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Comparison of the Synergistic Potentiation of Etoposide, Doxorubicin, and Vinblastine Cytotoxicity by Dipyridamole¹

Department of Medicine [S. B. H., D. M., R. S., J. S. V.] and Mathematics [I. S. A.] and the Cancer Center, University of California, San Diego, La Jolla, California 92093

Dipyridamole (DPM) enhanced sensitivity to etoposide (VP-16), doxorubicin (DOX), and vinblastine (VBL) in a human ovarian carcinoma cell line that was already relatively sensitive to all three agents. This interaction was shown to be truly synergistic by median effect analysis over a 2 log cell kill. The combination index at 50% cell kill (CI₅₀) was used to quantitate the extent of synergy. The CI₅₀s were 0.42, 0.66, and 0.30 for VP-16, DOX, and VBL, respectively. We compared the effect of DPM on the cellular pharmacology of each chemotherapeutic drug. DPM increased the steady state cellular content of VP-16 by a maximum of 3.2-fold, and that of DOX and VBL by 1.7- and 3.7-fold, respectively. There was a good correlation between the CI₅₀ and the DPM-induced increase in cellular drug content (r = 0.94). DPM had no effect on the initial influx VP-16 or DOX but did increase the initial influx of VBL by 3.5-fold. DPM inhibited the initial efflux of all three compounds. However, there was no relation between the extent of efflux inhibition and the magnitude of the DPM-induced increase in cellular drug content, indicating that DPM must have other effects as well. DPM has chemical characteristics similar to other known modulators of VP-16, DOX, and VBL sensitivity. When compared to verapamil, DPM was as efficacious but twice as potent in its synergistic enhancement of VP-16 sensitivity. These results demonstrate that DPM can markedly increase the cytotoxicity of VP-16, DOX, and VBL and suggest possible clinical applications.

¹ This work was supported by Grant CA-35309 from the National Institutes of Health, by Grant CH-368 from the American Cancer Society, and a grant from Bristol Laboratories, Inc. This work was conducted in part by the Clayton Foundation for Research—California Division. Dr. Howell is a Clayton Foundation investigator. A preliminary report of this work was presented at the meeting of the American Society of Clinical Oncology, New Orleans, LA, May 22, 1988.

² To whom requests for reprints should be addressed, at Department of Medicine T-012, University of California, San Diego, La Jolla, CA 92093.

Received 4/27/88. Revised 12/22/88. Revised 3/17/89. Accepted 3/22/89.