Exploring the cellular activity of camptothecin-triple-helix-forming oligonucleotide conjugates

Paola B. Arimondo, Craig J. Thomas, Kahina Oussedik, Brigitte Baldeyrou, Christine Mahieu, Ludovic Halby, Dominique Guianvarc'h, Amélie Lansiaux, Sidney Hecht, Christian Bailly, Carine Giovannangeli

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)324-333
Number of pages10
JournalMolecular and Cellular Biology
Volume26
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Camptothecin
Type I DNA Topoisomerase
Oligonucleotides
DNA Cleavage
DNA
Poisons
Cell Nucleus
Reporter Genes
Neoplasms
Gene Expression
Drug Therapy
Mutation
Enzymes
Therapeutics
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Arimondo, P. B., Thomas, C. J., Oussedik, K., Baldeyrou, B., Mahieu, C., Halby, L., ... Giovannangeli, C. (2006). Exploring the cellular activity of camptothecin-triple-helix-forming oligonucleotide conjugates. Molecular and Cellular Biology, 26(1), 324-333. https://doi.org/10.1128/MCB.26.1.324-333.2006

Exploring the cellular activity of camptothecin-triple-helix-forming oligonucleotide conjugates. / Arimondo, Paola B.; Thomas, Craig J.; Oussedik, Kahina; Baldeyrou, Brigitte; Mahieu, Christine; Halby, Ludovic; Guianvarc'h, Dominique; Lansiaux, Amélie; Hecht, Sidney; Bailly, Christian; Giovannangeli, Carine.

In: Molecular and Cellular Biology, Vol. 26, No. 1, 01.2006, p. 324-333.

Research output: Contribution to journalArticle

Arimondo, PB, Thomas, CJ, Oussedik, K, Baldeyrou, B, Mahieu, C, Halby, L, Guianvarc'h, D, Lansiaux, A, Hecht, S, Bailly, C & Giovannangeli, C 2006, 'Exploring the cellular activity of camptothecin-triple-helix-forming oligonucleotide conjugates', Molecular and Cellular Biology, vol. 26, no. 1, pp. 324-333. https://doi.org/10.1128/MCB.26.1.324-333.2006
Arimondo, Paola B. ; Thomas, Craig J. ; Oussedik, Kahina ; Baldeyrou, Brigitte ; Mahieu, Christine ; Halby, Ludovic ; Guianvarc'h, Dominique ; Lansiaux, Amélie ; Hecht, Sidney ; Bailly, Christian ; Giovannangeli, Carine. / Exploring the cellular activity of camptothecin-triple-helix-forming oligonucleotide conjugates. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 1. pp. 324-333.
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