ABSTRACT
BACKGROUND: Monocytes and neutrophils are activated during disseminated intravascular coagulation. Tissue factor, the main initiator of coagulation, is expressed by monocytes, while elastase is released by neutrophils. AIMS: This study investigated tissue factor production by peripheral monocytes after stimulation with human neutrophil elastase. METHODS: Tissue factor mRNA levels were investigated by the reverse transcriptase-polymerase chain reaction and tissue factor protein production was assessed by western blotting when monocytes were exposed to neutrophil elastase with or without preincubation using various inhibitors. RESULTS: Neutrophil elastase upregulated tissue factor mRNA and protein levels in monocytes. Both U73122 (phospholipase C inhibitor) and TMB-8 (intracellular calcium antagonist) prevented the upregulation of tissue factor mRNA. SB203580 (p38 mitogen-activated protein kinase inhibitor) suppressed this response, but PD98059 (extracellular signal-regulated kinase inhibitor) did not. Ro-318425 (ATP-competitive and selective protein kinase C (PKC) inhibitor) and Go 6976 (inhibitor of conventional PKCs and PKCµ) blocked the upregulation of tissue factor mRNA expression. Go 6983 (broad-spectrum PKC inhibitor) and CGP 4125 (staurosporine analog) partially attenuated it, as did a PKC theta/delta inhibitor. CONCLUSIONS: Neutrophil elastase mainly enhances tissue factor production by monocytes via the phospholipase C/conventional PKC/p38 MAPK pathway, although a novel PKC is also involved.
Subject(s)
Leukocyte Elastase/pharmacology , Monocytes/drug effects , Protein Kinase C/genetics , RNA, Messenger/metabolism , Thromboplastin/genetics , Type C Phospholipases/genetics , p38 Mitogen-Activated Protein Kinases/genetics , Calcium Channel Blockers/pharmacology , Carbazoles/pharmacology , Enzyme Inhibitors/pharmacology , Estrenes/pharmacology , Flavonoids/pharmacology , Gallic Acid/analogs & derivatives , Gallic Acid/pharmacology , Gene Expression Regulation , Humans , Imidazoles/pharmacology , Indoles/pharmacology , Maleimides/pharmacology , Monocytes/cytology , Monocytes/metabolism , Primary Cell Culture , Protein Kinase C/metabolism , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrrolidinones/pharmacology , RNA, Messenger/genetics , Signal Transduction , Thromboplastin/metabolism , Type C Phospholipases/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
BACKGROUND: Recently, combination S-1 and CDDP chemotherapy is considered as a standard regimen for unresectable or recurrent gastric cancer. Second-line chemotherapy is reportedly important to improve survival, and combination of Irinotecan and Mitomycin C as second-line chemotherapy has proven effective in phase II study of JCOG 0109-DI. PURPOSE: We assessed the efficacy of combination of Irinotecan and Mitomycin C as second-line chemotherapy for unresectable and recurrent gastric cancer. PATIENTS AND METHODS: We treated 12 patients receiving combination of Irinotecan and Mitomycin C as second-line chemotherapy between Nov. 2002 and Apr. 2006. RESULTS: The response rate was 42% including 2 complete response. Progression-free survival was 6.1 months, and time to progression was 5.4 months. Median survival time after the start of second-line chemotherapy was 11.2 months, and after first-line treatment 20.5 months. One-year survival rate was 50%, and 2-year survival rate was 33%. CONCLUSION: In our hospital, combination of Irinotecan and Mitomycin C as second-line chemotherapy prolonged median survival time, and seemed to be an effective regimen.
