Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse

Abstract

There is ample evidence to suggest that hematogenous metastasis may be related to the ability of tumor cells to promote aggregation of host platelets. Arachidonic acid metabolism in platelets and vessel walls may also contribute to the metastatic process. Several preliminary trials of platelet inhibitory agents have been performed. Ketoconazole (inhibitor of lipoxygenase and thromboxane synthetase), verapamil (calcium antagonist), forskolin (stimulator of platelet adenylate cyclase), and indomethacin (inhibitor of cyclooxygenase) were examined, alone and in combination, to investigate their effects on platelet aggregation and on hepatic metastases from human pancreatic tumor cells (RWP-2) in nude mice. The tumor cells were injected intrasplenically, and the animals were divided into control, single-drug and combination treatment groups. The agents were administered intraperitoneally 1 hr before and every 24 hr after the tumor cell injections for 6 days. Statistically significant differences were observed between the control and single-treatment groups on the reduction of liver tumor nodules (range P less than 0.001-0.032) and in the liver surface areas occupied by tumor (range P less than 0.001-0.013). Furthermore, when these agents were combined, similar reductions in liver tumor nodules were noted (range P less than 0.001-0.008), while even greater inhibitory effects were seen in the liver surface areas occupied by tumor (P less than 0.001) compared with the single-treatment groups. Also, the combination studies strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.