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

Abstract

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.

• Authors: Maria Duca, Dominique Guianvarc'h, Kahina Oussedik, Ludovic Halby, Anna Garbesi, Daniel Dauzonne, Claude Monneret, Neil Osheroff, Carine Giovannangeli, Paola B Arimondo
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 34 Issue 6 Pg. 1900-11 ( 2006) ISSN: 1362-4962 [Electronic] England
• PMID: 16598074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Oligodeoxyribonucleotides
• Topoisomerase II Inhibitors
• triplex DNA
• Etoposide
• DNA
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents, Phytogenic (chemistry, toxicity)
• DNA (chemistry)
• DNA Damage
• DNA Footprinting
• DNA Topoisomerases, Type II (metabolism)
• Drug Delivery Systems
• Enzyme Inhibitors (chemistry, toxicity)
• Etoposide (analogs & derivatives, toxicity)
• Humans
• Oligodeoxyribonucleotides (chemistry)
• Topoisomerase II Inhibitors