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Gabexate mesilate (GM), a synthetic serine protease inhibitor, suppresses nuclear factor-kappaB (NF-kappaB) activity in human monocytes or human umbilical vein endothelial cells (HUVECs). In this study we examine whether GM also suppresses NF-kappaB activation and induces apoptosis in human pancreatic cancer cell lines. The addition of tumor necrosis factor alpha (TNF-alpha) did not change the rates of growth of BxPC-3 and MIA PaCa-2. However, in the presence of GM and TNF-alpha, proliferation decreased in a dose-dependent manner. GM- and TNF-alpha-treated cells exhibited morphologic changes indicative of apoptosis, including chromatin condensation and nuclear fragmentation. The NF-kappaB activity of both cell lines was increased by the addition of TNF-alpha, while TNF-alpha-induced NF-kappaB activity was suppressed by prestimulation with GM in a dose-dependent manner. Caspase 3 and 7 activity was significantly increased by TNF-alpha with GM stimulation. Furthermore, GM also suppressed the invasive potential of both cell lines. These results indicate that GM inhibits TNF-alpha-induced NF-kappaB activation and enhances apoptosis in human pancreatic cancer cell lines.

The precise inhibitory action of gabexate mesilate (GM) on the various pancreatic enzymes remains unclear. We designed this study to investigate the enzyme inhibitory action of GM in the serum and directly in the pancreatic juice. We observed 16 cases with postoperative pancreatic drainage. Patients were randomly assigned to one of two groups, to receive GM at a dose of 600 mg/24 hr (treated group: 8 patients) or a physiological solution (control group: 8 patients) by continuous intravenous infusion. In both groups pancreatic juice and serum were sampled three times: before infusion began (T0) and at 12 hr (T1) and 24 hr after infusion ended (T2). At the end of the study, seven patients received octreotide and the volume of pancreatic secretion was determined. No statistical difference was observed in serum amylase and phospholipase A2 activity in the treated and control groups. On the contrary, amylase and phospholipase A2 activity in the pancreatic juice diminished significantly only in the treated group, and in these patients a GM metabolite was also detectable in the pancreatic secretion. The volume of pancreatic secretion decreased only after infusion of octreotide. The enzyme inhibition in the pancreatic gland itself and the central role of inhibition of phospholipase A2 in the enzyme cascade responsible for activating other proteases, confirm the therapeutic use of GM in acute pancreatitis. An association of GM and octreotide during acute pancreatitis should be useful because of their different mechanisms.

Systemic prostacyclin and thromboxane A2 production in rat experimental acute pancreatitis has been evaluated by measuring the urinary excretion of the 2,3-dinor 6-keto prostaglandin F1 alpha and 2,3-dinor thromboxane B2, respectively. Acute pancreatitis was induced by intraductal administration of 4.5% sodium taurocholate (0.1 ml/100 mg body weight) and intravenous cerulein perfusion (5 micrograms/kg/hr) for 6 hr, respectively. Urinary excretion of 2,3-dinor 6-keto prostaglandin F1 alpha and 2,3-dinor thromboxane B2 were much more important in sodium taurocholate- than in cerulein-induced acute pancreatitis. These data confirm an altered prostacyclin and thromboxane metabolism occurring in experimental acute pancreatitis. Phospholipase A2 activity and the effect of gabexate mesilate on the arachidonate metabolism were also evaluated.