Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.
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PMID:Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. 1085 Apr 35

Angiogenesis is essential for tumor growth. Since vascular endothelial growth factor (VEGF) represents the main angiogenic factor, the control of VEGF secretion could constitute the most important mechanism to achieve the inhibition of angiogenesis-related processes. High blood concentrations have been proven to correlate with poor prognosis in advanced cancer. In experimental conditions, chemotherapeutic agents such as taxol appeared to inhibit VEGF-induced angiogenesis, while at present there are no data about the influence of chemotherapy on VEGF secretion in cancer patients. This preliminary study was performed to evaluate the effect of taxol therapy on VEGF secretion in advanced cancer patients in relation to the clinical response. The study included 14 patients with metastatic breast cancer who were treated with taxol monochemotherapy (175 mg/m2 i.v. every 21 days for three cycles). Serum levels of VEGF were measured by ELISA in blood samples collected before therapy and at 21-day intervals. The clinical response consisted of partial response (PR) in three and stable disease (SD) in six patients, whereas the other five patients had progressive disease (PD). Abnormally high pre-treatment levels of VEGF were seen in 8/14 patients. VEGF mean values significantly decreased during taxol therapy in patients with PR or SD, whereas no decline was observed in patients with PD. Moreover, the percent of normalization or decline greater than 50% in VEGF levels was significantly higher in patients with PR or SD than in those with PD (5/9 vs. 0/5). This preliminary study would suggest that the efficacy of taxol therapy in metastatic breast cancer - at least in terms of disease stabilization - may be associated with a decrease in VEGF blood levels followed by potential inhibition of cancer-related neovascularization.
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PMID:Chemotherapy and angiogenesis in advanced cancer: vascular endothelial growth factor (VEGF) decline as predictor of disease control during taxol therapy in metastatic breast cancer. 1119 26

Plasma levels of D-dimer are elevated in cancer patients. Activation of the extrinsic coagulation system and the fibrinolytic cascade within a tumour is thought to be related with growth, invasion and metastasis. We have investigated the relationship between these markers of fibrin metabolism, standard clinicopathological variables and serum levels of angiogenic cytokines in three cohorts: group A (n=30) consisted of 30 healthy female volunteers, group B (n=23) of consecutive patients with operable breast cancer and group C (n=84) of patients with untreated or progressive metastatic breast cancer. Plasma D-dimers, fibrinogen, IL-6, vascular endothelial growth factor and calculated vascular endothelial growth factor load in platelets are clearly increased in patients with breast cancer. D-dimers were increased in nearly 89% of patients with progressive metastatic disease. The level of D-dimers was positively correlated with tumour load (P<0.0001), number of metastatic sites (P=0.002), progression kinetics (P<0.0001) and the cytokines related to angiogenesis: serum vascular endothelial growth factor (P=0.0016, Spearman correlation=0.285), calculated vascular endothelial growth factor load in platelets (P<0.0001, Spearman correlation=0.37) and serum interleukin-6 (P<0.0001, Spearman correlation=0.59). Similarly increased D-dimer levels were positively correlated with increased fibrinogen levels (P<0.0001, Spearman correlation=0.38). The association between markers of fibrin degradation in patients with progressive breast cancer suggests that the D-dimer level is a clinically important marker for progression and points towards a relation between haemostasis and tumour progression. A role of interleukin-6, by influencing both angiogenesis and haemostasis, is suggested by these observations.
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PMID:Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer. 1187 5

Serum and plasma concentrations of vascular endothelial growth factor (sVEGF and pVEGF), serum concentrations of interleukin 6 (IL-6), and VEGF platelet load (VEGF/pl) in the blood of healthy controls (n = 26), breast cancer patients with locoregional disease (n = 31), and patients with progressive advanced disease (n = 73) have been compared. The 95th percentile values for the control population were 250 pg/mL for sVEGF, 30 pg/mL for pVEGF, and 1.6 pg/mL for IL-6. The 95th percentile value of the calculated VEGF/pl was 1.0 pg/10(6) platelets in the control population. Serum VEGF concentrations correlated with platelet number in all the groups. Patients with thrombocytosis had a median sVEGF concentration of 833 pg/mL, compared to 249 pg/mL in other patients (P = 0.018). Serum IL-6 levels correlated with sVEGF levels and with the calculated VEGF/pl. Serum IL-6 concentration was significantly higher in patients with breast cancer compared to healthy controls (P < 0.0001). Median IL-6 serum levels were nearly 10 times higher in patients with metastatic breast cancer as compared to the those with locoregional disease (6.0 pg/mL versus 0.7 pg/mL, respectively). Plasma VEGF and the VEGF/pl were also significantly different in the 3 groups. The ratio between sVEGF and pVEGF tended to be smaller in the metastatic breast cancer group compared to the patients with locoregional disease (median, 7.5 versus 10.1, respectively; P = 0.066), suggestive of more intravasal platelet degranulation in the former group. Serum IL-6 level is the most discriminative factor separating healthy controls and the locoregional and metastatic breast cancer patient groups. These results suggest a role for tumor-derived IL-6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF.
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PMID:Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients. 1189 64

The effect of selective and non-selective cyclo-oxygenase inhibition on tumour growth and metastasis in an orthotopic model of breast cancer was investigated. 4T1 mammary adenocarcinoma cells were injected into the mammary fat pad of female BALB/c mice. When tumours reached a mean tumour diameter of 8.4+/-0.4 mm, mice were randomised into three groups (n=6 per group) and received daily intraperitoneal injections of the selective cyclo-oxygenase-2 inhibitor, SC-236, the non selective cyclo-oxygenase inhibitor, Indomethacin, or drug vehicle. Tumour diameter was recorded on alternate days. From 8 days after initiation of treatment, tumour diameter in animals treated with either SC-236 or indomethacin was significantly reduced relative to controls. Both primary tumour weight and the number of lung metastases were significantly reduced in the SC-236 and indomethacin treated mice. Microvessel density was reduced and tumor cell apoptosis increased in the primary tumour of mice treated with either the selective or non-selective cyclo-oxygenase inhibitor. In vitro, cyclo-oxygenase inhibition decreased vascular endothelial growth factor production and increased apoptosis of tumour cells. Our results suggest that cyclo-oxygenase inhibitors will be of value in the treatment of both primary and metastatic breast cancer.
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PMID:Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer. 1210 48

Prediction of survival for patients with metastatic breast cancer is often inaccurate and may be helped by new biological parameters. Tumour growth being angiogenesis-dependent, it has been hypothesised that the assessment of angiogenic factor production might reflect the clinical behaviour of cancer progression. This study was designed to investigate the clinical significance of vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in hormone-refractory metastatic breast cancer. Serum and plasma concentrations of VEGF and serum concentration of IL-6 were measured in 87 patients with a fully documented history of metastatic breast cancer using an enzyme-linked immunoassay. All patients had detectable levels of VEGF, whereas 39% patients had detectable serum levels of IL-6. There was a positive correlation between IL-6 levels and the theoretical VEGF load of platelets (P<0.001). The presence of high levels of serum IL-6, but not VEGF, was significantly correlated to a shorter survival. In a multivariate analysis along with clinical prognostic parameters, serum IL-6 was identified as an independent adverse prognostic variable for overall survival (P&<0.001). These results indicate that serum IL-6 levels correlate to poor survival in patients with hormone-refractory metastatic breast cancer. Vascular endothelial growth factor serum and plasma levels are not useful indicators of prognosis for these patients.
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PMID:Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. 1277 87

Vascular endothelial growth factor promotes angiogenesis, an important mediator of growth and metastasis in human breast cancer. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, is under investigation as an anti-angiogenic agent. This phase I/II trial evaluated the safety and efficacy of bevacizumab in patients with previously treated metastatic breast cancer. Seventy-five patients were treated with escalating doses of bevacizumab ranging from 3 mg/kg to 20 mg/kg administered intravenously every other week. Tumor response was assessed before the sixth (70 days) and 12th (154 days) doses. Safety was evaluated during every cycle. Eighteen patients were treated at 3 mg/kg, 41 at 10 mg/kg, and 16 at 20 mg/kg. Four patients discontinued study treatment because of an adverse event. Hypertension was reported as an adverse event in 17 patients (22%). The overall response rate was 9.3% (confirmed response rate, 6.7%). The median duration of confirmed response was 5.5 months (range, 2.3 to 13.7 months). At the final tumor assessment on day 154, 12 of 75 patients (16%) had stable disease or an ongoing response. The optimal dose of bevacizumab in this trial was 10 mg/kg every other week and toxicity was acceptable. These data support the initiation of trials in metastatic breast cancer combining bevacizumab with chemotherapy.
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PMID:A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. 1461 32

Targeted therapy for breast cancer has existed since 1986, when Beatson published his observations on oophorectomy. In the past 5 years monoclonal antibodies and tyrosine kinase inhibitors have been evaluated in phase I and II clinical trials of breast cancer. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) was the first such agent to be approved by the US Food And Drug Administration, following findings that it improved survival in patients with metastatic breast cancer. Gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE) has little activity as a single agent in unselected patients, but, preclinical data have suggested synergy with tamoxifen and other hormonal agents, as well as other growth factor inhibitors. Bevacizumab (Avastin; Genentech, Inc), a monoclonal antibody against vascular endothelial growth factor is being evaluated in metastatic breast cancer. Furthermore, agents targeting other pathways, such as the Ras pathway with farnesyl transferase inhibitors, and mTOR with rapamycin analogues are currently under investigation. In the next few years, and as trials with the above agents mature, we will further define the role of these targeted agents in the treatment of breast cancer.
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PMID:New targeted therapies in breast cancer. 1512 30

Monoclonal antibodies (mAbs) against growth factors or their receptors have been revealed to be effective therapeutic agents for solid tumors. Trastuzumab (humanized anti-HER2 mAb) is the first mAb approved for the treatment of a solid tumor, metastatic breast cancer. Large-scale phase III clinical trials are now ongoing to further evaluate the additive effects on chemotherapy and the efficacy as a maintenance monotherapy. Another anti-HER2 mAb CH401 that we developed also seems to have good potential. This chimeric mAb completely suppressed the growth of established human tumor xenografts in SCID mice after a single injection. Furthermore, CH401 characteristically showed much stronger induction of apoptosis in HER2-overexpressing gastric cancer cells compared to trastuzumab. Additional targets now being intensively evaluated are epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Both cetuximab (chimeric anti-EGFR mAb) and bevacizumab (humanized anti-VEGF mAb) have recently been shown to be of clinical value for metastatic colorectal cancer. Anti-idiotype mAbs are unique as active immunotherapeutic agents, and survival benefits have been observed in clinical trials for solid tumors.
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PMID:Monoclonal antibodies as effective therapeutic agents for solid tumors. 1529 22

An international meeting on 'New Drugs in Cancer Therapy' was held at the National Tumor Institute of Naples, on 17-18 June 2004. The first session of the meeting focused on analogs of conventional anti-cancer drugs, such as taxanes, platinum compounds, anthracyclines and topoisomerase I inhibitors. The data of a phase II trial of BMS-247550, an epothilone B analog, in patients with renal cell carcinoma were reported. Data were also presented on BBR-3464, a trinucleate platinum analog which was developed on the grounds of greater potency, a more rapid rate of DNA binding and the ability to induce apoptosis regardless of the p53 status of the cell. Pegylated-coated liposomal formulation doxorubicin (Caelyx) has shown efficacy in metastatic breast cancer and in advanced ovarian cancer; sabarubicin is a third-generation anthracycline with equal or superior potency to doxorubicin or idarubicin in a variety of human tumor cell lines of different histotypes. The main mechanisms of resistance to topoisomerase I inhibitors were discussed; data on diflomotecan were reported, showing a narrow therapeutic index of the drug. The second session of the meeting focused on the ErbB family as a target for anti-cancer therapy. Recent evidence of a correlation between epidermal growth factor receptor (EGFR) mutations at exons 18-21 and clinical response of advanced non-small cell lung cancer to gefitinib therapy was commented on. The issue of the association between ErbB2 expression and gefitinib activity was addressed, while clinical data of a phase II study of gefitinib in advanced breast cancer were presented. Monoclonal antibodies targeting EGFR represent another worthwhile way to interfere with EGFR-driven signal transduction. Cetuximab is reaching market registration in advanced colorectal cancer; in particular, due to the results of the BOND study. The recently presented results of the Bonner study strongly support the activity of this drug in head and neck cancer. A step forward in the research on anti-EGFR monoclonal antibodies may be represented by humanized monoclonal antibodies, such as EMD 72000 and ABX-EGF. Imatinib mesylate is probably the most outstanding example of an effective targeted therapy--its activity in gastrointestinal stromal tumors was so exciting that the drug reached the market without undergoing phase III evaluation. The third session of the meeting was on angiogenesis inhibitors. Drugs may interfere with the angiogenic process via different mechanisms and there is a sound rationale for combining anti-angiogenic agents with chemotherapy or multiple anti-angiogenic strategies. Clinical results obtained with direct anti-angiogenic agents have been negative up to now, but some exciting results have been seen with bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). A few VEGF-tyrosine kinase inhibiting small molecules, such as ZD6474, AZD2171 and PTK/ZK, are undergoing clinical trials. The fourth session of the meeting was on interference with intracellular signal transduction. Farnesyl transferase inhibitors exert their action by interfering with either pro-Ras or RhoB farnesylation. Several clinical studies of different phases with compounds belonging to this class have been carried out, either alone or in combination with chemotherapy; unfortunately, all of them have turned out to be negative. Cell cycle inhibitors, such as CYC-202 and BMS-387032, represent a class of interesting compounds which are in the early phase of development and whose clinical results are eagerly awaited. Another strategy to achieve cell cycle inhibition is to target heat shock protein 90, a molecular chaperone required for protein folding. Clinical data on depsipeptide, a histone deacetylase (HDAC) inhibitor with activity in T cell lymphoma, were presented. Suberoylanilide hydroxamic acid is another small molecular weight inhibitor of HDAC activity. Phase I/II clinical trials have shown low toxicity and evidence of anti-tumor activity; on the other hand, this compound has potential for synergism with radiotherapy, chemotherapy and biologicals.
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PMID:New drugs in cancer therapy, National Tumor Institute, Naples, 17-18 June 2004. 1565 20


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