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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tzanakakis
G N
GN
Surgical Service Veterans Administration Medical Center, Providence, Rhode Island.
Agarwal
K C
KC
Vezeridis
M P
MP
D000241:Adenosine / Q000097:blood; D000818:Animals; D004176:Dipyridamole / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009012:Mopidamol / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D009012:Mopidamol; D004176:Dipyridamole; D000241:Adenosine