoxifen treatment. These data are relevant to the concern for women given prophylactic tamoxifen for long periods in that even if there is a relatively small amount of cumulative tamoxifen-induced liver DNA damage, liver tumors could be promoted by other agents, even after the cessation of tamoxifen treatment.
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PMID:Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital. 783 23

Tamoxifen (TAM), a widely used agent in the hormonal therapy of breast cancer, is also an antagonist of P-glycoprotein (P-gp), a cell surface protein which confers drug resistance to cells. Here we report that in an estrogen receptor-deficient multidrug-resistant subline of MCF-7 human breast carcinoma cells (MCF-7/MDR), but not in the parent drug-sensitive cells (MCF-7/WT), clinically relevant concentrations (1-5 microM) of TAM inhibited the uptake and phosphorylation of ethanolamine and choline. These inhibitory effects resulted in decreased synthesis of the corresponding phospholipids. In view of the known dependence of P-gp function on phosphatidylethanolamine (PtdEtn), inhibition of PtdEtn synthesis may represent an additional mechanism by which TAM inhibits P-gp-mediated drug efflux.
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PMID:Tamoxifen inhibits uptake and metabolism of ethanolamine and choline in multidrug-resistant, but not in drug-sensitive, MCF-7 human breast carcinoma cells. 787 22

Tamoxifen is known to inhibit the growth of some human mammary carcinoma cells; this effect is accompanied by a decrease in the proportion of cells synthesizing DNA. In this work, flow cytometry of DNA and of bromodeoxyuridine labeling and the evaluation of the cell cycle-related antigens Ki-67, PCNA, and statin were used to investigate the changes in the proliferation kinetics of MCF-7 cells before and after treatment with 10(-7) M TAM. The treatment with TAM induced a significant decrease in the fraction of S-phase cells and an increase in those with a DNA content typical of G0/1 phase. The TAM-induced block in G0/1 is paralleled by a decrease in the frequency of cells expressing Ki-67 and PCNA, and by an increase in statin-positive (G0) cells. These results confirmed that the TAM-induced inhibition of cell growth is associated with major changes in the cell cycle parameters of MCF-7 cells, and provide the first experimental evidence that two main mechanisms are operating: the accumulation of cells in G1, before the onset of S-phase, and the exit of some cells from the cycling compartment.
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PMID:Cell cycle kinetic effects of tamoxifen on human breast cancer cells. Flow cytometric analyses of DNA content, BrdU labeling, Ki-67, PCNA, and statin expression. 790 38

Since its introduction in the early seventies, the list of indications for the use of the antiestrogen tamoxifen has been continuously expanded. Tamoxifen is now used for the treatment of metastatic breast cancer and for long-term and often indefinite administration as an adjuvant therapy. Large clinical trials in three countries are now evaluating the efficacy of tamoxifen as a preventive agent. However, tamoxifen therapy has been associated with an increased incidence of endometrial carcinoma. Laboratory and clinical data available to date on this controversial issue can be summarized as follows: a) Tamoxifen can have an estrogenic effect on endometrium in the presence of low estrogen levels. b) Tamoxifen treatment is probably associated with an increased incidence of endometrial cancer; however, this association appears to be linked to higher tamoxifen doses (40 mg/d). d) It is not known whether tamoxifen causes or allows the identification of occult endometrial carcinoma. e) At the present time there is evidence for a tumor promoting effect of tamoxifen on endometrial cancer at a dose of 20 mg per day. f) Replacement of tamoxifen by 'pure' antiestrogens or coadministration of progestins with tamoxifen do not appear to offer benefit unless clinical trials demonstrate a reduced incidence of endometrial problems. g) Patients must be evaluated for pre-existing endometrical carcinoma before starting tamoxifen therapy. f) Close followup of long-term tamoxifen patients with endometrial biopsies is recommended with individuals who experience symptoms.
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PMID:What do we know and what don't we know about tamoxifen in the human uterus. 798 54

Tamoxifen is an antiestrogen used in adjuvant therapy of breast carcinoma and could potentially prevent the development of mammary cancer. While it is widely clinically used, its exact mechanisms of action are not yet fully elucidated. MCF-7/6 cells are estrogen receptor-positive invasive human breast cancer cells with a functionally inactive cell surface E-cadherin. In this study, we report that tamoxifen, and to a lesser extent its metabolites 4-OH-tamoxifen and N-desmethyltamoxifen, restore the function of E-cadherin in MCF-7/6 cells. In an aggregation assay, 10(-6) M tamoxifen significantly increases the aggregation of MCF-7/6 cells. This effect is abrogated by a monoclonal antibody against E-cadherin (HECD-1), is fast (within 30 min), and does not require de novo protein synthesis. Tamoxifen was also found to inhibit the invasion of MCF-7/6 cells in organ culture. Our data is the first demonstration that tamoxifen can activate the function of an invasion suppressor molecule and suggest that the restoration of E-cadherin function may contribute to the therapeutic benefit of tamoxifen in breast cancer patients.
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PMID:Tamoxifen restores the E-cadherin function in human breast cancer MCF-7/6 cells and suppresses their invasive phenotype. 806 51

The whole-cell mode of the patch-clamp technique has been used to monitor ionic currents in T84 colonic carcinoma cells. The cells were stimulated by either a cAMP cocktail, ionomycin or hypotonicity. Sizeable currents with distinct kinetics were observed after the stimulation with the different agonists. These kinetically distinct Cl- currents also presented a differential sensitivity to the anti-oestrogen Tamoxifen and to the halide I-. Tamoxifen only inhibits the volume activated Cl- current without affecting the other two. Substitution of extracellular Cl- by I- shifted the reversal potential towards more negative values both in the hypotonicity and ionomycin activated Cl- currents. The cAMP activated current responded to the Cl- substitution by I- with a blockade of both outward and inward currents, in addition to the displacement of the zero current level towards positive values. Thus, the use of these two simple tools, I- and tamoxifen, allows the distinction of Cl- channels in epithelial cells.
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PMID:Differential effects of tamoxifen and I- on three distinguishable chloride currents activated in T84 intestinal cells. 813 72

Tamoxifen, an antiestrogen, and doxorubicin, an anthracycline antibiotic, are each utilized alone and in combination in the treatment of breast carcinoma. In view of conflicting reports relating to the interaction between these drugs, studies were undertaken to characterize the influence of tamoxifen on growth inhibition by doxorubicin in the MCF-7 breast tumor cell line in vitro. Studies combining 5 microM tamoxifen, a clinically relevant concentration, with various concentrations of doxorubicin, indicated that this drug combination produces antiproliferative effects that appear to be less than additive. Concentration-dependent growth inhibition was analyzed further using various concentrations of tamoxifen and doxorubicin by the combination index-isobologram method; this quantitative approach provided clear evidence of antagonism between these agents, a finding with potential relevance to the treatment of breast cancer.
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PMID:Antagonism between tamoxifen and doxorubicin in the MCF-7 human breast tumor cell line. 818 52

The effects of a new antiestrogen, droloxifene (DROL, (E)-alpha-[p-[2-(dimethylamino)ethoxy]-phenyl]-alpha'-ethyl-3- stilbenol), on human breast cancer cells in vitro and in vivo were studied. Since phenol red has a binding affinity to the estrogen receptor (ER), we studied the activities of drugs in medium with or without this indicator. Estradiol-17 beta (E2) stimulated the growth of ER-positive breast cancer cells, MCF-7, ZR-75-1 and T-47D, in medium without phenol red, but not in medium containing this indicator. In medium without phenol red, DROL had no marked effects on the growth of MCF-7 and ZR-75-1, but slightly stimulated the growth of T-47D. Tamoxifen (TAM) stimulated the growth of these 3 cells. DROL dose-dependently inhibited the E2-induced stimulation of growth of these cells in medium without phenol red, but TAM inhibited the growth only at high concentrations. The growth of ER-negative breast cancer cells, MDA-MB-231, was not influenced by E2, DROL or TAM. DROL was more effective than TAM against ER-positive Br-10 breast carcinoma in nude mice, but neither drug had effects on ER-negative MX-1 breast carcinoma. These results suggest that DROL shows an antitumor effect on ER-positive breast cancers, being less estrogenic and more antiestrogenic than TAM.
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PMID:The estrogenic and antiestrogenic activities of droloxifene in human breast cancers. 827 28

The effects of the anti-estrogens 4-hydroxytamoxifen (OHTam), ICI 164,384 and ICI 182,780 were tested on the MCF-7/LCC2 breast-carcinoma cell line, which grows significantly in the presence of OHTam and serves as a model for studying anti-estrogen resistance of estrogen-receptor-positive breast cancer. Cell proliferation and cathepsin-D secretion were strongly inhibited by either ICI 182,780 or ICI 164,384 alone or ICI 164,384 in combination with 17-beta-estradiol (E2) or OHTam. ICI 164,384 alone did not affect the cathepsin-D and pS2 mRNA levels, but antagonized the stimulatory effects of E2 or OHTam on these 2 mRNAs. OHTam was more effective than E2 in increasing cathepsin-D mRNA levels, supporting the idea that anti-estrogen-resistant breast cancer continues to overexpress cathepsin-D. These data show that the steroidal anti-estrogens ICI 164,384 and ICI 182,780 retain their ability to inhibit cell proliferation and the estrogen-responsiveness of cathepsin-D and pS2 genes in the OHTam-resistant MCF-7/LCC2 cell lines. These pure anti-estrogens may thus be efficient second-line treatments of some Tamoxifen-resistant tumors.
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PMID:Anti-proliferative and anti-estrogenic effects of ICI 164,384 and ICI 182,780 in 4-OH-tamoxifen-resistant human breast-cancer cells. 831 14

Greenway et al reported estrogen receptor existed in the carcinoma of the exocrine pancreas in 1981. We followed the study by using immunohistochemical method with monoclonal antibody ER-D5 (Amersham) and found high levels of estrogen receptor in 21 cases out of 27 carcinomas of the pancreas (77.8%). Furthermore, we gave randomly the hormone therapy by Tamoxifen 20 mg per day adding to immuno-chemotherapy (Tegaful, Mitomycin, Krestin, OK-432) to the patients with resected carcinoma of the pancreas. There was no significant difference of the survival rate of pancreatic carcinoma without hormone therapy between 10 cases with estrogen receptor and 4 cases without estrogen receptor at the 6th month and 12th month. However, in cases treated by Tamoxifen, remarkable high survival rate at 12 months of 11 cases with estrogen receptor was obtained to be 85.7% according to Kaplan-Meier method. Two cases without estrogen receptor died within 5 months. One year survival rate of Tamoxifen group (13 cases) was 78.6% and that of non Tamoxifen group (14 cases) was 21.4%. These findings indicated that estrogen receptor existed at the high level in the carcinoma tissues of the pancreas and anti-estrogen treatment might offer a new approach to the treatment of pancreatic carcinomas.
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PMID:[Hormone therapy of tamoxifen in resected carcinoma of the pancreas]. 836 72


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