title: Synergistic effect of prochlorperazine and dipyridamole on the cellular retention and cytotoxicity of doxorubicin.
abstract: 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 microm and 0.94 +/- 0.09 microm, 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 microM 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.
authors.affiliation: Department of Radiation Oncology, University of Miami Medical School and Sylvester Cancer Center, Florida 33136, USA. akrishan@mednet.med.miami.edu
authors.forename: A
authors.initials: A
authors.lastname: Krishan
authors.forename: K S
authors.initials: KS
authors.lastname: Sridhar
authors.forename: C
authors.initials: C
authors.lastname: Mou
authors.forename: W D
authors.initials: WD
authors.lastname: Stein
authors.forename: E
authors.initials: E
authors.lastname: Lyubimov
authors.forename: Y P
authors.initials: YP
authors.lastname: Hu
authors.forename: H
authors.initials: H
authors.lastname: Fernandez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism / Q000493:pharmacokinetics; D004176:Dipyridamole / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007262:Infusions, Intravenous; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010949:Plasma / Q000737:chemistry; D011346:Prochlorperazine / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003470:Culture Media; D004176:Dipyridamole; D004317:Doxorubicin; D011346:Prochlorperazine; D003630:Daunorubicin