Prostaglandin and thromboxane synthesis by M5076 ovarian reticulosarcoma during growth: effects of a thromboxane synthetase inhibitor.
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.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D015232:Dinoprostone; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D007093:Imidazoles / Q000494:pharmacology*; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism*; D015230:Prostaglandin D2; D011453:Prostaglandins / Q000096:biosynthesis*; D011457:Prostaglandins D / Q000096:biosynthesis; D011458:Prostaglandins E / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000096:biosynthesis*
D001095:Arachidonic Acids; D007093:Imidazoles; D011453:Prostaglandins; D011457:Prostaglandins D; D011458:Prostaglandins E; D013931:Thromboxanes; D016718:Arachidonic Acid; C039242:dazmegrel; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; D015230:Prostaglandin D2