Induction of DNA-protein crosslinks by antitumor 1-nitro-9-aminoacridines in L1210 leukemia cells.
Ledakrin [1-nitro-9-(3'-dimethylamino-N-propylamino)acridine], an antitumor drug of the 1-nitro-9-aminoacridine family, was able to induce DNA-protein crosslinks in intact L1210 leukemia cells, as demonstrated by the potassium-dodecyl sulfate precipitation technique. Ledakrin-induced DNA-protein crosslinks were not readily reversible nor were they accompanied by DNA double-strand breaks. Also, ledakrin produced virtually no crosslinks in isolated nuclei. Ledakrin-induced DNA-protein crosslinks seemed not to be mediated by topoisomerase II, unlike well-established effects of a chemically related antitumor drug, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). Four ledakrin analogs of divergent cytotoxic potencies also induced DNA-protein crosslinks but not DNA double-strand breaks in intact L1210 cells. A significant positive correlation existed between the ability of ledakrin and its 1-nitro analogs to induced DNA-protein crosslinks and the antiproliferative effects of these drugs. The results are consistent with the previously shown ability of 1-nitro-9-aminoacridines to covalently bind to macromolecules after metabolic activation in the cell. In addition to previously demonstrated DNA interstrand crosslinks and monofunctional adducts, DNA-protein crosslinks constitute another type of DNA lesion induced by 1-nitro-9-aminoacridines.
Woynarowski
J M
JM
Department of Pharmaceutical Technology and Biochemistry, Technical University, Gdansk, Poland.
McNamee
H
H
Szmigiero
L
L
Beerman
T A
TA
Konopa
J
J
D000609:Aminoacridines / Q000494:pharmacology*; D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism*; D009564:Nitracrine / Q000031:analogs & derivatives / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*
D000609:Aminoacridines; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D011506:Proteins; D000677:Amsacrine; D009564:Nitracrine; D004250:DNA Topoisomerases, Type II