6-ketoprostaglandin-f1-alpha 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

Since the highly metastatic variant M4 of the mFS6 fibrosarcoma has the peculiar feature of generating larger amounts of immunoreactive thromboxane B2 (TxB2) than the non-metastatic variant (M9), we used the thromboxane synthase inhibitor dazmegrel (UK-38,485) in an effort to influence its metastatic potential. TxB2 formation by tumor cells freshly harvested from the primary tumor could be completely inhibited by drug addition in vitro. TxB2 generation was inhibited with a dose-response curve, 2 microM being the lowest dazmegrel concentration giving 100% inhibition. Chronic treatment of tumor-bearing mice with dazmegrel (150 mg/kg b.w. twice daily by gavage) from the day of tumor-cell implantation until killing of the animals caused a more than 10-fold reduction in serum TxB2 formation; TxB2 generation by tumor cells was also significantly depressed. This treatment, however, did not significantly modify either primary tumor weight or metastasis formation. Our data suggest that selective inhibition of thromboxane generation in either blood or tumor cells does not prevent spontaneous metastasis formation in the murine model studied.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Fibrosarcoma; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Thromboxane-A Synthase; Thromboxanes

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

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

Topics: 6-Ketoprostaglandin F1 alpha; Breast Neoplasms; Dinoprostone; Female; Gas Chromatography-Mass Spectrometry; Humans; Lymphatic Metastasis; Neoplasm Metastasis; Prognosis; Prostaglandins; Prostaglandins E

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

Topics: 6-Ketoprostaglandin F1 alpha; Clinical Laboratory Techniques; Diagnosis, Differential; Gas Chromatography-Mass Spectrometry; Humans; Male; Neoplasm Metastasis; Prognosis; Prostatic Hyperplasia; Prostatic Neoplasms; Reference Values