title: Decreased nucleotide excision repair activity and alterations of topoisomerase IIalpha are associated with the in vivo resistance of a P388 leukemia subline to F11782, a novel catalytic inhibitor of topoisomerases I and II.
abstract: OBJECTIVE
  The purpose of the study was to investigate the mechanisms associated with antitumor activity and resistance to F11782, a novel dual catalytic inhibitor of topoisomerases with DNA repair-inhibitory properties.
  
  
  METHODS
  For that purpose, an F11782-resistant P388 leukemia subline (P388/F11782) has been developed in vivo and characterized.
  
  
  RESULTS
  Weekly subtherapeutic doses of F11782 (10 mg/kg) induced complete resistance to F11782 after 8 weekly passages. This resistant P388/F11782 subline retained some in vivo sensitivity to several DNA-topoisomerase II and/or I complex-stabilizing poisons and showed marked collateral sensitivity to cisplatin, topotecan, colchicine, and Vinca alkaloids, while proving completely cross-resistant only to merbarone and doxorubicin. Therefore, resistance to F11782 did not appear to be associated with a classic multidrug resistance profile, as further reflected by unaltered drug uptake and no overexpression of resistance-related proteins or modification of the glutathione-mediated detoxification process. In vivo resistance to F11782 was, however, associated with a marked reduction in topoisomerase IIalpha protein (87%) and mRNA (50%) levels, as well as a diminution of the catalytic activity of topoisomerase IIalpha. In contrast, only minor reductions in topoisomerases IIbeta and I levels were recorded. However, of major interest, nucleotide excision repair activity was decreased 3-fold in these P388/F11782 cells and was more specifically associated with a decreased (67%) level of XPG (human xeroderma pigmentosum group G complementing protein), an endonuclease involved in this DNA repair system.
  
  
  CONCLUSIONS
  These findings suggest that both topoisomerase IIalpha and XPG are major targets of F11782 in vivo and further demonstrate the original mechanism of action of this novel compound.
authors.affiliation: Division of Experimental Cancer Research, Pierre Fabre Research Center, Castres, Cedex, France. anna.kruczynski@pierre-fabre.com
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczynski
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Barret
authors.forename: Benoît
authors.initials: B
authors.lastname: Van Hille
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chansard
authors.forename: Jackie
authors.initials: J
authors.lastname: Astruc
authors.forename: Yoann
authors.initials: Y
authors.lastname: Menon
authors.forename: Carole
authors.initials: C
authors.lastname: Duchier
authors.forename: Laurent
authors.initials: L
authors.lastname: Créancier
authors.forename: Bridget T
authors.initials: BT
authors.lastname: Hill
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D015152:Blotting, Northern; D002384:Catalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D020125:Mutation, Missense; D009281:Naphthalenes / Q000008:administration & dosage / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D011714:Pyrans / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009281:Naphthalenes; D009943:Organophosphorus Compounds; D011714:Pyrans; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C061400:etoposide phosphate; D005047:Etoposide; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin; C405744:tafluposide