ABSTRACT
We have previously reported that angiopoietin-1 was correlated with pulmonary fibrosis. Here, we investigated the serum levels of angiopoietin-1 in patients with malignant peritoneal mesothelioma, which originate from mesenchymal cells similar to lung fibroblasts. We showed that patients with peritoneal mesothelioma had significantly higher serum levels of angiopoietin-1 in comparison with a population with a history of asbestos exposure without peritoneal mesothelioma, and the Kaplan-Meier method revealed a significant correlation between serum angiopoietin-1 levels and survival. This is the first report about the relationship between angiopoietin-1 and peritoneal mesothelioma.
Subject(s)
Angiopoietin-1/blood , Mesothelioma/blood , Mesothelioma/mortality , Peritoneal Neoplasms/blood , Peritoneal Neoplasms/mortality , Asbestos/toxicity , Asbestosis/blood , Environmental Exposure , Female , Humans , Male , Mesothelioma/epidemiology , Middle Aged , Peritoneal Neoplasms/epidemiology , Pulmonary Fibrosis/complications , SurvivalABSTRACT
BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to conventional chemotherapy and radiotherapy. Therefore, diagnosing MPM early is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. MPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM. METHODS: HMGB1 production from MPM cell lines was measured using ELISA. Serum HMGB1 levels were also examined in 61 MPM patients and 45 individuals with benign asbestos-related diseases. RESULTS: HMGB1 concentrations of 2 out of 4 MPM cell lines were higher than that of normal mesothelial cell line, Met-5A. We demonstrated that patients with MPM had significantly higher serum levels of HMGB1 than the population who had been exposed to asbestos but had not developed MPM. The difference in overall survival between groups with serum HMGB1 levels that were lower and higher than assumed cut-off values was significant. CONCLUSIONS: Our data suggest that serum HMGB1 concentration is a useful prognostic factor for MPM.
Subject(s)
Adenocarcinoma/blood , Biomarkers, Tumor/blood , Carcinoma, Squamous Cell/blood , HMGB1 Protein/blood , Lung Neoplasms/blood , Mesothelioma/blood , Pleural Neoplasms/blood , Aged , Area Under Curve , Asbestosis/blood , Case-Control Studies , Cell Line, Tumor , Female , HMGB1 Protein/metabolism , Humans , Kaplan-Meier Estimate , Male , Mesothelioma/metabolism , Mesothelioma/pathology , Middle Aged , Pleural Neoplasms/metabolism , Pleural Neoplasms/pathology , Proportional Hazards Models , ROC Curve , Statistics, NonparametricABSTRACT
BACKGROUND/AIMS: The present study investigated adenosine-induced apoptosis in human malignant pleural mesothelioma cells. METHODS: MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out using malignant pleural mesothelioma cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells, and p53 or A(3) adenosine receptor was knocked-down by transfecting each siRNA into cells. RESULTS: Adenosine induced apoptosis in all the malignant pleural mesothelioma cells used here, independently of caspase activation. The adenosine effect was prevented by the adenosine transporter inhibitor dipyridamole, the adenosine kinase inhibitor ABT-702, or the A(3) adenosine receptor inhibitor MRS1191. Adenosine upregulated expression of the p53 mRNA and protein, that is abolished by ABT-702, but not by knocking-down A(3) adenosine receptor. Adenosine-induced apoptosis in NCI-H28 cells was significantly inhibited by knocking-down p53 and in part by knocking-down A(3) adenosine receptor. CONCLUSION: The results of the present study show that AMP converted from intracellularly transported adenosine upregulates p53 expression to induce caspase-independent apoptosis in malignant pleural mesothelioma cells and that A(3) adenosine receptor also participates partially in the apoptosis by the different mechanism.
Subject(s)
Adenosine Monophosphate/metabolism , Adenosine/physiology , Apoptosis , Tumor Suppressor Protein p53/metabolism , Up-Regulation , Adenosine/metabolism , Adenosine/pharmacology , Adenosine A1 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine A3 Receptor Antagonists/pharmacology , Adenosine Monophosphate/physiology , Apoptosis Inducing Factor/genetics , Apoptosis Inducing Factor/metabolism , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Caspases/metabolism , Cell Line, Tumor , Cell Survival/drug effects , GATA2 Transcription Factor/genetics , GATA2 Transcription Factor/metabolism , Gene Expression , Gene Knockdown Techniques , Humans , In Situ Nick-End Labeling , Mesothelioma , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Pleural Neoplasms , RNA Interference , Receptor, Adenosine A3/genetics , Receptor, Adenosine A3/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
BACKGROUND: Pemetrexed in combination with cisplatin (Pem/Cis) is the only approved chemotherapeutic regimen for malignant pleural mesothelioma (MPM). At the time of launch, limited safety information was available. The purpose of this postmarketing all-case registry study was to investigate the safety and effectiveness of pemetrexed in patients with MPM. METHODS: From January 2007 to May 2008, MPM patients to be treated with pemetrexed in Japan were registered to this study to monitor its safety and effectiveness. Supply of pemetrexed was restricted to institutions with experienced medical oncologists based on predetermined criteria. RESULTS: Of 953 patients registered, data from 903 patients were eligible for analysis. Most patients were male, with median age of 65 years and 68.5% had a history of asbestos exposure. More than 90% of patients received the first cycle of Pem/Cis treatment; median number of treatment cycles was 4.0. Treatment-associated death was reported in 0.8% of patients. The incidence of Interstitial lung disease (ILD) associated with Pem/Cis during the observation period was 0.9%. The frequency of ILD in patients with pre-existing asbestosis was higher than that in patients without it. For tumor response, the overall response rate was 25.0% (95% confidence interval (CI): 22.2-28.0%). The six-month survival rate estimated by the Kaplan-Meier method was 75.9%. CONCLUSIONS: This large scale all case registry study appeared to have enrolled a major portion of Japanese MPM patients. Treatment with pemetrexed was generally well tolerated and showed safety and effectiveness comparable to prior clinical trials.
