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Molecular and Cellular Biology, January 2006, p. 324-333, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.324-333.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Exploring the Cellular Activity of Camptothecin-Triple-Helix-Forming Oligonucleotide Conjugates{dagger}

Paola B. Arimondo,1* Craig J. Thomas,2 Kahina Oussedik,1 Brigitte Baldeyrou,3 Christine Mahieu,3 Ludovic Halby,1 Dominique Guianvarc'h,1,{ddagger} Amélie Lansiaux,3 Sidney M. Hecht,2 Christian Bailly,3 and Carine Giovannangeli1

UMR 5153 CNRS-Muséum National d'Histoire Naturelle USM0503, INSERM UR565, 43 rue Cuvier, 75231 Paris Cédex 05,1 INSERM U524 and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place Verdun, 59045 Lille, France,3 Departments of Chemistry and Biology, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, Virginia 229012

Received 29 April 2005/ Returned for modification 28 June 2005/ Accepted 13 October 2005

Topoisomerase I is a ubiquitous DNA-cleaving enzyme and an important therapeutic target in cancer chemotherapy for camptothecins (CPTs). These drugs stimulate DNA cleavage by topoisomerase I but exhibit little sequence preference, inducing toxicity and side effects. A convenient strategy to confer sequence specificity consists of the linkage of topoisomerase poisons to DNA sequence recognition elements. In this context, triple-helix-forming oligonucleotides (TFOs) covalently linked to CPTs were investigated for the capacity to direct topoisomerase I-mediated DNA cleavage in cells. In the first part of our study, we showed that these optimized conjugates were able to regulate gene expression in cells upon the use of a Photinus pyralis luciferase reporter gene system. Furthermore, the formation of covalent topoisomerase I/DNA complexes by the TFO-CPT conjugates was detected in cell nuclei. In the second part, we elucidated the molecular specificity of topoisomerase I cleavage by the conjugates by using modified DNA targets and in vitro cleavage assays. Mutations either in the triplex site or in the DNA duplex receptor are not tolerated; such DNA modifications completely abolished conjugate-induced cleavage all along the DNA. These results indicate that these conjugates may be further developed to improve chemotherapeutic cancer treatments by targeting topoisomerase I-induced DNA cleavage to appropriately chosen genes.

* Corresponding author. Mailing address: UMR 5153 CNRS-Muséum National d'Histoire Naturelle USM0503, INSERM UR565, 43 rue Cuvier, 75231 Paris Cédex 05, France. Phone: 33 1 40793859. Fax: 33 1 40793705. E-mail: arimondo{at}mnhn.fr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Laboratoire de Chimie Organique Biologique, Université Paris 6, UMR 7613, 75005 Paris, France.

Molecular and Cellular Biology, January 2006, p. 324-333, Vol. 26, No. 1
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.1.324-333.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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