XK469, a selective topoisomerase IIbeta poison.
XK469 (NSC 697887) is a synthetic quinoxaline phenoxypropionic acid derivative that possesses unusual solid tumor selectivity and activity against multidrug-resistant cancer cells. We report here that XK469 and its S(-) and R(+)-isomers induce reversible protein-DNA crosslinks in mammalian cells. Under protein denaturing conditions, the protein-DNA crosslinks are rendered irreversible and stable to DNA banding by CsCl gradient ultracentrifugation. Several lines of evidence indicate that the primary target of XK469 is topoisomerase IIbeta. Preferential targeting of topoisomerase IIbeta may explain the solid tumor selectivity of XK469 and its analogs because solid tumors, unlike leukemias, often have large populations of cells in the G(1)/G(0) phases of the cell cycle in which topoisomerase IIbeta is high whereas topoisomerase IIalpha, the primary target of many leukemia selective drugs, is low.
Gao
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H
Department of Radiology, Colleges of Pharmacy and Medicine, The Ohio State University, Columbus, OH 43210, USA.
Huang
K C
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Yamasaki
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EF
Chan
K K
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Chohan
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Snapka
R M
RM
D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002499:Centrifugation, Density Gradient; D002522:Chlorocebus aethiops; D003432:Cross-Linking Reagents / Q000378:metabolism; D004247:DNA / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D011810:Quinoxalines; C118180:XK 469; D004247:DNA; D004250:DNA Topoisomerases, Type II