title: Effect of structural modification at the 4, 3', and 2' positions of doxorubicin on topoisomerase II poisoning, apoptosis, and cytotoxicity in human melanoma cells.
abstract: BACKGROUND
  The mechanism of the cytotoxicity of anthracyclines is pleiotropic and its significance in cell growth inhibition seems to be highly specific and dependent on cell type and anthracycline drug. Resistance and the high cardiotoxicity of anthracyclines have stimulated many studies aimed at identifying critical substituents required for optimal activity. Many authors point to the fact that the double-strand breaks, the consequence of the activity of topoisomerase II poisons, and the inability of cells to repair the DNA lesions are the signal for apoptosis. The aim of this study was to define the influence of 4-demetoxy 2'-halogenated analogs with altered basicity at the 3'-position on topoisomerase II and the relationship of that interaction with apoptosis and the cytotoxicity of these novel anthracyclines. Parental human ME18 melanoma cells and the ME18/R subline, obtained experimentally, resistant to doxorubicin (DOX), exposed to 1.7 and 8.6 microM DOX or its analogs, annamycin and WP903 (both 0.3 and 3.0 microM) were studied.
  
  
  METHODS
  The MTT test was used to assay cytotoxicity. Interaction of the drugs with topoisomerase II and apoptosis were done by Western blot and fluorescence microscopy using Hoechst 33342.
  
  
  RESULTS
  The structural changes at positions 4, 2', and 3' can influence topoisomerase II interaction and apoptotic activity, although correlation between these events and cytotoxic consequences has not been proved.
  
  
  CONCLUSIONS
  The biological response of the cells to the structurally similar anthracyclines may be variable and probably depends on the cell type which seems to be an additional problem in the multifactorial resistance of tumor cells to anthracyclines.
authors.affiliation: Department of Biochemistry and Biopharmaceuticals, National Institute of Medicines, Chełmska 30/34, 00-725, Warsaw, Poland. b-gruber@il.waw.pl
authors.forename: Beata M
authors.initials: BM
authors.lastname: Gruber
authors.forename: Elzbieta L
authors.initials: EL
authors.lastname: Anuszewska
authors.forename: Irena
authors.initials: I
authors.lastname: Bubko
authors.forename: Aneta
authors.initials: A
authors.lastname: Goździk
authors.forename: Izabela
authors.initials: I
authors.lastname: Fokt
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C080315:annamycin