Stimulation of topoisomerase II-mediated DNA cleavage by an indazole analogue of lucanthone.
Lucanthone is an antitumour drug used as an adjuvant in radiation therapy. The drug intercalates into DNA and inhibits topoisomerase II. An indazole analogue of lucanthone (IA-5) was examined for its ability to modulate topoisomerase II-DNA cleavable complex formation in vitro. The drug contains a methylbenzothiopyranoindazole chromophore instead of the methyl-thioxanthenone nucleus of lucanthone. Using a radiolabelled linear plasmid DNA as a substrate, both lucanthone and the indazole analogue were shown to promote the cleavage of DNA by human topoisomerase II. Sequencing experiments with different restriction fragments indicated that the indazole drug promoted DNA cleavage primarily at sites having a C on the 3' side of the cleaved bond (-1 position). By contrast, in the same sequencing methodology lucanthone exerted a much weaker effect on topoisomerase II. The sequence selectivity of IA-5 is reminiscent of that of the anticancer drug mitoxantrone and its anthrapyrazole analogue losoxantrone, which is structurally close to IA-5. Binding to DNA and topoisomerase II inhibition are two distinct processes contributing separately to the cytotoxic activity of the indazole drug.
Dassonneville
L
L
Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret and INSERM Unite 524, IRCL, Lille, France.
Bailly
C
C
D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D008154:Lucanthone / Q000031:analogs & derivatives / Q000494:pharmacology*; D015394:Molecular Structure
D007191:Indazoles; D004247:DNA; D004250:DNA Topoisomerases, Type II; D008154:Lucanthone