RT Journal Article
SR Electronic
T1 Topoisomerase II-mediated DNA cleavage activity and irreversibility of cleavable complex formation induced by DNA intercalator with alkylating capability.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 237
OP 244
VO 41
IS 2
A1 X B Kong
A1 L Rubin
A1 L I Chen
A1 G Ciszewska
A1 K A Watanabe
A1 W P Tong
A1 F M Sirotnak
A1 T C Chou
YR 1992
UL http://molpharm.aspetjournals.org/content/41/2/237.abstract
AB A group of chrysophanol and emodin derivatives with DNA-intercalating capability and with or without alkylating potential have been synthesized and shown to have antitumor activity in vitro. The topoisomerase II (Topo II)-mediated DNA cleavage activities induced by representative compounds 3-(2-chloroethylamino) methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31690), 3-bis [(2-chloroethyl)amino]methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31662), and 3-(2-hydroxyethylamino)methy-1,8-dihydroxy-9,10-anthraquinon e (SK-31694), and their cytotoxicities, have been investigated. All three compounds inhibited the kinetoplast DNA decatenation catalyzed by DNA Topo II. These compounds inhibited leukemia cell growth and stimulated, in a dose-dependent manner from 0.5 to 60 microM, the formation of Topo II-DNA cleavable complexes, when 3'-32P-labeled DNA was used. The mapping of Topo II-mediated DNA cleavage sites using HindIII-digested 3'-32P-labeled DNA showed that, at 10 microM, these compounds induced protein-linked DNA breaks that correlated with cytotoxicity, with respect to their maximal efficacy or the reciprocal concentration for the half-maximal effect. The reversibility study showed that the amounts of protein-linked DNA cleavage induced by 4'-(9-acridinylamino)methanesulfon-m-anisidide and VP-16 as well as SK-31694, which lacks alkylating potential, were markedly decreased during 30-sec exposure to 65 degrees or 0.5 M NaCl. In contrast, protein-linked DNA cleavages induced by SK-31662, which has two alkylating functionalities, and by SK-31690, which has one alkylating functionality in its structure, cannot be reversed during the 15-min exposure to 65 degrees or 0.5 M NaCl. These data suggest that Topo II is a major cellular target for cytotoxicity of these compounds. Furthermore, DNA intercalators with alkylating potential interact with Topo II-DNA cleavable complexes in an irreversible manner, with enhanced toxicity.