The interaction between host platelets and circulating tumor cells is thought to facilitate hematogenous metastasis by an unknown mechanism. We have proposed that prostacyclin (PGI[unreadable]2[unreadable]), a natural product of the vessel wall and the most potent platelet antiaggregatory agent known, may function as an endogenous antimetastatic agent. Previously, we demonstrated that PGI[unreadable]2[unreadable] inhibits platelet-enhanced tumor cell adhesion to plastic plates, type IV collagen, and endothelial cells, and significantly inhibits metastasis in vivo. Recent work from our laboratory demonstrated that PGI[unreadable]2[unreadable] inhibits tumor-cell-induced platelet aggregation in a dose-dependent manner, as well as platelet alpha and dense granule release. We tested for possible synergism between PGI[unreadable]2[unreadable] and other compounds known to effect platelet aggregation. These compounds include thromboxane synthase inhibitors, phosphodiesterase inhibitors, and calcium channel blockers. All of these compounds, as well as PGI[unreadable]2[unreadable], are thought to effect platelet aggregation by affecting intraplatelet levels of free Ca[unreadable]2+[unreadable]. We observed that agents from all three groups tested combine in a synergistic manner with PGI[unreadable]2[unreadable] to significantly inhibit tumor-cell-induced platelet aggregation at concentrations which, by themselves, had little or no inhibitory effect on platelet aggregation. Additionally, we determined that the probable mechanism through which nafazatrom, a antimetastatic compound, exerts its effects. Nafazatrom was found to be a reducing substrate for the peroxidase activity of prostaglandin H synthase. In ram seminal vesicle preparations, nafazatrom induced an elevation in levels of 6-keto-PGF[unreadable]1-alpha[unreadable], the non-enzymatic hydrolysis product of PGI[unreadable]2[unreadable]. We are currently screening compounds for actions similar to that of nafazatrom and have found one that is a good reducing substrate for prostaglandin H synthase and is an effective antimetastatic agent in vivo. Our future research will be directed toward identifying compounds for their ability to increase PGI[unreadable]2[unreadable] levels in vitro and in vivo. Inhibition of metastasis will be examined in vivo using PGI[unreadable]2[unreadable] and PGI[unreadable]2[unreadable]-stimulating compounds in concert with other classes of platelet antiaggregatory agents. (L)