6-ketoprostaglandin-f1-alpha and Fibrosarcoma

We investigated whether there is a relationship between the production of eicosanoids by murine solid tumors and their response to the prostaglandin H (PGH) synthase inhibitor indomethacin. Three sarcomas, designated FSA, NFSA, and SA-NH, and two carcinomas, designated MCA-K and HCA-I, syngeneic to C3Hf/Kam mice were used. In general, FSA and NFSA produced more PGH synthase products than lipoxygenase products, whereas HCA-I produced both types of metabolites in large quantities. All three tumors responded well to indomethacin treatment by slowing their growth. In contrast, MCA-K and SA-NH tumors produced insignificant quantities of PGH synthase products, but substantial amounts of lipoxygenase products. Their growth was not affected by treatment with indomethacin. Indomethacin did not influence tumor cell survival either in vitro or in vivo, but it reduced the proportion of S-phase cells in the tumors. The antitumor effect of indomethacin was not reduced by immunosuppression of the tumor host and was independent of tumor immunogenicity, implying that indomethacin acted through nonimmunological mechanisms. Thus, the effectiveness of indomethacin was directly related to the ability of tumors to produce PGs. Consequently, the eicosanoid profile of tumors could serve as a valuable way to select patients likely to respond to indomethacin and other PGH synthase inhibiting agents.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Biomarkers, Tumor; Carbon Radioisotopes; Female; Fibrosarcoma; Indomethacin; Liver Neoplasms, Experimental; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Prognosis; Prostaglandins; Sarcoma, Experimental; Thromboxane B2; Tritium

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