title: Effect of verapamil and other agents on the distribution of anthracyclines and on reversal of drug resistance.
abstract: We studied the intracellular distribution of drugs within anthracycline-sensitive and -resistant cells by computer-assisted digitized video fluorescence microscopy. We found that the antitumor antibiotic, daunorubicin, distributes differently in anthracycline-sensitive and -resistant human leukemia cells (HL-60). Verapamil and other agents known to circumvent resistance in pleiotropic drug-resistant cell lines were able to change the pattern of distribution of daunorubicin in the anthracycline-resistant HL-60 cells back to the distribution found in anthracycline-sensitive HL-60 cells. To investigate the biochemical basis for this effect, we studied the distribution of daunorubicin and doxorubicin in a hydrophobic/hydrophilic (membrane/cytoplasmic) environment using the two-compartment cell-free system of Folch. Our results demonstrate that various unrelated drugs known to overcome resistance will also change the distribution of the anthracyclines in the hydrophobic/hydrophilic compartments. Our data allow the hypothesis that various unrelated agents known to circumvent resistance may act by altering the hydrophobic/hydrophilic solubility of anthracyclines in the resistant cell.
authors.forename: A A
authors.initials: AA
authors.lastname: Hindenburg
authors.forename: M A
authors.initials: MA
authors.lastname: Baker
authors.forename: E
authors.initials: E
authors.lastname: Gleyzer
authors.forename: V J
authors.initials: VJ
authors.lastname: Stewart
authors.forename: N
authors.initials: N
authors.lastname: Case
authors.forename: R N
authors.initials: RN
authors.lastname: Taub
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002460:Cell Line; D003630:Daunorubicin / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D009279:Naphthacenes / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes; D004317:Doxorubicin; D014700:Verapamil; D003630:Daunorubicin