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Prevention of human pancreatic cancer cell‐induced hepatic metastasis in nude mice by dipyridamole and its analog RA‐233
Author(s) -
Tzanakakis George N.,
Agarwal Kailash C.,
Vezeridis Michael P.
Publication year - 1993
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(19930415)71:8<2466::aid-cncr2820710807>3.0.co;2-q
Subject(s) - dipyridamole , medicine , metastasis , pancreatic cancer , platelet , in vivo , pharmacology , pancreatic tumor , in vitro , cell , nude mouse , cancer research , cancer , endocrinology , chemistry , biology , biochemistry , microbiology and biotechnology
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.