Inhibitory effects of dipyridamole on growth, nucleoside incorporation, and platelet-activating capability in the U87MG and SKNMC human tumor cell lines.
The effects of dipyridamole on tumor cell function were examined in cultures of two lines of human origin, the SKNMC neuroblastoma line that activates platelets by a mechanism which is dependent on the release of adenosine 5'-diphosphate and the U87MG glioblastoma line that induces platelet activation by the generation of thrombin. Cells grown in the presence of dipyridamole at 1 microM showed greater than 80% inhibition of uptake of adenosine, thymidine, and uridine with both lines. At 5 microM tumor cell growth was inhibited by 70% (U87MG) and 90% (SKNMC) but without concomitant cytotoxicity as determined by clonogenic assay (50% inhibitory concentration approximately 20 microM). At 10 microM dipyridamole cyclic adenosine 3':5'-monophosphate levels increased 150% with both cell lines but no changes above baseline values were seen at 2.5 microM. The two cell lines showed different responses to being cultured in the presence of dipyridamole in terms of their ability to subsequently activate platelets. U87MG cells cultured in 10 microM dipyridamole showed a doubling of the lag time as compared with cells grown in the absence of dipyridamole but with full aggregation; with SKNMC cells the aggregation rate was reduced and cells grown in 10 microM dipyridamole showed no reversible first wave, a 5-fold increase in lag time and a 75% inhibition in total aggregation. Since therapeutic doses of dipyridamole result in plasma concentrations of approximately 3.5 microM these results suggest that potential antimetastatic effects of dipyridamole could be direct arising from inhibition of important steps in tumor cell metabolism or indirect by suppressing one or more of the mechanisms involved in the ability of tumor cells to activate platelets.
Bastida
E
E
del Prado
J
J
Almirall
L
L
Jamieson
G A
GA
Ordinas
A
A
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003029:Coagulants / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D004176:Dipyridamole / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009705:Nucleosides / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects*
D003029:Coagulants; D009705:Nucleosides; D004176:Dipyridamole; D000242:Cyclic AMP