Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides.
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.
Duca
Maria
M
UMR 5153, CNRS, Paris, France.
Guianvarc'h
Dominique
D
Oussedik
Kahina
K
Halby
Ludovic
L
Garbesi
Anna
A
Dauzonne
Daniel
D
Monneret
Claude
C
Osheroff
Neil
N
Giovannangeli
Carine
C
Arimondo
Paola B
PB
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000633:toxicity; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D018983:DNA Footprinting; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity; D005047:Etoposide / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D059005:Topoisomerase II Inhibitors; C051802:triplex DNA; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II