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Synergism between Dipyridamole and Cisplatin in Human Ovarian Carcinoma Cells in Vitro¹

Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California 92093-0812 [A. J., J. V., R. S., S. B. H.], and the Department of Physiology and Pharmacology, Lynn Hall, Purdue University, West Lafayette, Indiana 47907 [T. C. K. C.].

Dipyridamole (DPM), a nucleoside membrane transport inhibitor, enhanced the cytotoxicity of cisplatin (DDP) for human ovarian carcinoma 2008 cells by a factor of 4.7 ± 0.4-fold (mean ± SD) and for the 10-fold DDP-resistant 2008/C13*5.25 subline by a factor of 5.8 ± 2.7-fold. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM enhancement of DDP cytotoxicity was schedule dependent; it was greatest when cells were exposed to DPM continuously during and following a 1-h exposure to DDP and less pronounced when DPM exposure was limited to pretreatment or concurrent treatment only. DPM increased DDP uptake in a concentration-dependent manner as measured with both [^195mPt]-DDP and the DDP analogue [³H]-cis-dichloro(ethylenediamine) platinum. Nitrobenzylthioinosine, another nucleoside membrane transport inhibitor, did not enhance DDP cytotoxicity or uptake at concentrations that produced equivalent degrees of inhibition of [³H]uridine uptake. DPM did not interact synergistically through an increase in cellular cyclic AMP levels. DPM did not increase trypan blue or propidium iodide uptake, or change cell size, indicating that it did not nonspecifically increase membrane permeability. We conclude that DPM interacts synergistically with DDP and that, while an increase in DDP uptake is one component of the mechanism of this interaction, there are additional components since maximal effect was observed only with prolonged DDP exposure.

¹ This investigation was supported by a grant from the Academy of Finland, Ida Montinin Säätiö and Alfred Kordelinin Säätiö, by grants CA 35309 and TE3209290 from the National Institutes of Health, and by a grant from Bristol-Myers Squibb. This work was conducted in part by the Clayton Foundation for Research-California Division. A. J. and S. B. H. are Clayton Foundation investigators.

² To whom requests for reprints should be addressed, at UCSD Cancer Center, 9500 Gilman Drive, La Jolla, CA 92093-0812.

Received 12/ 5/91. Accepted 4/24/92.

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