thromboxane-b2 and Pancreatic-Neoplasms

Primary objective was to determine response rate of patients with advanced pancreatic cancer to a novel lipoxygenase and thromboxane A2 synthetase inhibitor (CV6504); secondary objectives included estimation of pharmacokinetics of CV6504, target-enzyme inhibition, safety and tolerance, quality of life and survival.. Thirty-one patients with advanced pancreatic cancer were planned to receive CV6504, 100 mg TDS, orally for three months, at which point CT scans were performed to assess therapeutic response rates. Steady state concentrations of CV6504 and thromboxane B2 (an indirect measure of thromboxane A2 synthetase (TA2S) inhibition) were made. Of the 31 patients entered into the study, 23 were considered fully evaluable for response.. The drug was well tolerated with few side effects; no partial or complete responses were seen, but 10 patients had stable disease at 3 months; quality of life was maintained during therapy; mean CV6504 steady state plasma concentrations of 14 +/- 6 ng/ml resulting in 75 +/- 18% inhibition of TA2S were achieved; median-survival time for all patients considered eligible for assessment of efficacy was 36.6 weeks after the initial dose of study medication. The actuarial one-year survival was approximately 25%.. CV6504 inhibits its target enzyme in vivo, maintains stable disease in 32% of evaluable patients and is well tolerated.

Topics: Antineoplastic Agents; Benzoquinones; Disease Progression; Disease-Free Survival; Drug Evaluation; Female; Humans; Linoleic Acid; Lipoxygenase Inhibitors; Male; Middle Aged; Pancreatic Neoplasms; Thromboxane B2

In the present study, we studied the effect of various prostaglandins (PGs) on alloxan-induced cytotoxicity to rat insulinoma (RIN) cells. Of all the PGs tested, PGE(1), PGE(2), PGI(2), PGF(1 alpha), and PGF(3 alpha) protected RIN cells from alloxan-induced cytotoxicity (P<0.05 compared to alloxan), whereas thromboxane B(2) and 6-keto-PGF(1 alpha) were not effective. PGE(1) induces a statistically significant increase in the activities of superoxide dismutase and glutathione peroxidase and decrease in lipid peroxides in alloxan-treated RIN cells (P<0.001). PGE(1) restored nitric oxide/lipid peroxide ratio to normalcy, suggesting that PGE(1) suppresses oxidant stress induced by alloxan in RIN cells in vitro. Furthermore, PGE(1) prevented DNA damage and apoptosis induced by alloxan. These results indicate that PGE(1) prevents alloxan-induced cytotoxicity to RIN cells in vitro.

Topics: 6-Ketoprostaglandin F1 alpha; Alloxan; Alprostadil; Animals; Antioxidants; Apoptosis; Bucladesine; Cell Death; Dinoprostone; DNA Damage; Epoprostenol; Glutathione Peroxidase; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Lipid Peroxides; Malondialdehyde; Nitric Oxide; Nitroprusside; Oxidative Stress; Pancreatic Neoplasms; Prostaglandins; Prostaglandins F; Rats; Superoxide Dismutase; Thromboxane B2; Tumor Cells, Cultured

Arachidonic acid metabolites known to affect platelet function also interfere with tumor growth and metastases. The purpose of this study was to evaluate the anti-metastatic potential of ketoconazole, a thromboxane synthetase and 5-lipoxygenase inhibitor, on hepatic metastasis from a human pancreatic adenocarcinoma in nude mice and its effect on serum prostaglandin levels.. The human pancreatic tumor cells (RWP-2) were injected intrasplenically in nude mice grouped into control, ketoconazole (270 microg), ketoconazole (360 microg), and ketoconazole (540 microg). The agent was administered intraperitoneally 30 min before and every 24 h after the tumor cell inoculation for 8 days. In a separate experiment thromboxane B2 (TxB2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2) and 6-Keto-F1a (stable prostacyclin derivative) were measured on blood from controls, tumor bearing animals and animals bearing tumors treated with 270 microg of ketoconazole.. Statistically significant differences were observed between the control and three-treatment groups on the reduction of liver tumor nodules (p < 0.001), and in the liver surface areas occupied by tumor (p < 0.001). The TxB2 levels decreased from 150.6 ng/mL in the tumor bearing to 104.8 ng/mL in the ketoconazole treated animals (p < 0.05). PGD2, PGE2 and 6-keto-F1a levels increased to 7.1 ng/mL, 8.3 ng/mL, and 13.6 ng/mL from 3 ng/mL, 5.8 ng/mL, and 0.02 ng/mL respectively (p < 0.001).. These results indicate that ketoconazole significantly reduced hepatic metastases from the human pancreatic carcinoma RWP-2 in the nude mouse model, and inhibited thromboxane B2 formation, potentiating a concomitant redirection of platelet endoperoxide metabolism into PGD2, PGE2, and 6-keto-F1a. It is hypothesized that the changes in the arachidonic acid metabolism mediate the ameliorating effect of ketoconazole on experimental hepatic metastasis.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Animals; Antineoplastic Agents; Dinoprostone; Humans; Injections, Intraperitoneal; Ketoconazole; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms; Prostaglandin Antagonists; Prostaglandin D2; Prostaglandins; Thromboxane B2; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The mechanism leading to the hypercoagulability in pancreatic carcinoma is unclear. The rapid progress of the disease after its diagnosis and the inaccessibility of the tumor make studies on the mechanism difficult in man. With the successful induction of this malignancy and conversion of it into an ascites tumor in Syrian golden hamsters, interactions between isolated tumor cells and individual hemostatic components can be investigated. In this paper, studies on in vitro tumor cell-platelet interactions and some hemostatic changes in hamsters following intravenous injection of isolated tumor cells are described. Freshly isolated tumor cells and tumor-cell sonicates, but not those that had been kept at 4 or -70 C overnight, induced comparable aggregation of human platelets in both heparinized and citrated platelet-rich plasmas (hPRP and cPRP). The aggregation was not followed by clot formation; a specific synthetic thrombin inhibitor had no effect on the aggregation in either hPRP or cPRP. Washed and gel-filtered platelets, even in the presence of 5% of citrated or heparinized platelet-poor plasma (cPPP or hPPP) failed to be aggregated by tumor cells. Tumor-cell-induced platelet aggregation was accompanied by thromboxane formation and serotonin release, both of which were several orders of magnitude greater in cPPP than in hPRP. Aspirin, apyrase, and PGI2 all inhibited tumor-cell-induced platelet aggregation in both PRPs, but the inhibition by aspirin was minimal. Intravenous infusion of isolated tumor cells into normal hamsters resulted in a 50% reduction of platelet count and a 20-30% decline in antithrombin III and fibrinogen. Platelet aggregates and fibrin strands were seen in the lungs of these animals.

Topics: Animals; Antithrombin III; Apyrase; Ascites; Aspirin; Blood Coagulation; Blood Platelets; Cricetinae; Epoprostenol; Fibrinogen; Humans; Mesocricetus; Microscopy, Electron; Pancreatic Neoplasms; Platelet Aggregation; Platelet Count; Serotonin; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Bile; Gallbladder Neoplasms; Humans; Pancreatic Neoplasms; Thromboxane B2; Thromboxanes