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

Abstract

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.

• Authors: G N Tzanakakis, K C Agarwal, M P Vezeridis
• Journal: Cancer (Cancer) Vol. 71 Issue 8 Pg. 2466-71 (Apr 15 1993) ISSN: 0008-543X [Print] United States
• PMID: 8453569 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Mopidamol
• Dipyridamole
• Adenosine

Topics

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