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)

Two adenocarcinoma cell lines, Breast M25-SF and Breast M, were established from tumor tissue resected surgically from a patient with breast cancer. One, Breast M25-SF, expresses interleukin-2 receptor (IL-2R) on the cell surface and the other, Breast M does not. The effects of recombinant interleukin-2 (rIL-2) on the proliferation of these cell lines were investigated. The growth of Breast M25-SF was significantly promoted by rIL-2 ranging from 1.25 U/ml to 640 U/ml. Anti-CD25 (Tac) antibody significantly blocked the growth enhancement of Breast M25-SF by rIL-2. Breast M, however, did not respond to rIL-2. To confirm more directly the promotion of Breast M25-SF growth by rIL-2, cloning of IL-2 responders from parent Breast M25-SF cells was carried out by limiting dilution without feeder cells in 96-well microplates. No colony formation was found in 24 wells without rIL-2. Eleven, 13 and 6 clones were established from groups of 24 wells containing rIL-2 at 200, 20 and 2 U/ml respectively. All of the clones expressed IL-2R and respond to rIL-2. By using a sensitive polymerase chain reaction technique, we demonstrated that Breast M25-SF but not Breast M expressed IL-2 mRNA, and IL-2 secretion from Breast M25-SF but not Breast M was also confirmed by radioimmunoassay. These findings suggest a role for IL-2 in autocrine support of Breast M25-SF growth. IL-2 may play an important role in the growth control of breast carcinoma cells.
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PMID:Increased proliferation of a human breast carcinoma cell line by recombinant interleukin-2. 792 45

Gross cystic disease (GCD) represents an advanced form of fibrocystic disease of the breast. Bearers of macrocysts have been reported to be at risk of developing breast cancer. Natural killer (NK) cells are a lymphocyte subset deeply involved in immunosurveillance against neoplasia. We investigated whether breast cyst fluid (BCF) aspirated from patients with GCD could affect in vitro the spontaneous and lymphokine-inducible NK activity of peripheral blood mononuclear (PBM) cells concomitantly drawn from the same patients. PBM cells exposed to BCF were evaluated by a standard cytotoxic assay, using K562 cells as a target, in the presence or absence of lymphokines. In vitro incubation of PBM cells with BCF resulted in a consistent decrease of NK cell activity (mean level of suppression about 50%; p < 0.001). Furthermore, exposure of PBM cells to BCF completely prevented the IFN-gamma-dependent enhancement and consistently reduced the IL-2-induced NK activity (p < 0.01). The phenomenon was more apparent for type II cyst BCF. Our data are compatible with an immunosuppressive effect of BCF, potentially leading to altered "local immunosurveillance".
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PMID:Natural killer (NK) cell activity of women with gross cystic disease is inhibited in vitro by breast cyst fluid. 801 60

The antitumor efficacy of IL-2 is limited to renal cancer and melanoma. Several cytokines have been associated with IL-2 in an attempt to improve its activity, without, however, any clear benefit. Recent experimental and clinical studies have suggested the possibility to manipulate the host biological response by immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On the bases of these considerations, we have designed a neuroimmunotherapeutic protocol with low-dose IL-2 subcutaneous therapy (3 million IU/day for 6 days/week for 4 weeks) plus MLT (40 mg/day orally, starting 7 days before IL-2) in advanced solid neoplasms other than renal cancer and melanoma, which are generally resistant to IL-2 alone. The study included 82 patients, 72 of whom showed distant organ metastases. Tumor histotypes were, as follows: non-small cell lung cancer: 19; hepatocarcinoma: 16; colon cancer: 15; gastric cancer: 11; cancer of pancreas: 11; breast cancer: 6; miscellaneous: 4. Objective tumor regression were achieved in 17/82 (21%) patients, consisting of CR in 4 (liver: 2; pancreas: 1; stomach: 1) and PR in 13 (lung: 4; liver: 4; stomach: 2; pancreas: 1; breast: 1; colon: 1). The median duration of response was 8+ months. A stabilization of disease was obtained in 30 patients, while the other 35 patients progressed. The lack of progression was associated with a significantly higher increase in lymphocyte and eosinophil mean number and with a significantly lower increase in neopterin mean levels. The treatment was well tolerated in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cancer immunotherapy with low-dose interleukin-2 subcutaneous administration: potential efficacy in most solid tumor histotypes by a concomitant treatment with the pineal hormone melatonin. 802 99

Angiogenesis is a major new prognostic factor in breast cancer. Small vessels quantitatively assessed by staining with anti-CD31 antibodies correlate with lymph node involvement and are a better independent predictor of survival. There are many vascular growth factors, but predominant in primary tumors assessed by nuclease protection assays are vascular endothelial growth factor and platelet-derived endothelial cell growth factor. Acidic and basic fibroblast growth factor are also detectable. A common feature of these angiogenic factors is heparin binding, so novel analogues of suramin that can compete for heparin binding have been developed. These are more potent in vitro against endothelial cells and are less toxic in vivo, thereby giving a much better therapeutic ratio. Protein kinase C is also important in endothelial growth, as it is in carcinoma growth. Thus, a novel agent inhibiting this pathway, and inducing transforming growth factor-beta production has been assessed in a Phase I trial; this agent is bryostatin. It does not cause marrow suppression and has stimulatory effects of tumor necrosis factor-alpha and interleukin (IL)-6 production. High expression of epidermal growth factor (EGF) receptors and erbB-2 has been related to poor prognosis. EGF receptors are mainly regulated by transcription, as are some cases of high erbB-2 expression. Thus, a novel approach to gene therapy is being developed using direct tumor injection of cDNA, with a tumor specific promoter ligated to the IL-2 gene. This avoids many problems associated with targeting. Because IL-2 stimulation of cytotoxic T-cells will depend on appropriate antigen presentation, human lymphocyte antigen Class I expression was studied, as was the peptide transporter system RING4 (TAP1). Losses were found in 50% of cases, and in some cases only in lymph nodes but not primary cancers, thereby providing evidence for a role in suppressing metastasis. Thus, many new approaches to therapy are possible as a result of understanding growth factors and intracellular signaling pathways.
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PMID:Gene therapy through signal transduction pathways and angiogenic growth factors as therapeutic targets in breast cancer. 803 35

In summary, it is well established that moderate calorie restriction or reduction in overall high calorie food intake prevents or forestalls the development of age-associated disease incidence such as breast cancer and renal disease in rodents. A similar approach could also readily be applied in humans for preventing the risk and rise of life-shortening diseases. Many age-associated diseases, particularly autoimmune diseases with viral etiology, appear to be exacerbated in the presence of adverse lipid intake such as an increased level of vegetable oils or trans-fatty acids from the usage of hydrogenated dietary oils. At present, nearly 35-40% of the total calories are from dietary fats and/or of lipid origin. Although usage of saturated fat, which increases cardiovascular disease, has been reduced to a large extent in the United States, consumption of both monounsaturated and polyunsaturated fats of omega-6 origin has either increased or simply been substituted in place of saturated fats. Further, for the past 50 years, a significant reduction in highly polyunsaturated fat consumption such as marine oil has also occurred specifically in the United States. The reduction in omega-3 lipids of marine or vegetable source occurs primarily because of short shelf life due to rancidity. However, the increased consumption of omega-6 or a vegetable source of oils and decreased omega-3 intake may increase in vivo the production of free radicals and higher proinflammatory cytokines. Our ongoing studies reveal that proinflammatory vegetable oil could increase autoimmune disease by increasing the free radical formation by decreasing the antioxidant enzyme mRNA levels, thereby further decreasing immune function, particularly the production of anti-inflammatory cytokines such as IL-2 and TGF beta mRNA levels. In contrast, omega-3 lipid intake in the presence of an antioxidant supplement appears to exert protection against autoimmunity by enhancing antioxidant enzymes and TGF beta mRNA levels and by preventing the rise in oncogene expression. However, detailed studies are required to establish the protective and deleterious role of different commonly consumed lipids or dietary oils by the general population, particularly during middle and aging years. Further, we also propose that combining nonsteroidal drug therapy along with moderate calorie reduction in the presence of more protective omega-3 dietary lipids of either marine or vegetable source and decreasing the levels of mono- and polyunsaturated lipids may provide additional protection against the age-associated rise in malignancy and autoimmune disorders.
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PMID:Dietary lipids and risk of autoimmune disease. 805 Jan 92

Recombinant IL-2 (rIL-2) was administered intrapleurally according to an original protocol to 11 patients with malignant pleural effusion, 7 of whom suffered from breast cancer and 4 from esophageal cancer. The pleural effusions either disappeared or decreased roentgenographically, and malignant cells disappeared from all 13 pleural cavities in the 11 patients, confirming the validity of this therapy to be 100%. The mean survival time from the initial administration of rIL-2 was 15.9 months. We ensured that the concentration of IL-2 in the effusion was maintained at a high level for a sufficient period of time, and that the lymphokine-activated killer (LAK) activity of lymphocytes in the effusion was augmented. Fever, eosinophilia, and a transient increase in the pleural effusion were the main side effects, but the symptoms were temporary and not serious. The results of this study therefore suggest the efficacy of intrapleural rIL-2 for patients with malignant pleural effusion.
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PMID:The intrapleural administration of recombinant interleukin-2 (rIL-2) to patients with malignant pleural effusion: clinical trials. 811 18

In order to investigate the mode of action of tumour-derived immunosuppressive factor from breast cancer (TDS) we examined its function on human T-cells stimulated via CD3 and co-stimulated via CD28 or the IL-2 receptor. When added at the initiation of culture, TDS inhibited anti-CD3 stimulation and co-stimulation by anti-CD28. In contrast, co-stimulation with IL-2 greatly diminished the TDS inhibition of anti-CD3 stimulated cells. Activation by IL-2 alone was also inhibited at the initiation of culture. When PBMC were activated with IL-2 or anti-CD3 for three days and then exposed to TDS for a further 3 days, only the proliferation of the cells pre-activated with IL-2 was inhibited; the cells pre-activated via CD3 were refractory to TDS inhibition. Pre-activation with anti-CD3 for 48 h was required for this to develop. The cytotoxicity of cells pre-activated with anti-CD3 was lower than that of cells exposed to IL-2, but killing obtained from cultures pre-activated with anti-CD3 plus IL-2 was equivalent to that obtained with IL-2 alone and additionally, these pre-activated cells were not subject to inhibition upon subsequent exposure to TDS.
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PMID:Co-stimulation with IL-2, but not via CD28, overcomes immunosuppression by breast tumour-derived factors on the in vitro stimulation of human T-cells. 825

Current adoptive immunotherapy strategies in cancer patients require large numbers of activated T-cells and are limited by the availability of autologous tumour. We describe a novel method of T-cell activation that produced relatively rapid, high-fold expansion of stored, frozen lymphocytes obtained from the lymph nodes of 20 breast cancer patients during axillary dissection but does not require autologous tumour. In vitro exposure of thawed cells to bryostatin-1 (B), a non-tumour promoting protein kinase C activator and ionomycin (I), a calcium ionophore, at day 0 followed by culture in low dose interleukin-2 (IL-2 20 units ml-1) and restimulation again on day 10 results in 269-28,206 fold (geometric mean = 2254) expansion in cell numbers counted 17 days after initial stimulation. Analysis of cell surface markers revealed that B/I expanded human cells were predominantly T-cells (83-97%) and consisted of a mixture of CD8+ (46-74%) and CD4+ (4-30%) cells. B/I expanded cells did not lyse autologous tumour cells when tested in a 4-h 51Cr release assay, but murine studies reported previously have demonstrated specific and curative in vivo efficacy in MCA-105 tumour-bearing mice despite an inability to lyse autologous tumour in vitro. B/I expanded T-cells from five of six patients secreted the cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in response to co-culture with autologous tumour cells but not with irrelevant tumour. These results are analogous to findings in a murine model, in which non-cytolytic B/I expanded T-cells mediated specific, curative anti-tumour effects in vivo, and lay the groundwork for a clinical trial of this novel strategy for the adoptive immunotherapy of breast cancer patients.
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PMID:Expansion and tumour specific cytokine secretion of bryostatin-activated T-cells from cryopreserved axillary lymph nodes of breast cancer patients. 830 69

In patients with Stage II or III breast cancer and in patients with liver metastases from breast cancer, we examined cellular interaction in the cytotoxicity against autologous tumor cells by interleukin-2(IL-2)-cultured lymphocytes (CL) and fresh peripheral blood lymphocytes (FPBL) treated with immunochemotherapy including OK-432 and cyclophosphamide. In flow cytometric analysis, CD8+CD11b+ and CD16+ cells significantly decreased after immuno-chemotherapy in both groups of patients. A protocol study in Stage II or III breast cancer patients showed suppressive activity of FPBL on the cytotoxic activity of CL in 3/9 of the non-treatment group but no suppressive activity and enhancing activity in 3/7 in the immuno-chemotherapy group. Moreover, in 19 patients with liver metastases from breast cancer treated with immuno-chemotherapy including adoptive immunotherapy, FPBL in 6/19 showed enhancing activity, and in 8/19 suppressive activity in the lysis of autologous tumor cells. In assays in vitro using autologous and allogeneic tumor cells, FPBL showed a partial specificity in cellular interaction against autologous tumor cells. CD4-depleted FPBL inhibited cytotoxicity of CL, while CD8-depleted FPBL enhanced cytotoxicity of CL in patients with liver metastases. These results suggest that immuno-chemotherapy eliminates the suppressive population in FPBL and may induce tumor regression if combined with adoptive immunotherapy using CL.
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PMID:Cellular interaction against autologous tumor cells between IL-2-cultured lymphocytes and fresh peripheral blood lymphocytes in patients with breast cancer given immuno-chemotherapy. 850 45

This work was designed to study the proliferative response of tumor-associated lymphocytes (TAL) from neoplastic effusions against autologous tumor cells and the immunophenotype pattern of TAL from neoplastic effusions and that of PBMC of the same patients. We also compared the serum levels of the cytokines interleukin (IL) 1 beta, 2 and 6, tumor necrosis factor-alpha (TNF alpha) and soluble IL-2 receptor (sIL-2R) with those present in neoplastic effusions of the same patients. Moreover, we examined the ability of TAL and peripheral blood mononuclear cells (PBMC) to produce and release the cytokines and sIL-2R and to express membrane CD25 following their stimulation with phytohemagglutinin (PHA) in vitro. Finally, we compared the cytokines/sIL-2R production and membrane CD25 expression by PHA-stimulated PBMC of the patients with neoplastic effusions with a series of 90 cancer patients without neoplastic effusions and 20 normal healthy subjects. Thirteen neoplastic pleural and eight peritoneal effusions were collected from 11 patients with primary lung cancer, 7 with primary epithelial ovarian cancer, 1 with breast cancer, 1 with pleural mesothelioma, and 1 with pancreatic cancer. The proliferative response of TAL from neoplastic effusions against autologous tumor cells was lower than the response to PHA, IL-2, and anti-CD3, but significant. The percentage distribution of CD3+ and CD8+ lymphocyte subpopulations was higher in peritoneal than in pleural effusions, while the CD16+ subset was higher in pleural than in peritoneal effusions. The percentage distribution of CD16+ was significantly lower in pleural effusions than in PBMC of patients with pleural effusions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor-associated lymphocytes (TAL) are competent to produce higher levels of cytokines in neoplastic pleural and peritoneal effusions than those found in sera and are able to release into culture higher levels of IL-2 and IL-6 than those released by PBMC. 852 43


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