6-ketoprostaglandin-f1-alpha and Adenocarcinoma

To explore the role of hypercoagulation in the metastasis of carcinoma.. The effect of Tetramethylpyrazine (TTMP) on platelet functions among the 25 advanced cases of lung carcinoma, and 26 matched control subjects were investigated in the study. Their ages varied from 31-86 years (mean 58.2) in lung carcinoma group (13 male, 12 female) and 36 to 61 (mean 52.9) in the control group (16 male, 10 female). The pathologic types were as follows: 7 cases of squamous cell cancer, 12 adenocarcinoma, 2 small cell carcinoma and 4 undistinguished type. The TNM stage revealed 14 cases in stage IIIa, 3 in stage IIIb and 8 in stage IV. The site of metastasis included mediastinal lymph node, pleura, supraclavicular lymph node, brain, spine, costa, skin and pericardium. The levels of plasma TXB2, 6-keto-PGF1 alpha, VIII:C, vWF, AT-III:a, AT-III:Ag, Fg and blood PAdT, PAgT were measured before and after the intravenous infusion of 80 mg TTMP in patients with lung carcinoma.. The levels of TXB2, 6-keto-PGF1 alpha, VIII:C, vWF and Fg in lung carcinoma group were significantly elevated, while the levels of PAdT was greatly decreased, compared with the control group, no significant differences in levels of PAgT, AT-III:a and AT-III:Ag were found between the two groups. After the infusion of TTMP the levels of PAdT, PagT, VIII:C, dWF and Fg were decreased significantly, while TXB2, 6-keto-PGF1 alpha, AT-III:a and AT-III:Ag remained unchanged.. TTMP inhibits the adhesion and aggregatory functions of blood platelet and the activity of coagulation factors. It might be one of the mechanisms of TTMP's antimetastasis of lung carcinoma.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrazines; Thromboxane B2

The PC-3 Low Invasive cells and the PC-3 High Invasive cells were used to investigate the correlation of the COX-2 expression and its arachidonic acid metabolites, prostaglandins, with their invasiveness through Matrigel using a Boyden chamber assay. The COX-2 expression in PC-3 High Invasive cells was approximately 3-fold higher than in PC-3 Low Invasive cells while the COX-1 expression was similar in both cell sublines. When incubated with arachidonic acid, PGE2 was the major prostaglandin produced by these cells. PC-3 High Invasive cells produced PGE2 approximately 2.5-fold higher than PC-3 Low Invasive cells. PGD2 was the second most abundant prostaglandin produced by these cells. Both indomethacin (a nonspecific COX inhibitor) and NS-398 (a specific COX-2 inhibitor) inhibited the production of prostaglandins and the cell invasion. PGE2 alone did not induce the cell invasion of PC-3 Low Invasive cells. However, PGE2 reversed the inhibition of cell invasion by NS-398 and enhanced the cell invasion of the PC-3 High Invasive cells. In contrast, PGD2 slightly inhibited the cell invasion. These results suggest that in the PC-3 Low Invasive cells, COX-2-derived PGE2 may not be sufficient to induce cell invasion while in the PC-3 High Invasive cells, PGE2 may be sufficient to act as an enhancer for the cell invasion. Further, PGD2 may represent a weak inhibitor and counteracts the effect of PGE2 in the cell invasion.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Arachidonic Acid; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Humans; Indomethacin; Isoenzymes; Male; Membrane Proteins; Neoplasm Invasiveness; Nitrobenzenes; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostatic Neoplasms; Sulfonamides; 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

Nuclear factor-kappaB (NF-kappaB) is a transcriptional regulator of inducible expression of genes including cyclooxygenase-2 (COX-2), regulating cell proliferation. NF-kappaB is kept silent in the cytoplasm via interaction with the inhibitory protein IkappaBalpha and transmigrated into the nucleus upon activation. However, constitutive NF-kappaB has been found in the nucleus of some cancer cells. We investigated the role of NF-kappaB in COX-2 expression and cell proliferation in human gastric cancer AGS cells. AGS cells were treated with antisense oligodeoxynucleotide (AS ODN) or sense oligodeoxynucleotide (S ODN) for the NF-kappaB subunit p50, or they were transfected with a mutated IkappaBalpha gene (MAD-3 mutant) or a control vector, pcDNA-3. AGS cells were treated with COX-2 inhibitors such as indomethacine and NS-398 or prostaglandin E2. mRNA expression for COX-2, and protein levels for p50, IkappaBalpha, and COX-2 were determined by reverse transcription polymerase chain reaction and Western blot analysis. The NF-kappaB levels were examined by electrophoretic mobility shift assay. Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) levels were determined by enzyme-linked immunosorbent assay. Cell proliferation was assessed by viable cell counting, [3H] thymidine incorporation, and colony formation. The nuclear level of p50 decreased in AGS cells treated with AS ODN. The IkappaBa mutant was observed in cells transfected with the mutated IkappaBa gene. NF-kappaB was inhibited in cells treated with AS ODN or transfected with the mutated IkappaBalpha gene, compared with the cells treated with S ODN or transfected with control vector. Cell proliferation, mRNA expression and protein level of COX-2, and production of TXB2 and 6-keto-PGF1alpha were inhibited in cells treated with AS ODN or transfected with the mutated IkappaBalpha gene, which had lower NF-kappaB levels than cells treated with S ODN or transfected with control vector. COX-2 inhibitors suppressed cell proliferation and production of TXB2 and 6-keto-PGF1alpha, in a dose-dependant manner. Prostaglandin E2 prevented the inhibition of proliferation in cells treated with AS ODN or transfected with the mutated IkappaBalpha gene. In conclusion, NF-kappaB mediates COX-2 expression, which may be related to cell proliferation, in human gastric cancer cells.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Cell Division; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; DNA-Binding Proteins; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Proteins; Isoenzymes; Membrane Proteins; Mutagenesis; NF-kappa B; NF-KappaB Inhibitor alpha; Nitrobenzenes; Oligonucleotides, Antisense; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Stomach Neoplasms; Sulfonamides; Thromboxane B2; Transfection; Tumor Cells, Cultured

To elucidate the possible inhibitory effect of a novel carboxamide derivative (IS-741) on biliary carcinogenesis, Syrian hamsters were subjected to cholecystoduodenostomy and ligation of the distal end of the common duct, and then given a regular diet (group I) or a diet containing 200 p.p.m. of IS-741 (group II). All hamsters were subcutaneously injected with N-nitrosobis(2-oxopropyl)amine until 10 weeks after surgery, and continued to feed on their respective dietary regimen until termination of the experiment at 16 weeks after surgery. Biliary adenocarcinomas were evaluated histologically. Non-cancerous and cancerous hepatobiliary tract tissues were analyzed for phospholipase A(2) (PLA(2)) activity, myeloperoxidase (MPO) activity, and the concentrations of prostaglandin (PG), i.e., prostaglandin E(2), 6-ketoprostaglandin F(1)alpha and thromboxane B(2). IS-741 significantly inhibited the development and multiplicity of hepatobiliary adenocarcinomas and reduced the proliferating cell nuclear antigen labeling indices in non-cancerous hepatobiliary tissues, compared with group I. The anti-cancerous effect of IS-741 was associated with a significant inhibition of PLA(2) and MPO levels in non-cancerous tissues of the extrahepatic biliary tract and the liver, and in cancerous tissue of the liver. Furthermore, IS-741 reduced the production of PGs in non-cancerous hepatobiliary tissues, compared with group I. Although the precise mechanism of action of IS-741 in preventing biliary tumorigenesis remains to be elucidated, it is likely to be related to modulation of arachidonic acid metabolism and/or suppression of neutrophil accumulation.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Animals; Anticarcinogenic Agents; Biliary Tract; Biliary Tract Neoplasms; Carcinogens; Choledochostomy; Common Bile Duct; Cricetinae; Dinoprostone; Enzyme Inhibitors; Female; Liver; Mesocricetus; Neutrophil Infiltration; Nitrosamines; Peroxidase; Phospholipases A; Proliferating Cell Nuclear Antigen; Pyridines; Thromboxane B2

We studied the effect of ovarian cancer and its chemotherapy on the urinary excretion of prostacyclin (PGI2) and thromboxane A2 (TxA2) hydration and metabolic products. In six patients we measured 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha (PGI2 products) and thromboxane B2 (TxB2) and 2,3-dinor-TxB2 (TxA2 products) by HPLC followed by radioimmunoassay before, during and after the combined infusion of cisplatin, 4'epi-adriamycin and cyclophosphamide. Before the first cytostatic infusion, the urinary excretion of prostanoids was on average 4.4-5.8 times higher than in patients with ovarian endometriosis (n = 19). The infusion of cytostatics led to a 50-120% rise in the excretion of prostanoids during the first post-infusion 9 hours, but in the subsequent 10 hours their output was 25-45% below the initial value and remained low for at least 2 weeks. Following repetitive courses of cytostatics (2-4 per patient), prostanoid excretion tended to normalise. These data suggest that ovarian cancer is associated with increased production of PGI2 and TxA2, and that cytostatics suppress this production. This may be of biological significance in tumour behaviour and in the effect of cytostatics.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cystadenocarcinoma; Endometriosis; Epirubicin; Female; Humans; Middle Aged; Ovarian Neoplasms; Thromboxane B2

The metabolism of 1-14C arachidonic acid (AA) by arterial wall in patients with renal cell carcinoma and in control patients undergoing nephrectomy was investigated by a high pressure liquid chromatography (HPLC) system. No differences in 1-14C AA uptake and in the total amount of metabolites were found between the two groups, whereas the amounts of cyclooxygenase and lipoxygenase pathway (COP and LOP) metabolites produced by patients with renal cell carcinoma were significantly lower and, respectively, higher than those produced by the control group. The COP/LOP ratio was 7.2 +/- 5.5 in the control group in comparison to 1.9 +/- 0.5 in renal cell carcinoma patients. The decrease in COP metabolites was due to a markedly reduced synthesis of prostacyclin (PGI2), with no changes in thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E2 (PGE2) production. The changes in PGI2 and 12-hydroxy-eicosatetraenoic acid (12-HETE) (metabolite of LOP) vascular production were not related to tumor dimension. The decrease in PGI2 synthesis may represent a factor favoring metastasis and thrombosis in neoplastic patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Arachidonic Acid; Arachidonic Acids; Arteries; beta-Thromboglobulin; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Epoprostenol; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Kidney Neoplasms; Lipoxygenase; Prostaglandin-Endoperoxide Synthases

Tissue contents of prostaglandins (PG) PGE2, PGE2a and 6-keto-PGF1a (degradation product of PGI2) were determined in specimens of advanced human ovarian cancer (n = 11). The PG levels (ng/mg tissue protein) varied widley: PGE2 17-515; PGF2a 2-43 and 6-keto-PGF1a 5-105. Tumors of patients without response to chemotherapy contained more PGE2, PGF2a and 6-keto-PGF1a than did tumors responding to chemotherapy. PG production was investigated in two ovarian carcinoma-derived cell lines. The ability of these cells to synthesize PG varied depending on the cell density. An increase of cell number was associated with a decrease of PG yield. PG formation was inhibited by indomethacin in a concentration-dependent manner. The present study suggests that ovarian carcinoma cells form PG in vivo and vitro.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Animals; Cell Line; Dinoprost; Dinoprostone; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Prostaglandins; Prostaglandins E; Prostaglandins F

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Epoprostenol; Female; Humans; Lung Neoplasms; Male; Middle Aged; Platelet Aggregation; Pneumonectomy; Thromboxane B2; Thromboxanes

A comparison of tissue concentrations and biosynthesis of prostaglandin (PG)E2, PGF2 alpha, 6-keto-PGF1 alpha (degradation production of PGI2) and thromboxane (TX)B2 (degradation product of TXA2) was made in normal mammary glands obtained from virgin female Sprague-Dawley rats and in N-nitrosomethylurea (NMU)-induced mammary adenocarcinomas. The tissue concentrations (ng/g wet weight) of all 4 compounds were significantly higher in the NMU-induced tumor than in normal mammary tissue: PGE2, 210 +/- 37 vs 25 +/- 6; PGF2 alpha, 287 +/- 48 vs 23 +/- 8; 6-keto-PGF1 alpha, 294 +/- 42 vs 31 +/- 8; and TXB2, 260 +/- 49 vs 27 +/- 5 (mean +/- S.E.M.). Microsomal prostaglandin synthetase activity in NMU-induced tumors was also significantly higher than in normal tissue for all but 6-keto-PGF1 alpha: PGE2, 226 +/- 16 vs 50 +/- 9; PGF2 alpha, 28 +/- 3 vs 4 +/- 1; 6-keto-PGF1 alpha, 14 +/- 2 vs 11 +/- 2; and TXB2, 17 +/- 1 vs 10 +/- 1 ng/mg protein (mean +/- S.E.M.). There was no apparent relationship between either tumor size or age and the ability of microsomal enzyme to synthesize prostaglandins, although the content of prostaglandins extracted from tumor tissue was inversely related to the tumor size.

Topics: 6-Ketoprostaglandin F1 alpha; Adenocarcinoma; Animals; Dinoprost; Dinoprostone; Female; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Methylnitrosourea; Microsomes; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Thromboxane B2