6-ketoprostaglandin-f1-alpha and Colonic-Neoplasms

To examine whether antithrombin (AT) could prevent hepatic ischemia/reperfusion (I/R)-induced hepatic metastasis by inhibiting tumor necrosis factor (TNF)-alpha-induced expression of E-selectin in rats.. Hepatic I/R was induced in rats and mice by clamping the left branches of the portal vein and the hepatic artery. Cancer cells were injected intrasplenically. The number of metastatic nodules was counted on day 7 after I/R. TNF-alpha and E-selectin mRNA in hepatic tissue, serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of PGI2, were measured.. AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-alpha and E-selectin in animals subjected to hepatic I/R. Argatroban, a thrombin inhibitor, did not suppress any of these changes. Both AT and argatroban inhibited I/R-induced coagulation abnormalities. I/R-induced increases of hepatic tissue levels of 6-keto-PGF(1alpha) were significantly enhanced by AT. Pretreatment with indomethacin completely reversed the effects of AT. Administration of OP-2507, a stable PGI2 analog, showed effects similar to those of AT in this model. Hepatic metastasis in congenital AT-deficient mice subjected to hepatic I/R was significantly increased compared to that observed in wild-type mice. Administration of AT significantly reduced the number of hepatic metastases in congenital AT-deficient mice.. AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-alpha-induced expression of E-selectin through an increase in the endothelial production of PGI2. These findings also raise the possibility that AT might prevent hepatic metastasis of tumor cells if administered during the resection of liver tumors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombins; Arginine; Cell Line, Tumor; Colonic Neoplasms; E-Selectin; Epoprostenol; Fibrin Fibrinogen Degradation Products; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Pipecolic Acids; Rats; Rats, Inbred F344; Reperfusion; RNA, Messenger; Sulfonamides; Tumor Necrosis Factor-alpha

Several studies have shown an overexpression of cyclooxygenase-2 (COX-2) and elevated levels of prostacyclin (PGI(2)) and thromboxane (TXA(2)) in colon cancer. In this report, we determined the distribution of inducible form of nitric oxide synthase (iNOS), PGI(2), and TXA(2) in cancerous and adjoining areas of specimens from human colon and breast cancer obtained during surgery. Additionally, we investigated differences in expression and histological localization of COX-2 in colon and breast cancer.. Specimens were obtained during surgery, one centrally located, the second from an adjacent, cancer-free area. Activity of iNOS was determined, using the conversion of L-[(14)C]arginine to L-[(14)C]citrulline. PGI(2) and TXA(2) were measured as their stable metabolites, using enzyme immunoassay. A standard immunoperoxidase method was used for immunohistochemical expression of COX-2.. Significant differences in iNOS, PGI(2), and TXA(2) expressions between colon and breast cancer were noted, with an enhanced expression of COX-2 in colon cancer, including the cancerous, adjoining, and stromatous fields.. Increased expression of iNOS and production of prostanoids in colon cancer parallels the increase in COX-2, confirming the importance of this enzyme in colon cancer. The overexpression of COX-2, prostanoids, and nitric oxide in areas adjoining the tumor indicates increased metastatic potential for neoplastic cells in this area. Inflammatory changes in the tissue adjoining the cancer may play a role. COX-2 may result in the formation of new blood vessels and the spread of cancer.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Colonic Neoplasms; Cyclooxygenase 2; Female; Humans; Isoenzymes; Male; Membrane Proteins; Middle Aged; Neovascularization, Pathologic; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxane B2

1. This study was designed to elucidate the effects of guar gum, a dietary fibre, on changes in prostanoid contents induced by 1,2-dimethylhydrazine, a carcinogenic agent, in rat colonic mucosa. 2. Prostanoid contents were determined using high performance liquid chromatography; five prostanoids, namely 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, prostaglandin D2 and thromboxane B2, were detected. 3. Four subcutaneous injections of dimethylhydrazine, 60 mg/kg every 6 days, increased the mucosal concentrations of prostaglandin E2 and thromboxane B2 by approximately 50%. Other prostanoids did not change significantly throughout the experiments. 4. In rats treated with dimethylhydrazine and a fibre diet a significant increase in thromboxane B2 content was not observed, although a significant increase in prostaglandin E2 content was observed. These effects were observed in rats fed with fibre diet over 20 days but not observed in rats fed with fibre diet over 10 days. 5. From these results and the report that aspirin use at low doses is effective in the reduction of the risk of fatal colonic cancer, inhibiting thromboxane B2 synthesis by fibre diet might be involved in the protective effect against the occurrence of colonic cancer.

Topics: 1,2-Dimethylhydrazine; 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Carcinogens; Chromatography, High Pressure Liquid; Colon; Colonic Neoplasms; Dietary Fiber; Dimethylhydrazines; Dinoprostone; Galactans; Injections, Subcutaneous; Intestinal Mucosa; Male; Mannans; Plant Gums; Prostaglandin D2; Prostaglandins; Rats; Rats, Sprague-Dawley; Thromboxane B2

Epidemiological and laboratory animal model studies suggest that the effect of dietary fat on colon carcinogenesis depends on the amount and its type. In the present study, we investigated the modulating effect of high-fat diets rich in omega-3, omega-6 and omega-9 fatty acids on liver, colon and small intestine mucosal ornithine decarboxylase (ODC) and tyrosine-specific protein kinase (TPK) activities and plasma, liver and colon mucosal prostaglandin E2 (PGE2) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) levels in male F344 rats. At 6 weeks of age, groups of animals were fed the low-fat diet containing 5% corn oil (LFCO), or high-fat diets containing 23.5% corn oil (HFCO), 23.5% olive oil (HFOO) and 20.5% fish oil + 3% corn oil (HFFO). Two weeks later, all animals except the vehicle-treated groups received azoxymethane (AOM) s.c. once weekly for 2 weeks at a dose rate of 15 mg/kg body wt. All animals were killed 5 days later and liver, colon and small intestine mucosa were analyzed for ODC, TPK and PGs and plasma for PGs. Carcinogen treatment enhanced the ODC and TPK activities (P < 0.0001) in the liver and colon of animals, irrespective of dietary treatment. Dietary HFCO compared with LFCO significantly increased the ODC (P < 0.01) and membrane TPK (P < 0.05) activities in the liver and colon of carcinogen-treated animals, whereas the HFOO and HFFO diets significantly (P < 0.002) suppressed the ODC and membrane TPK (P < 0.05) activities in the liver and colon mucosa compared with the HFCO diet. Carcinogen treatment also significantly (P < 0.01) increased the PG levels in plasma, liver and colon. Feeding of the HFFO diet significantly suppressed both the basal levels and ex vivo production of PGE2 and 6-keto PGF1 alpha levels compared with the HFCO diet, whereas the HFOO diet only decreased PGE2 in liver and colon. These results thus demonstrate that high levels of corn oil in the diet increase colon and liver ODC, TPK and PGs whereas high dietary levels of fish oil and olive oil suppress these activities.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Colonic Neoplasms; Dietary Fats; Dinoprostone; Fatty Acids; Intestinal Mucosa; Intestine, Small; Liver; Male; Ornithine Decarboxylase; Protein-Tyrosine Kinases; Rats; Rats, Inbred F344

Prostaglandins have been shown to play a central role in the formation of cancer. The synthesis of prostacyclin and its bioavailability may be an important local determinant for metastasis. As the amount of the biologically active substance is dependent in part on the half-life (T/2) we examined the question as to whether the T/2 of prostaglandin I2 (PGI2) is altered in patients suffering from colonic cancer at various stages of the disease. In addition, the influence of various therapeutic regimens was investigated. In 58 patients with various stages of colonic cancer no significant difference in PGI2-T/2 could be detected. No significant difference could be found before (10, 11 +/- 1, 9 min) and after (10, 03 +/- 1, 8 min) tumor resection, before (9, 89 +/- 1, 5 min) and after 10, 35 +/- 1,8 min) chemotherapy, before (10, 36 +/- 1, 5 min) and after (10, 89 +/- 2, 31 min) irradiation as well as before (8, 86 +/- 1, 9 min) and after (9, 07 +/- 1, 2 min) tumor resection at least 4 to 6 years ago. In 14 healthy people PGI2-T/2 (10, 05 +/- 2, 1 min) did not differ significantly. In all the 58 patients the plasma levels of 6-oxo-PGF1 alpha, the stable derivative of PGI2 were measured. As compared to healthy controls (less than 1 pg/ml) the actual 6-oxo-PGF1 alpha values of patients with colonic cancer were significantly increased. However, no correlation to the T/2 of PGI2 (r between 0, 03 and 0, 21, n.s.) in plasma in vitro could be discovered. After curative tumor resection and after chemotherapy the plasma levels of 6-oxo-PGF1 alpha were significantly lower than before. The data suggest that in patients suffering from colonic cancer the speed of degradation of PGI2 is not a key determinant in local hemostatic dysregulation favouring early metastasis. However, PGI2 or its stable derivatives may be involved in the development of colonic cancer.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Colonic Neoplasms; Epoprostenol; Female; Half-Life; Humans; Male; Middle Aged; Neoplasm Staging