TY - CHAP
T1 - Mechanism of antitumor drug action
T2 - Poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide
AU - Nelson, E. M.
AU - Tewey, K. M.
AU - Liu, Leroy-Fong
PY - 1984
Y1 - 1984
N2 - The intercalative acridine derivative 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), but not its isomer o-AMSA, is a potent antitumor drug that in mammalian cells stimulates the formation of DNA strand breaks that are characterized by tightly bound proteins. Using purified mammalian DNA topoisomerases, we have analyzed the effects of these antitumor drugs on topoisomerase-DNA interactions. The antitumor drug m-AMSA dramatically stimulates the formation of a topoisomerase II-DNA complex that is detected on protein-denaturant treatment: both single- and double-stranded DNA breaks are produced and a topoisomerase II subunit is linked covalently to each 5' end of the broken DNA strands. The noncytotoxic isomer, o-AMSA, which does not induce significant amounts of DNA breaks in cultured cells, exhibits a correspondingly smaller effect in stimulating formation of the complex in vitro. The agreement between in vitro and in vivo studies suggests that mammalian DNA topoisomerase II may be the primary target of m-AMSA and that the drug-induced complex formation between topoisomerase II and DNA may be the cause of cytotoxicity and other effects such as DNA sequence rearrangements and sister-chromatid exchange.
AB - The intercalative acridine derivative 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), but not its isomer o-AMSA, is a potent antitumor drug that in mammalian cells stimulates the formation of DNA strand breaks that are characterized by tightly bound proteins. Using purified mammalian DNA topoisomerases, we have analyzed the effects of these antitumor drugs on topoisomerase-DNA interactions. The antitumor drug m-AMSA dramatically stimulates the formation of a topoisomerase II-DNA complex that is detected on protein-denaturant treatment: both single- and double-stranded DNA breaks are produced and a topoisomerase II subunit is linked covalently to each 5' end of the broken DNA strands. The noncytotoxic isomer, o-AMSA, which does not induce significant amounts of DNA breaks in cultured cells, exhibits a correspondingly smaller effect in stimulating formation of the complex in vitro. The agreement between in vitro and in vivo studies suggests that mammalian DNA topoisomerase II may be the primary target of m-AMSA and that the drug-induced complex formation between topoisomerase II and DNA may be the cause of cytotoxicity and other effects such as DNA sequence rearrangements and sister-chromatid exchange.
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M3 - Chapter
C2 - 6324188
AN - SCOPUS:0021333644
VL - 20
SP - 1361
EP - 1365
BT - ISOTOPENPRAXIS
ER -