Inhibition of Ehrlich ascites tumor in vivo by PAF-antagonists

Abstract

Several lines of evidence support that PAF modulates the inflammatory and immune responses, and that tumors may inhibit both these processes. In the present study we analysed the effect of PAF antagonists on the growth of Ehrlich Ascites Tumor (EAT) in vivo. Mice were inoculated intraperitoneally with 1 × 10 3 EAT cells and the tumor growth evaluated by counting the number of peritoneal cells, 1, 6 and 10 days after tumor implantation. BN 52021 was administered intraperitoneally, intravenously or subcutaneously once or twice a day, at 1.0, 2.5, 5.0 and 20.0 mg/kg. Control animals received 0.1 ml of the vehicle in the same schedule. It was found that i.p. and i.v. administration of BN 52021 (5 mg/kg, twice a day) significantly inhibited EAT growth (80.8% and 56.0% respectively). Other routes and doses were less effective. Another PAF antagonist, SRI 63441 (5 mg/kg, i.p., twice a day) also inhibited EAT growth (80.4%). The BN 52021 added to EAT cells in culture, at concentration of 10 −3 and 10 −4 M, did not affect the viability and proliferation of tumors cells. In an attempt to understand the mechanism of this inhibition, we analyzed the peritoneal macrophages for spreading ability and H 2O 2 release. It was found that 24 h after tumor implantation there was an increase in the spreading ability of peritoneal macrophages (75%) and that, as the tumor grew, the spreading index fell to control levels (<10%). In the groups treated with BN 52021 (5 mg/kg/twice a day) the spreading remained elevated (50–60%) at all the times examined. Release of H 2O 2, measured by horseradish peroxidase-phenol red oxidation, was below detectable levels throughout tumor growth. Treatment with BN 52021 as above, significantly stimulated the release of H 2O 2, 6 and 10 days after tumor implantation (0.4 to 0.6 nmol/10 5 cells). The data presented show that PAF antagonists inhibit EAT growth in vivo and that this inhibition is concomitant with activation of peritoneal macrophages. These results suggest that macrophages can critically influence tumor growth and that PAF or PAF-like substances may modulate macrophages-tumor interactions.