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)

The immunosuppressive activity of tumor cells may be mediated by tumor-derived cytokines such as transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10). A human breast cancer cell line derived from malignant ascites (BRC 173) secreted TGF-beta, but not IL-10, into tissue culture supernatant (TCS). BRC 173 TCS suppressed natural killer (NK) and lymphokine-activated killer (LAK) cell activity and also blocked the generation of HLA-A*0201-restricted tumor-reactive cytotoxic T-lymphocyte (CTL) lines in vitro. Human alpha 2-macroglobulin (alpha 2M), a plasma protein and cytokine carrier that binds isoforms in the TGF-beta family, was tested for its ability to neutralize the immunosuppressive activity in BRC 173 TCS. alpha 2M was converted to its activated conformation by reaction with methylamine (alpha 2M-MA) and then incubated with normal human peripheral blood lymphocytes (PBL) in the presence of IL-2 and BRC 173 TCS. Lysis of NK targets (K562) and LAK cell targets (DM6 melanoma) by the PBL was examined after 6 days of culture. PBL cultured in IL-2, without TCS or alpha 2M-MA, were lytic for both target cells. BRC 173 TCS substantially suppressed the lytic activity of the PBL in the presence of IL-2. When TGF-beta-neutralizing antibody was added to the PBL culture medium with IL-2 and TCS, a majority of the lytic activity was restored. alpha 2M-MA (280 nM) neutralized almost all of the immunosuppressive activity in the TCS, restoring 80-100% of the lytic activity without any apparent effect on the activity of IL-2. The ability of alpha 2M-MA to counteract immunosuppressive cytokines in breast cancer TCS was evident in serum-containing and serum-free medium. These studies demonstrate the activated alpha 2M can function as a selective cytokine neutralizer to thereby promote the activation of NK, LAK, and tumor-specific CTL responses.
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PMID:Activated alpha 2-macroglobulin reverses the immunosuppressive activity in human breast cancer cell-conditioned medium by selectively neutralizing transforming growth factor-beta in the presence of interleukin-2. 955 59

Matrix metalloproteinases (MMPs) are thought to play a significant role in tumor invasion and metastasis as well as angiogenesis. Batimastat, also known as BB-94, acts as an inhibitor of metalloproteinase activity by binding the zinc ion in the active site of MMPs. In our study, the hormone-independent MDA435/LCC6 human breast cancer cell line was used to seed solid tumors s.c. into the region of the mammary fat pad in athymic nude mice. Mice were treated with 50 mg/kg batimastat i.p. Tumor volume measurements showed a statistically significant decrease in tumor size between batimastat-treated and control animals. In contrast, we also used the same MDA435/LCC6 cell line to propagate a malignant ascites in nude mice, which yielded a very different response to batimastat. Batimastat, in previously published literature, had been shown to prolong the life of mice bearing ovarian ascites tumors. Treatment with batimastat in our ascites model produced no increase in survival or significant suppression of ascites formation. However, treated animals showed dramatic tumor cell consolidation and less dispersed ascites cells compared with control animals. Two potential targets of batimastat, gelatinase A and B (MMP-2 and -9, respectively), were examined in both tumor sites. These metalloproteinases were present in both solid tumor and ascites fluid and in both cases were host derived and not produced by the tumor. We conclude that batimastat may have different effects on tumor progression and growth depending on the site of tumor implantation.
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PMID:The matrix metalloproteinase inhibitor batimastat (BB-94) retards human breast cancer solid tumor growth but not ascites formation in nude mice. 981 89

To determine the significance of interleukin (IL)-10 in antitumor immune response, the effect of the down-regulation of tumor-derived IL-10 on locoregional immunotherapy was investigated. C3H/HeN mice were intraperitoneally (i.p.) inoculated with IL-10-producing murine breast cancer cell line, FM3A, and treated with locoregional administration of OK-432 with or without anti-IL-10 monoclonal antibody (mAb). Anti-IL-10 mAb did not affect the in vitro growth of FM3A cells. Administration of OK-432 plus anti-IL-10 mAb remarkably delayed the retention of malignant ascites and prolonged the survival of mice compared with the administration of OK-432 alone. Spleen cells which were collected from mice treated with OK-432 plus anti-IL-10 mAb and further stimulated in vitro with inactivated FM3A cells exhibited significantly higher cytotoxicity against FM3A cells than those from mice treated with OK-432 alone or from the control mice. The expression of major histocompatibility complex (MHC) class II molecules on spleen cells was up-regulated in vitro by the addition of OK-432 and anti-IL-10 mAb. Using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), cytokine mRNA levels of peritoneal exudate cells (PEC) and spleen cells were assessed on day 7 (before treatment) and day 14 (after treatment). In PEC, increased expression of IL-2 was observed with the administration of OK-432 plus anti-IL-10 mAb. In spleen cells, the expression of IL-2, IL-12 and IFN-gamma were strongly induced, and IL-4 expression was reduced by the administration of OK-432 plus anti-IL-10 mAb. It is suggested that down-regulation of tumor-derived IL-10 induces the up-regulation of the T helper type (Th) 1 population, resulting in an enhancement of the efficacy of locoregional immunotherapy with OK-432.
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PMID:Down-regulation of IL-10 enhances the efficacy of locoregional immunotherapy using OK-432 against malignant effusion. 1036 57

Malignant ascites is a common complication of advanced intraabdominal neoplasms for which standard treatments are suboptimal. Evidence suggests that tumor-mediated angiogenesis and enhanced vascular permeability in the peritoneal wall due to high levels of vascular endothelial growth factor play a fundamental role in the pathogenesis of malignant ascites. To explore the advantage of viral vector-mediated "targeted antiangiogenic therapy" in ascites formation, we constructed and administered adenoviral vectors encoding several different antiangiogenic proteins (angiostatin, endostatin, platelet factor 4, and a fusion protein between angiostatin and endostatin) alone or in combination intraperitoneally in mice with peritoneal carcinomatosis from breast cancer (TA3 cells) and ovarian cancer (SKOV-3 i.p. and ES-2 cell lines) to explore the potential of additive or synergistic activity. Our data demonstrated statistically significant downregulation of ascites formation, tumor growth, vascularity, and prolongation of animal survival after intraperitoneal treatment with antiangiogenic adenoviral vectors in three different ascites tumor models. Combined treatment proved to be more effective than treatment with one vector alone. Reduced ascites formation was accompanied by decreased microvascular density in the peritoneal wall and increased apoptosis of tumor cells after administration of antiangiogenic vectors in vivo. Of interest was the observation that AdPF4 caused a significant decrease in the level of VEGF secreted by tumor cells both in vitro and in TA3 ascites tumor-bearing animals in vivo. These data suggest that adenoviral vector-mediated delivery of genes encoding antiangiogenic proteins may represent a potentially new treatment modality for malignant ascites.
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PMID:Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites. 1156 Jul 66

Demographics, treatment patterns, treatment efficacy and clinical predictors of survival were studied in 76 consecutive patients with malignant ascites. Sixty-four percent of patients were female, and mean age was 63 years. The most common primary malignancies were ovarian cancer, carcinoma of unknown primary, breast cancer, colorectal carcinoma and lymphoma. Ascites was present at the time of diagnosis of malignancy in 39%. Diuretics were administered in 22% of patients with a 22% response in ascites; all responding patients had hepatic metastases. Systemic anticancer therapy was administered in 38%, with a 38% objective response in ascites. Five peritoneovenous shunts were placed, with one shunt functional at 2 weeks. Paracentesis was performed in 71% of patients with complications potentially due to paracentesis occurring in 24% of these patients. Median survival was 78 days from the clinical diagnosis of ascites. Multivariate analysis revealed significantly shortened survival in patients with liver metastases and elevated serum bilirubin, while ovarian cancer was a significant independent predictor of prolonged survival.
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PMID:Malignant ascites: demographics, therapeutic efficacy and predictors of survival. 1205 99

The current modalities for treating cancer employ not only single but multiple approaches involving surgery, radiotherapy and chemotherapy. Unfortunately, the survival outcome is not promising even with these approaches. Alternative approaches for cancer therapy are now emerging. Immunotherapy is aiming at both increasing the power, and in redirecting the specificity of the patients' immune system to attack the tumor cells. Recently, many studies using tumor associated lymphocytes (TAL) isolated from malignant ascites cultured in a media containing interleukin-2 exhibit antitumor responses. IL-2 is a lymphokine produced by T-cells. It facilitates activation, sustained growth and rescue from apoptosis. Lately, newly developed IL-15 has also exhibited antitumor activity similar to IL-2. IL-15 is a newly described cytokine produced from monocytes-marcrophages and T-cells. It has a different molecular structure but it functions like IL-2 by binding to the IL-2R beta and gammac chain. These antitumor responses are mediated by the cytotoxic T lymphocytes (CTL) that recognize the antigen in the context of the MHC molecules using the T cell receptors. CD8+-CTL recognize the peptide epitopes that are processed from the cellular proteins in the context of the MHC class I molecules. These peptides have a restricted length of 8-11 amino acids. The folate binding protein (FBP) is overexpressed in over 90% of ovarian and 20-50% in breast cancers. The FBP is the source of the antigenic peptides that are recognized by a number of these CTL-TAL, and is antigenic to both ovarian and breast cancer in vivo. To define the antitumor response of IL-15 and its' FBP immunogenicity, a peptide defining epitope E39 and E75 were presented by the PMBC derived dendritic cells (DC) from healthy donors isolated by the CD14 method to ovarian and breast CTL-TAL. Stimulating both ovarian and breast CTL- TAL by E39 or E75 pulsed DC (DC-E39, DC-E75), in the presence of IL-15 and IL-2 can rapidly enhance or induce the E39 or E75 specific CTL activity. The antitumor activities were measured by a chromium release assay for the tumor specific lysis activity using the ovarian and breast cancer cell lines. The tumor specific lysis activity for the ovarian TALs for IL-15 vs IL-2 were 28.6 +/- 3.9% and 30.3 +/- 3.2%, respectively and in the breast TALs, they were 14.8 +/- 3.1% vs 13.5 +/- 2.9%, respectively. Using autologous tumor cells, a slightly higher tumor specific lysis activity was obtained for the ovarian TALs cultured in IL-15 compared to IL-2 (72.0 +/- 8.2% vs 68.5 +/- 3.6%). However, for the breast TALs, they were 39.5 +/- 4.2% vs 41.5 +/- 3.3%, respectively. IL-15 is a newly developed cytokine that shows promising antitumor activity similar to IL-2. However, it requires lower dosage and is less toxic. Therefore, IL-15 might be a potential anticancer immunotherapeutic agent.
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PMID:The comparison of cytotoxic T-lymphocyte effects of dendritic cells stimulated by the folate binding protein peptide cultured with IL-15 and IL-2 in solid tumor. 1249 51

We review the case of an elderly woman with invasive lobular breast cancer presenting as malignant ascites. This unusual presentation is discussed, as well as the options for treatment. Most invasive lobular breast cancers are hormone receptor positive and the roles of hormonal and chemotherapy are reviewed.
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PMID:Metastatic lobular breast cancer presenting with malignant ascites: case report and review of literature. 1296 64

A retrospective analysis of intraperitoneal mitoxantrone instillation therapy for malignant ascites in advanced breast and gynecologic pelvic cancers was performed to confirm the efficacy and safety of this therapy. Several smaller phase II trials had suggested good palliative effects. In 143 patients (37 breast cancer and 106 gynecologic cancers), 257 instillations were registered. Response in breast cancer was induced in 49% and in 63% with gynecologic cancer. Severe or life-threatening clinical or laboratory side effects related to intraperitoneal mitoxantrone occurred in 2.7% (clinical) or 1.9% (laboratory) of the 257 instillations. Induction of adverse side effect was dose dependent. Intraperitoneal chemotherapy with mitoxantrone for treatment of malignant ascites in breast cancer and gynecologic malignancy is effective and well tolerated. For this treatment 30 mg mitoxantrone in > or = 1000 mL carrier solution (e.g., saline) is recommended. A minimal concentration of at least 10 micrograms/mL should be achieved.
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PMID:Intraperitoneal chemotherapy with mitoxantrone in malignant ascites. 1456 37

Exosomes are nanovesicles that are released into the extracellular environment during the fusion of multivesicular bodies with the plasma membrane. Exosomes released from dendritic cells, dexosomes, have several biological functions, for example as immunostimulants. Some tumor cells also secrete exosomes (Tu-exosomes). Although experimental data obtained with the use of dexosomes suggest a biological function of Tu-exosomes, this still remains poorly understood. To examine the function of Tu-exosomes, we established a method for collecting highly purified Tu-exosomes, using paramagnetic beads coated with antibodies against tumor-specific proteins such as HER2/neu. With these antibody-coated beads (Ab-beads), it was possible to collect HER2-expressing Tu-exosomes of high purity. Tu-exosomes were also collected from malignant ascites, which contain exosomes secreted from various types of cells such as tumor cells, lymphoid cells and mesothelial cells. The isolation of Tu-exosomes was confirmed by FACS analysis. With regard to their biological functions, Tu-exosomes cultured with a human breast cancer cell line bound to the cell surface and increased tumor cell proliferation. These data indicate that Tu-exosomes may have physiological functions.
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PMID:Purification, characterization and biological significance of tumor-derived exosomes. 1630 29

The relative incidence of primary peritoneal carcinoma (PPCa) and advanced (FIGO stage III or IV) ovarian serous carcinoma (AOSCa) was assessed over 5 years at a UK cancer center, and the sociodemographic, clinical, and survival data were compared. There were 23 women with PPCa and 55 with AOSCa. The ratio of PPCa:AOSCa was higher than previously reported. No statistical difference was found between the two groups with regard to age (mean 64.43 vs 64.07 years, P= 0.9), parity (1.6 vs 1.8, P= 1.0), personal/family history of another malignancy (although five patients with AOSCa but none with PPCa had personal histories of breast cancer), or serum CA125, CA19.9, and carcinoembryonic antigen (CEA) levels. Similar numbers in both groups had malignant ascites, although 5.8% of patients with AOSCa but none with PPCa had negative cytology. Tumor grade, stage, treatment, and survival were similar (median 586 vs 641 days, P= 0.66). This analysis of the largest published UK series of patients with PPCa does not support previous reports that patients with PPCa are older than those with AOSCa and have a worse prognosis; it suggests that both groups have similar sociodemographic characteristics, clinical profiles, and survival.
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PMID:Primary peritoneal carcinoma in a UK cancer center: comparison with advanced ovarian carcinoma over a 5-year period. 1651 79


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