title: Time-lapse live cell imaging and flow analysis of multidrug resistance reversal by verapamil in bladder cancer cell lines.
abstract: OBJECTIVE
  To examine the effects of verapamil on the intracellular drug pharmacokinetics of epirubicin using alternative dosing schedules. The results might inform the choices for optimizing clinical chemotherapy.
  
  
  METHODS
  Sensitive parental (MGH-U1) and multidrug resistant (MDR) (MGH-U1R and MGH-U1-MMC) bladder cancer cell lines were used. Fluorescence time-lapsed studies were performed on cells incubated with epirubicin alone or combined with verapamil. Flow cytometry was performed after the alternative dosing regimens.
  
  
  RESULTS
  Verapamil reversed the epirubicin localization patterns in MDR cells. Time-lapse imaging showed that nuclear epirubicin accumulation in MDR cells with verapamil followed the parental curve. The maximal reversal took >60 minutes. Flow cytometry showed increased epirubicin uptake in MDR cells co-incubated with verapamil. Preincubation was not as effective as co-incubation.
  
  
  CONCLUSIONS
  The results of our model indicate that longer exposure to MDR-class drugs, exemplified by epirubicin, increases uptake and the MDR reversing action of co-treatment with verapamil. The present results highlight the need for additional clinical trials of drug dosing and scheduling for combination intravesical chemotherapy regimens.
authors.affiliation: Department of Urology, Southampton University Hospitals, National Health Service Trust, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Featherstone
authors.forename: Bashir A
authors.initials: BA
authors.lastname: Lwaleed
authors.forename: Alan G
authors.initials: AG
authors.lastname: Speers
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Hayes
authors.forename: Brian R
authors.initials: BR
authors.lastname: Birch
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Cooper
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000493:pharmacokinetics*; D005434:Flow Cytometry; D006801:Humans; D018613:Microscopy, Confocal; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D015251:Epirubicin; D014700:Verapamil