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 compared tumor necrosis factor (TNF) metabolism by wild-type MCF-7 (WT) cells, by 40-fold doxorubicin resistant (40F) breast cancer cells and by PC3 and LNCaP prostate cancer cell lines. MCF-7 WT and LNCaP cell lines were sensitive to TNF cytotoxicity and both lines produced two major intracellular TNF degradation products of 15 kDa and 5.5 kDa. The MCF-7 40F and the PC3 cell lines were resistant to TNF and produced multiple TNF degradation products with molecular weights lower than 15 kDa. Both the breast and prostate lines showed TNF receptor crosslinking patterns consistent with a molecular weight of 55 kDa. The breast and LNCaP lines expressed TNF receptors with an apparent dissociation constant (Kd) of 0.4 to 0.6 nM, while the TNF resistant line had a Kd of 2 nM. Similar receptor numbers per cell were found for all cell types (4,000 to 8,000/cell), and comparable levels of TNF internalization were noted. TNF-conditioned medium from the TNF-sensitive cell types was cytotoxic toward both the TNF-sensitive and TNF-resistant lines, and the toxicity was significantly blocked by an anti-TNF monoclonal antibody. Hydrophobic interaction column HPLC fractionation of the TNF-degradation products produced by MCF-7 WT and LNCaP cells revealed that the trimeric, monomeric, and 5.5 kDa fractions possessed the greatest in vitro antitumor activity. These findings suggest that a TNF degradation product, produced selectively by TNF-sensitive cells, may contribute to the antitumor action of TNF.
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PMID:Selective formation of tumor necrosis factor-alpha (TNF) degradation products contributes to TNF mediated cytotoxicity. 131 75

The combined effects of recombinant human tumor necrosis factor (TNF), interferon-gamma (IFN) and tamoxifen (TAM) on the proliferation of human breast cancer cell lines were investigated. In estrogen receptor positive MCF-7 cells, relatively resistant to TAM or TNF, cytotoxicity significantly increased in combinations of TNF and IFN, and of a cytokine and TAM. The cytotoxicity of TNF increased when cells were pretreated with IFN, but not vice versa. Sequential treatment with IFN following TNF and TAM also exhibited significant antiproliferative effect on both cell lines. The combined or sequential cytokines and TAM treatments are possible modalities to overcome breast cancers unresponsive to endocrine treatment.
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PMID:Synergistic cytotoxic effects of tumor necrosis factor, interferon-gamma and tamoxifen on breast cancer cell lines. 144 24

Synergistic enhancement of anti-tumor effects through the combined use of natural human interferon-alpha (nHuIFN-alpha) and natural human tumor necrosis factor-alpha (nHuTNF-alpha) enabled us to decrease the effective dose of each cytokine and consequently to reduce side effects. One hundred and twenty patients with advanced or recurrent solid cancer were entered in the trial from April 1985 to January 1988, of whom 112 patients were evaluable. A mixture of nHuINF-alpha and nHuTNF-alpha was injected intravenously as the maintenance dose 1 x 10(6)U or more/day for over 8 weeks. There was no response in 40 patients injected with the maintenance dose of 1 x 10(6)U/day, but of 72 patients receiving more than 2 x 10(6)U/day (10 micrograms of nHuIFN-alpha and 3 micrograms of nHuTNF-alpha), 4 had complete responses, 10 had partial responses, and 4 had minor responses. The overall response rate was 12.5% (14/112) and the rate was 19.5% in 72 patients with more than 2 x 10(6)U/day. Positive responses were as follows: hepatoma 3/8), renal cell cancer (4/11), breast cancer (4/17), ovarian cancer (1/2), malignant thymoma (1/1) and liposarcoma (1/1). Serious adverse effects like hypotension, oliguria and severe hepatobiliary toxicity were never experienced. The effective and adequate dose of the mixed preparation was considered 2 to 4 x 10(6)U/day/body.
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PMID:Early phase II study of interferon-alpha and tumor necrosis factor-alpha combination in patients with advanced cancer. 157 56

Primary breast cancers from 19 patients and draining lymph nodes from nine of them (seven containing metastatic tumor) were used in growing tumor-infiltrating lymphocytes (TIL) in culture. TIL were studied for proliferation, phenotype, cytotoxicity, and the ability to secrete cytokines in response to autologous tumor. Lymphocytes from primary breast tumors proliferated in 15 of 19 cultures, a median of 6.7 x 10(3)-fold in 65 days. For eight of nine patients, lymphocytes derived from draining lymph nodes proliferated in culture, a median of 110-fold in 49 days. Breast TIL became predominantly CD4+ cells over time in culture and were 73% CD4+ and 21% CD8+ (means) at 63 days (median). Lymph node lymphocytes were 63% CD4+ at 51 days. TIL were poorly lytic in 4-hour 51Cr release assays. Lysis of autologous tumor occurred in only one of 12 breast TIL and one of nine lymph node cultures. This lysis was low (15% at effector:target = 40:1) and was nonspecific (non-major-histocompatibility-complex restricted). Cytokine secretion was tested by co-culturing TIL with autologous or allogeneic tumors for 24 hours. Cytokines were measured in culture supernatants by enzyme-linked immunosorbent assay or radioimmunoassay. TIL from three of 11 patients specifically secreted granulocyte macrophage-colony-stimulating factor, tumor necrosis factor-alpha and interferon-gamma when stimulated by autologous tumor and not by a panel of four to five allogeneic breast cancers. Cytokine secretion has made possible the identification of lymphocytes infiltrating breast cancers with specific immune reactivity. This finding will guide the development of new immunotherapies for patients with breast cancer.
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PMID:Characterization of lymphocytes infiltrating human breast cancer: specific immune reactivity detected by measuring cytokine secretion. 163 79

Somatic cell hybrids between MCF-7 human breast cancer cells and normal immortalized human mammary epithelial cells have been obtained by polyethylene glycol-mediated cell fusion. The hybrid cells are suppressed in their ability to form tumors in nude mice, as well as in traits specific to the tumorigenic MCF-7 parent: growth factor independence, tumor necrosis factor sensitivity, and pS2 gene expression. In addition, they display other characteristics of the "normal" parent, including increased expression relative to the MCF-7 cells of the genes for the extracellular matrix component fibronectin, the intermediate filament keratin 5, and the angiogenesis inhibitor thrombospondin. The levels of keratins 8 and 18 also resemble those of the nontumorigenic parent. These results provide evidence for the existence of tumor suppressor gene products in immortal mammary epithelial cells. We propose a characteristic "suppressed" tumor cell phenotype, which encompasses altered cytoarchitecture, angiogenesis capabilities, and growth factor requirements.
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PMID:Suppression of tumor-forming ability and related traits in MCF-7 human breast cancer cells by fusion with immortal mammary epithelial cells. 169 Apr 27

Fasting venous blood collected from 83 patients with breast cancer was analyzed for triglycerides; total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol; tumor necrosis factor (TNF alpha); glucose; creatinine; insulin; glucagon; growth hormone; cortisol; and thyrotropin. Patients with stage IV disease had significantly higher (P less than 0.05) triglyceride concentrations and significantly lower (P less than 0.05) concentrations of total and HDL cholesterol than did patients with less advanced disease or age-matched controls. Furthermore, LDL cholesterol concentrations in patients with boney metastases were significantly lower (P less than 0.05) than concentrations in patients with liver or liver plus boney metastases or in controls. These results could not be attributed to smoking habits, alcohol consumption, or treatment. We observed no correlations between serum concentrations of lipid and concentrations of TNF alpha, insulin, glucose, creatinine, cortisol, growth hormone, or thyrotropin. However, there was a significant (P less than 0.05) negative correlation between total cholesterol and glucagon and between LDL cholesterol and glucagon for patients with stage II, III, and IV disease, suggesting that glucagon may reduce LDL cholesterol concentrations by an as-yet-unidentified mechanism.
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PMID:Alterations of serum lipids in breast cancer: effects of disease activity, treatment, and hormonal factors. 176 85

We studied the effects of interleukin-1 alpha (IL-1) and tumor necrosis factor-alpha (TNF), alone and in combination, on MCF-7 breast cancer cells to determine whether these cytokines alter cell growth, TNF gene expression, and TNF secretion. We found that IL-1 alone and TNF alone inhibited cell growth in a dose-dependent manner. Each cytokine arrested growth in the G0/G1 phase of the cell cycle, with maximum growth inhibition at 1000 U/ml (P less than 0.05) and 100 U/ml (P less than 0.01), respectively. However, the combination of these two cytokines did not result in greater growth inhibition or a greater percentage of cells arrested in the G0/G1 phase of the cell cycle compared with each cytokine alone. We examined the effect of exogenous IL-1 and TNF on TNF gene expression by Northern blot analysis. In the absence of any cytokine, these cells do not express TNF mRNA. Exposure to IL-1 (1000 U/ml) induced TNF mRNA at 3 h; however, mRNA levels diminished thereafter to barely detectable levels by 24 h. Exposure to TNF (1000 U/ml) also induced TNF mRNA at 3 h, but in contrast to IL-1, the level of enhanced expression persisted at these levels through 72 h of exposure. Secretion of TNF by these cells is induced by exogenous TNF, but not by IL-1. IL-1 and TNF in combination do not produce greater inhibition of growth, greater amounts of TNF mRNA at 3 h, or greater secretion of TNF than that produced by TNF alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 alpha and tumor necrosis factor-alpha (TNF alpha) inhibit growth and induce TNF messenger RNA in MCF-7 human breast cancer cells. 177 75

We have studied the mechanism of the synergistic effect of the combination of tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha) on cell cycle progression using two-parameter flow cytometry in vitro and an immunohistochemical staining method in vivo. The cells used were human colon cancer cell line RPMI 4788 in vitro and in vivo, and human breast cancer cell line MX-1 and human renal cancer cell line NAMKO-1 in vivo. In the in vitro experiment, the cell cycle progressed normally as time elapsed in the control group. However, in the group treated with TNF-alpha and IFN-alpha in combination (combination group), it appeared that the transition from the S phase to the G2/M phase was blocked, and the cells that accumulated in the S phase died. In the in vivo experiment with male nude mice of a CD-1 genetic background, the antitumor effect on all three kinds of cancer cells was significantly greater in the combination group than in the control group. The cell labeling index on staining with bromodeoxyuridine in the combination group became markedly larger and the mitotic index smaller than in the other groups. From these results, it was concluded that in the combination group, both in vitro and in vivo, tumor cells markedly accumulated in the S phase and their progression from the S phase to the G2/M phase in the cell cycle was inhibited.
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PMID:Mechanism of the combined antitumor effect of natural human tumor necrosis factor-alpha and natural human interferon-alpha on cell cycle progression. 182 50

New approaches are needed in the treatment of advanced breast cancer. In vitro studies have shown that recombinant tumor necrosis factor (TNF) is a growth inhibitor for the MCF-7, ZR-75-1, and BT-20 human breast cancer cell lines. Based on these considerations, the Southwest Oncology Group performed a Phase II trial of recombinant TNF (Genentech) (150 micrograms/m2) given by 30-minute intravenous infusion on days 1 to 5 of every other week for 8 weeks. Patients with metastatic breast cancer who had received one prior chemotherapy regimen for advanced disease were eligible. Of the 22 patients who were entered, 3 were ineligible. Nineteen patients who had a performance status of 2 or less could be examined (median age, 53 years). One possible fatal toxic reaction has been seen in a patient who had intracranial bleeding caused by a previously undiagnosed brain metastasis; no other treatment-related deaths have occurred. Toxicity has included nausea, vomiting, fever, chills, myalgia, and fatigue. No Grade 4 toxicity has been observed. Grade 3 toxic reactions have included hypotension (two patients), diarrhea (one patient), transient leukopenia (two patients), and reversible elevations of liver function test values (two patients). No objective responses have been observed. Twelve of 19 patients have died (median survival time, 8.5 months). Recombinant TNF is inactive as a single agent in patients with previously treated metastatic breast cancer.
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PMID:A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer. 191 10

Since overexpression of HER2/neu oncogenes in breast cancer cells is associated with resistance to the cytotoxic effect of tumor necrosis factor (TNF), we investigated whether this correlation also existed for ovarian cancer targets. Nine continuously cultured human ovarian cancer lines were studied and compared to 3 breast cancer lines. Three of the ovarian and 1 breast cancer line demonstrated amplified HER2/neu genes by Southern analysis, increased HER2/neu RNA by Northern analysis, and marked immunoperoxidase staining for HER2/neu protein. The other 8 lines contained unamplified genes and undetectable RNA and protein. All 4 overexpressed lines were relatively resistant to the cytotoxic effects of TNF. Interestingly, they were also resistant to lymphokine-activated killer cells. In contrast, 7 of 8 nonexpressed lines showed sensitivity to TNF and all 8 were sensitive to lymphokine-activated killer cells. There was no difference in sensitivity to lysis by hydrogen peroxide or peptide defensins between over- and nonexpressed lines. These data indicate that expression of HER2/neu oncogenes may impart a proliferative advantage in tumor cells due to induction of resistance to several different cytotoxic mechanisms.
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PMID:Resistance of human ovarian cancer cells to tumor necrosis factor and lymphokine-activated killer cells: correlation with expression of HER2/neu oncogenes. 197 19


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