title: Use of the proton pump inhibitor pantoprazole to modify the distribution and activity of doxorubicin: a potential strategy to improve the therapy of solid tumors.
abstract: OBJECTIVE
  Limited drug distribution within solid tumors is an important cause of drug resistance. Basic drugs (e.g., doxorubicin) may be sequestered in acidic organelles, thereby limiting drug distribution to distal cells and diverting drugs from their target DNA. Here we investigate the effects of pantoprazole, a proton pump inhibitor, on doxorubicin uptake, and doxorubicin distribution and activity using in vitro and murine models.
  
  
  METHODS
  Murine EMT-6 and human MCF-7 cells were treated with pantoprazole to evaluate changes in endosomal pH using fluorescence spectroscopy, and uptake of doxorubicin using flow cytometry. Effects of pantoprazole on tissue penetration of doxorubicin were evaluated in multilayered cell cultures (MCC), and in solid tumors using immunohistochemistry. Effects of pantoprazole to influence tumor growth delay and toxicity because of doxorubicin were evaluated in mice.
  
  
  RESULTS
  Pantoprazole (>200 μmol/L) increased endosomal pH in cells, and also increased nuclear uptake of doxorubicin. Pretreatment with pantoprazole increased tissue penetration of doxorubicin in MCCs. Pantoprazole improved doxorubicin distribution from blood vessels in solid tumors. Pantoprazole given before doxorubicin led to increased growth delay when given as single or multiple doses to mice bearing MCF7 xenografts.
  
  
  CONCLUSIONS
  Use of pantoprazole to enhance the distribution and cytotoxicity of anticancer drugs in solid tumors might be a novel treatment strategy to improve their therapeutic index.
authors.affiliation: Authors' Affiliations: Department of Medical Biophysics and Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Krupa J
authors.initials: KJ
authors.lastname: Patel
authors.forename: Carol
authors.initials: C
authors.lastname: Lee
authors.forename: Qian
authors.initials: Q
authors.lastname: Tan
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D004317:Doxorubicin; D000077402:Pantoprazole