title: In vivo effect of oracin on doxorubicin reduction, biodistribution and efficacy in Ehrlich tumor bearing mice.
abstract: BACKGROUND
  The limitation of carbonyl reduction represents one possible way to increase the effectiveness of anthracycline doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells. In vitro, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased the antiproliferative effect of DOX in MCF-7 breast cancer cells. Moreover, ORC significantly decreases DOX toxicity in non-cancerous MCF-10A breast cells and in hepatocytes. The present study was designed to test in mice the in vivo effect of ORC on plasma and tissue concentrations of DOX and its main metabolite DOXOL. The effect of ORC on DOX efficacy in mice bearing solid Ehrlich tumors (EST) was also studied.
  
  
  METHODS
  DOX and DOX + ORC combinations were iv administered to healthy mice. Blood samples, livers and hearts were collected during the following 48 h. DOX and DOXOL concentrations were assayed using HPLC. The mice with inoculated EST cells were treated repeatedly iv with DOX and DOX + ORC combinations, and the growth of tumors was monitored.
  
  
  RESULTS
  ORC in combination with DOX significantly decreased DOXOL plasma concentrations during four hours after administration, but this significantly affected neither DOX plasma concentrations nor DOX or DOXOL concentrations in the liver and heart at any of intervals tested. In EST bearing mice, ORC did not significantly affect DOX efficacy on tumor growth. However, EST was shown to be an improper model for the testing of ORC efficacy in vivo, as ORC did not inhibit DOXOL formation in EST.
  
  
  CONCLUSIONS
  In vivo, ORC was able to retard DOXOL formation but was not able to improve DOX efficacy in EST-bearing mice.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Králové, CZ 500 05, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Hanušová
authors.forename: Pavel
authors.initials: P
authors.lastname: Tomšík
authors.forename: Lenka
authors.initials: L
authors.lastname: Kriesfalusyová
authors.forename: Alena
authors.initials: A
authors.lastname: Pakostová
authors.forename: Iva
authors.initials: I
authors.lastname: Boušová
authors.forename: Lenka
authors.initials: L
authors.lastname: Skálová
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D004983:Ethanolamines; D007546:Isoquinolines; C103439:oracine; D004317:Doxorubicin; C010013:adriamycinol