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

Cancer. 1993 Apr 15;71(8):2466-71. doi: 10.1002/1097-0142(19930415)71:8<2466::aid-cncr2820710807>;2-q.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine / blood
  • Animals
  • Dipyridamole / pharmacology*
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Humans
  • Liver Neoplasms / blood
  • Liver Neoplasms / prevention & control*
  • Liver Neoplasms / secondary*
  • Mice
  • Mice, Nude
  • Mopidamol / pharmacology*
  • Pancreatic Neoplasms* / blood
  • Platelet Aggregation / drug effects*
  • Tumor Cells, Cultured


  • Mopidamol
  • Dipyridamole
  • Adenosine