title: G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors.
abstract: OBJECTIVE
  The formation of G-quadruplex structures at telomeric DNA sequences blocks telomerase activity, offering an original strategy to design and develop new antitumor agents. The pentacyclic acridinium salt RHPS4 is one of the most effective and selective G4 ligands able to rapidly disrupt telomere architecture, resulting in apoptosis of cancer cells. Here, we studied the therapeutic index of RHPS4 and its integration with chemotherapeutics in preclinical model of solid tumors.
  
  
  METHODS
  The antitumoral activity of RHPS4 was evaluated on human xenografts of different histotypes and compared with that of standard antineoplastic agents. Moreover, the effect of RHPS4/chemotherapeutics combinations on cell survival was studied and the most favorable combination was evaluated on tumor-bearing mice.
  
  
  RESULTS
  RHPS4 was active in vivo as single agent and showed a high therapeutic efficacy when compared with conventional drugs. Moreover, RHPS4 had antitumoral activity in human melanoma xenografts inherently resistant to chemotherapy and exhibited antimetastatic activity. RHPS4 also showed a strong synergistic interaction with camptothecins and this effect was strictly dependent on the drug sequence employed. Treatment of mice with irinotecan followed by RHPS4 was able to inhibit and delay tumor growth and to increase mice survival.
  
  
  CONCLUSIONS
  Our data show that RHPS4 has a good pharmacodynamic profile and in combination therapy produces a strong antitumoral activity, identifying this drug as promising agent for clinical development.
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Roma, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Marco
authors.initials: M
authors.lastname: Scarsella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Riggio
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Lidia
authors.initials: L
authors.lastname: Staszewsky
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.forename: Malcolm F
authors.initials: MF
authors.lastname: Stevens
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Barbara
authors.initials: B
authors.lastname: Antoniani
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.forename: Gabriella
authors.initials: G
authors.lastname: Zupi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
mesh_terms: D000166:Acridines / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D008024:Ligands; D002166:Camptothecin