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Synergistic Effect of Prochlorperazine and Dipyridamole on the Cellular Retention and Cytotoxicity of Doxorubicin¹

Division of Experimental Therapeutics, Department of Radiation Oncology [A. K., C. M., Y. H.], Division of Medical Oncology, Department of Medicine [K. S., H. F.], University of Miami Medical School and Sylvester Cancer Center, Miami, Florida 33136, and Biological Chemistry Department, Hebrew University of Jerusalem, Jerusalem, Israel 91904 [W. D. S., E. L.]

Incubation of drug-resistant human tumor cells with a combination of prochlorperazine and dipyridamole has additive/synergistic effect on the cellular retention and cytotoxicity of doxorubicin. In patients administered a fixed dose of doxorubicin and prochlorperazine with escalating doses of dipyridamole, mean plasma levels of dipyridamole and prochlorperazine achieved were as high as 3.01 ± 0.41 µm and 0.94 ± 0.09 µm, respectively. Plasma samples from patients were analyzed in an in vitro assay to monitor the effect on the cellular retention of tritium-labeled daunorubicin in MDR₁-transfected P388 cells. In 22 of 49 of the plasma samples analyzed, the daunorubicin in efflux blocking activity was one-half or greater than that of cells incubated with 12.5 µM verapamil, a well-known efflux blocker. These observations suggest that a combination of prochlorperazine and dipyridamole may enhance cellular doxorubicin retention by blocking efflux while reducing normal tissue toxicity and unwanted side effects in vivo.

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