title: DNA damage persistence as determinant of tumor sensitivity to the combination of Topo I inhibitors and telomere-targeting agents.
abstract: OBJECTIVE
  We previously reported that the G-quadruplex (G4) ligand RHPS4 potentiates the antitumor activity of camptothecins both in vitro and in tumor xenografts. The present study aims at investigating the mechanisms involved in this specific drug interaction.
  
  
  METHODS
  Combination index test was used to evaluate the interaction between G4 ligands and standard or novel Topo I inhibitors. Chromatin immunoprecipitation was performed to study the presence at telomeres of various types of topisomerase, while immunolabeling experiments were performed to measure the activation of DNA damage both in vitro and in tumor xenografts.
  
  
  RESULTS
  We report that integration of the Topo I inhibitor SN-38, but not the Topo II poison doxorubicin with telomere-based therapy is strongly effective and the sequence of drug administration is critical in determining the synergistic interaction, impairing the cell ability to recover from drug-induced cytotoxicity. The synergistic effect of this combination was also observed by using novel camptothecins and, more interestingly, mice treated with ST1481/RHPS4 combination showed an inhibition and delay of tumor growth as well as an increased survival. The study of the mechanism(s) revealed that treatment with G4 ligands increased Topo I at the telomeres and the functional relevance of this observation was directly assessed by showing that standard and novel camptothecins stabilized DNA damage both in vitro and in xenografts.
  
  
  CONCLUSIONS
  Our results demonstrate an outstanding efficacy of Topo I inhibitors/G4 ligands combination, which likely reflects an enhanced and persistent activation of DNA damage response as a critical determinant of the therapeutic improvement.
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Tor Vergata University, Rome, Italy. biroccio@ifo.it
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.forename: Marco
authors.initials: M
authors.lastname: Franceschin
authors.forename: Malcolm F G
authors.initials: MF
authors.lastname: Stevens
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.forename: Giovanni
authors.initials: G
authors.lastname: Beretta
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zupi
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
mesh_terms: D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004357:Drug Synergism; D054856:G-Quadruplexes / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016615:Telomere / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; C433984:ST 1481; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin