thromboxane-b2 and Neoplasm-Metastasis

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

Topics: Animals; Cell Division; Dinoprostone; Female; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasm Metastasis; Prostaglandins; Thromboxane B2

In order to establish metastatic lesions, 2.5 x 10(6) AH100B cells were injected into the left carotid artery of male Donryu rats. Each metastatic nodule in the liver or kidney, 1 mm or less in diameter, thus obtained was then injected into the peritoneal cavity in which these metastatic cells come to free. About 3 weeks later, each ascites was collected from the rats, while not bloody. Then, cancer cells obtained from each ascites were suspended in Dulbecco's PBS without Ca2+ and Mg2+ (pH 7.2) after washing. Then, 10(6) metastasized or control cancer cells were incubated in 0.1 ml of PBS mentioned above together with 0.1 microCi of (1-14C)-AA at 24 degrees C for 3 min, respectively. After the extraction procedure, AA metabolites formed were separated by means of TLC, and each TLC plate was subjected to autoradiography. In the metastasized cells, PG production ability was generally accelerated and especially in that of PGF2 alpha as compared with that of the control.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Dinoprost; Kidney Neoplasms; Liver Neoplasms, Experimental; Male; Neoplasm Metastasis; Peritoneal Neoplasms; Prostaglandins; Rats; Thromboxane B2

The five stable metabolites [prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in M5076 ovarian reticulosarcoma (M5) homogenates at various times after tumor implantation (Days 15, 18, 21, and 24). Vegetating tumor showed an active AA overall metabolism, which significantly increased during tumor growth. Synthesis of selected products (TXB2, PGD2, and PGE2) increased markedly over time (up to 10.6, 3.5, and 0.9 micrograms/g, respectively). The overall metabolic profile was TXB2 much greater than PGD2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 on Day 15 and TXB2 much greater than PGD2 much greater than PGF2 alpha greater than 6-keto-PGF1 alpha on Day 24. TXB2 was also by far the most abundant product of in vitro-cultured M5 cells. Chronic treatment of M5-bearing mice with dazmegrel (UK-38,485), a selective thromboxane synthetase inhibitor (100 mg/kg p.o. daily, from Day 7 to killing), resulted in incomplete TXB2 synthesis inhibition, AA metabolism diversion toward the other prostaglandins, and no effects of tumor growth and metastasis. More frequent dazmegrel treatment (100 mg/kg p.o. every 8 h from Day 1 to killing) resulted in complete TXB2 synthetase inhibition, AA metabolism diversion, and increased tumor growth and metastasis. These data do not support the hypothesis of thromboxane synthetase inhibitors reducing tumor growth. However, since TXB2 suppression was accompanied by the production of other products possibly interfering in tumor growth, no conclusions on the effective role of TXA2 in malignancy can be drawn.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Dinoprostone; Female; Gas Chromatography-Mass Spectrometry; Imidazoles; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Ovarian Neoplasms; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Growth of BN175, a malignant fibrosarcoma, was correlated with high plasma TXB2 and PGE2 levels. This statistically significant increase was first detected 17 days after inoculation of the tumor, at which time the tumors were 20 mms in diameter. A further increase in tumor size was associated with still higher PGE2 and TXB2 values. At the same time, progressive alterations in platelet function, as measured by ADP-induced platelet aggregation, were observed. 6-keto-PGF1 alpha levels remained normal throughout the whole experiment. It was concluded that tumor growth was associated with changes in PG synthesis and platelet function, although it remains unclear whether these changes were caused by some host immunological response towards the tumor or were predominantly the result of tumor PG-synthesis.

Topics: Animals; Culture Techniques; Dinoprostone; Female; Fibrosarcoma; Gamma Rays; Neoplasm Metastasis; Neoplasm Transplantation; Platelet Aggregation; Prostaglandins; Prostaglandins E; Rats; Thromboxane B2

BN/Bi inbred female rats fed diets containing different amounts of polyunsaturated fatty acids, either of the omega-3 or omega-6 type, each received an implant of a syngeneic mammary adenocarcinoma. When the diameter of the tumors reached 20 mm, they were surgically removed; 2 weeks thereafter the animals were sacrificed and lung metastases were counted. Cellular immune response was determined before tumor inoculation; certain prostaglandin values in plasma and platelet aggregation were measured before and after tumor inoculation. Plasma prostaglandin E2 and thromboxane B2 values were significantly decreased in those rats fed a diet containing menhaden oil. 6-Keto-prostaglandin F1 alpha, cellular immune response, and platelet function were not significantly different in either one of the diet groups. Tumor growth in the groups of rats receiving the omega-3 fatty acids in their diet was significantly inhibited in comparison with that in the rats receiving the omega-6 fatty acids. However, the number of metastases was not significantly altered.

Topics: Adenocarcinoma; Animals; Fatty Acids, Unsaturated; Feeding Behavior; Female; Immunity, Cellular; Mammary Neoplasms, Experimental; Neoplasm Metastasis; Neoplasm Transplantation; Platelet Aggregation; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

WHT/Ht mice were transplanted s.c. with NC carcinoma, and the tumours were excised after 2 weeks. The mice were treated orally throughout the experiments with prednisolone 500 micrograms kg-1 or mepacrine 3.6 mg kg-1, starting the day after tumour transplantation or, with prednisolone, the day after tumour excision. In some experiments the mice were also treated with the cytotoxic drugs methotrexate 2 mg kg-1 and melphalan 1.4 mg kg-1. The excised tumours were weighed; some of them, and samples of serum, were extracted for prostanoids which were measured by radioimmunoassay. The chemotherapy lengthened the survival of the mice, but prednisolone or mepacrine had little or no effect on survival, metastasis, the response to chemotherapy, tumour size or the formation of tumour prostanoids.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Male; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Prednisolone; Prostaglandins E; Quinacrine; Thromboxane B2

Platelets may promote the development of metastasis, and tumor cells that aggregate platelets are believed to be more malignant. We studied three different human mammary carcinoma cell lines, which had different interactions with human platelet-rich plasma (PRP). The MCF-7 and the T47-D cell lines induced an adenosine diphosphate (ADP)-mediated platelet aggregation. The third cell line, MDA-MB 231 did not induce any platelet aggregation. On the contrary, this cell line inhibited ADP- and arachidonic acid-induced platelet aggregation. This inhibiting activity is mainly adenosine-mediated. The mechanism by which platelets may contribute to the dissemination of cancer could be related to platelet growth factors. MCF-7 and T47-D cell lines induced a release of platelet-derived growth factor (PDGF). On the contrary, the MDA-MB 231 cell line did not induce any platelet release. The role of these platelet growth factors in tumor cell growth is discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Alprostadil; Apyrase; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Breast Neoplasms; Carcinoma; Cell Line; Creatine Kinase; Humans; Neoplasm Metastasis; Platelet Aggregation; Thromboxane B2

Lewis lung primary carcinomas have been extracted for eicosanoids, and the findings examined in relation to lung metastases. The order of the 5 compounds measured was PGE2 greater than PGE1 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than TXB2. On the basis of the observation that the balance of PGI2 and TXA2 is altered in metastasis (Honn et al., 1983), the effects of Nafazatrom, a PGI2 enhancing agent, and imidazole, a thromboxane synthetase inhibitor, were tested. The experimental approach taken was to study spontaneous lung metastases after removal of the primary tumour at 13 days after tumour cell inoculation. Both Nafazatrom and imidazole decreased the lung weight when given during the period either before or after the excision of the primary tumour. There was a general trend toward an increase in the number of small lung nodules (greater than 2 mm) and a decrease in large lung nodules (greater than 2 mm) as a result of the chemotherapy. Mean survival time of the mice was significantly different among the five groups, with the mice surviving the longest in the group treated with Nafazatrom after the excision of the primary tumour.

Topics: Animals; Body Weight; Carcinoma; Imidazoles; Lung; Lung Neoplasms; Mice; Neoplasm Metastasis; Organ Size; Prostaglandins; Prostaglandins E; Prostaglandins F; Pyrazoles; Pyrazolones; Thromboxane B2

Tissue contents of prostaglandin E2 (PGE2), thromboxane B2 (TxB2, a metabolite of proaggregatory thromboxane A2) and 6-keto-PGF1 alpha (a metabolite of antiaggregatory prostacyclin, PGI2) were measured from ovarian cancer (n = 13), borderline malignant, benign ovarian tumor and normal ovary of postmenopausal women. TxB2 contents were significantly (p less than 0.05) increased in metastatic ovarian cancer tissue, compared to local ovarian cancer, borderline malignant, benign tumor or normal ovarian tissues, while in 6-keto-PGF1 alpha production there was no difference between these groups. PGE2 contents were also increased in metastatic ovarian cancer tissue. These data suggest the association between local PG production and advanced ovarian cancer tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Dinoprostone; Epoprostenol; Female; Humans; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Prostaglandins E; Thromboxane B2; Thromboxanes

Tissue prostaglandin (PG) content and production by human breast cancers were measured in 24 human mammary carcinoma specimens. The 5 compounds studied were PGE1, PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and TXB2. The tissue content of all 5 compounds was higher in neoplastic tissue in comparison with the paired noncancerous breast tissue. However, microsomal PG synthetase activity in vitro in noncancerous and neoplastic breast tissue was comparable. Increased thromboxane formation was associated with three clinical variables--tumour size, axillary lymph node metastases and distant metastasis. A lesion negative for either oestrogen or progesterone receptor content tended to produce more TXB2 but lower PGE2 and 6-keto-PGF1 alpha. Results obtained in this pilot study may provide clues as to what direction future larger studies could take in the search for reliable prognostic indicators for breast cancer.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Alprostadil; Breast Neoplasms; Dinoprost; Dinoprostone; Humans; Lymphatic Metastasis; Microsomes; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins E; Prostaglandins F; Receptors, Estrogen; Receptors, Progesterone; Thromboxane B2