Prevention of human pancreatic cancer cell-induced hepatic metastasis in nude mice by dipyridamole and its analog RA-233.

Abstract

Several studies have provided evidence suggesting that platelets play a key role in tumor metastasis. A number of antiplatelet agents have been used to prevent tumor metastasis in animal models and humans. Antiplatelet agents, dipyridamole (adenosine transport inhibitor), and RA-233 (inhibitor of cAMP PDE) were used to prevent tumor-cell-platelet interactions both in in vitro and in vivo systems; however, the data were not very conclusive. Our studies used dipyridamole and RA-233 alone and in combination to investigate their effects on human pancreatic tumor cells (RWP-2)-induced platelet aggregation in human blood and on hepatic metastasis in nude mice. To examine effects of dipyridamole and RA-233 on liver metastasis, the tumor cells (RWP-2) were injected intrasplenically in nude mice grouped into control, dipyridamole (8 mg/kg), RA-233 (8 mg/kg), and dipyridamole plus RA-233 (8 mg/kg each). The agents were administered intraperitoneally 1 hour before and 24 hours after the tumor cell injection. When dipyridamole and RA-233 were used alone, only weak to moderate effects were seen on RWP-2 tumor cell-induced platelet aggregation. However, these agents, when combined, strongly inhibited the tumor cell-induced aggregation in human platelet-rich plasma. In tumor metastasis experiments, reductions of approximately 70% in hepatic nodules and 90% in surface area occupied by the tumor were seen with the combination treatment (dipyridamole plus RA-233) as compared with the control group of mice. This study suggests that the combination of dipyridamole and RA-233 provides an effective intervention for the antithrombotic approach to the treatment of cancer metastases.