Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides.

Duca M, Guianvarc'h D, Oussedik K, Halby L, Garbesi A, Dauzonne D, Monneret C, Osheroff N, Giovannangeli C, Arimondo PB
Nucleic Acids Res. 2006 34 (6): 1900-11

PMID: 16598074 · PMCID: PMC1447649 · DOI:10.1093/nar/gkl126

Human topoisomerase II (topo II) is the cellular target for a number of widely used antitumor agents, such as etoposide (VP16). These agents 'poison' the enzyme and induce it to generate DNA breaks that are lethal to the cell. Topo II-targeted drugs show a limited sequence preference, triggering double-stranded breaks throughout the genome. Circumstantial evidence strongly suggests that some of these breaks induce chromosomal translocations that lead to specific types of leukaemia (called treatment-related or secondary leukaemia). Therefore, efforts are ongoing to decrease these secondary effects. An interesting option is to increase the sequence-specificity of topo II-targeted drugs by attaching them to triplex-forming oligonucleotides (TFO) that bind to DNA in a highly sequence-specific manner. Here five derivatives of VP16 were attached to TFOs. The active topo II poisons, once linked, induced cleavage 13-14 bp from the triplex end where the drug was attached. The use of triple-helical DNA structures offers an efficient strategy for targeting topo II-mediated cleavage to DNA specific sequences. Finally, drug-TFO conjugates are useful tools to investigate the mechanistic details of topo II poisoning.

MeSH Terms (11)

Antineoplastic Agents, Phytogenic DNA DNA Damage DNA Footprinting DNA Topoisomerases, Type II Drug Delivery Systems Enzyme Inhibitors Etoposide Humans Oligodeoxyribonucleotides Topoisomerase II Inhibitors

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