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 M. Hecht, Christian Bailly, Carine Giovannangeli

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28 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Arimondo, P. B., Thomas, C. J., Oussedik, K., Baldeyrou, B., Mahieu, C., Halby, L., Guianvarc'h, D., Lansiaux, A., Hecht, S. M., Bailly, C., & 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