DNA damage persistence as determinant of tumor sensitivity to the combination of Topo I inhibitors and telomere-targeting agents.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Annamaria Biroccio, Manuela Porru, Angela Rizzo, Erica Salvati, Carmen D'Angelo, Augusto Orlandi, Daniela Passeri, Marco Franceschin, Malcolm F G Stevens, Eric Gilson, Giovanni Beretta, Gabriella Zupi, Claudio Pisano, Franco Zunino, Carlo Leonetti
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 8 Pg. 2227-36 (Apr 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21355072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• 3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium
• Acridines
• ST 1481
• Topoisomerase I Inhibitors
• Irinotecan
• Camptothecin

Topics

• Acridines (administration & dosage, pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Camptothecin (administration & dosage, analogs & derivatives, pharmacology)
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• DNA Damage
• Drug Synergism
• G-Quadruplexes (drug effects)
• HCT116 Cells
• HT29 Cells
• Humans
• Irinotecan
• Male
• Mice
• Mice, Nude
• Telomere (drug effects, genetics, metabolism)
• Topoisomerase I Inhibitors (administration & dosage, pharmacology)
• Treatment Outcome
• Xenograft Model Antitumor Assays