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Triple Helix-Forming Oligonucleotides Conjugated to Indolocarbazole Poisons Direct Topoisomerase I-Mediated DNA Cleavage to a Specific Site

2001; American Chemical Society; Volume: 12; Issue: 4 Linguagem: Inglês

10.1021/bc000162k

1520-4812

Paola B. Arimondo, Christian Bailly, Alexandre S. Boutorine, Pascale Moreau, Michelle Prudhomme, Jian‐Sheng Sun, Thérèse Garestier, Claude Hélène,

Neutropenia and Cancer Infections

Topoisomerase I is an ubiquitous DNA-cleaving enzyme and an important therapeutic target in cancer chemotherapy for camptothecins as well as for indolocarbazole antibiotics such as rebeccamycin. To achieve a sequence-specific cleavage of DNA by topoisomerase I, a triple helix-forming oligonucleotide was covalently linked to indolocarbazole-type topoisomerase I poisons. The three indolocarbazole−oligonucleotide conjugates investigated were able to direct topoisomerase I cleavage at a specific site based upon sequence recognition by triplex formation. The efficacy of topoisomerase I-mediated DNA cleavage depends markedly on the intrinsic potency of the drug. We show that DNA cleavage depends also upon the length of the linker arm between the triplex-forming oligonucleotide and the drug. Based on a known structure of the DNA-topoisomerase I complex, a molecular model of the oligonucleotide conjugates bound to the DNA−topoisomerase I complex was elaborated to facilitate the design of a potent topoisomerase I inhibitor−oligonucleotide conjugate with an optimized linker between the two moieties. The resulting oligonucleotide−indolocarbazole conjugate at 10 nM induced cleavage at the triple helix site 2-fold more efficiently than 5 μM of free indolocarbazole, while the other drug-sensitive sites were not cleaved. The rational design of drug−oligonucleotide conjugates carrying a DNA topoisomerase poison may be exploited to improve the efficacy and selectivity of chemotherapeutic cancer treatments by targeting specific genes and reducing drug toxicity.