Comparison of the synergistic potentiation of etoposide, doxorubicin, and vinblastine cytotoxicity by dipyridamole.
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.
Howell
S B
SB
Department of Medicine, University of California, San Diego, La Jolla, California 92093.
Hom
D
D
Sanga
R
R
Vick
J S
JS
Abramson
I S
IS
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D004176:Dipyridamole / Q000494:pharmacology*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D010051:Ovarian Neoplasms; D014410:Tumor Stem Cell Assay; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology*
D014747:Vinblastine; D004176:Dipyridamole; D005047:Etoposide; D004317:Doxorubicin