Title | Topoisomerase II-mediated DNA cleavage activity and irreversibility of cleavable complex formation induced by DNA intercalator with alkylating capability. |
Publication Type | Journal Article |
Year of Publication | 1992 |
Authors | Kong XB, Rubin L, Chen LI, Ciszewska G, Watanabe KA, Tong WP, Sirotnak FM, Chou TC |
Journal | Mol Pharmacol |
Volume | 41 |
Issue | 2 |
Pagination | 237-44 |
Date Published | 1992 Feb |
ISSN | 0026-895X |
Keywords | Alkylating Agents, Anthraquinones, Cell Division, DNA Topoisomerases, Type I, DNA Topoisomerases, Type II, DNA, Neoplasm, Humans, Intercalating Agents, Leukemia, Experimental, Leukemia, Myeloid, Nucleic Acid Conformation, Tumor Cells, Cultured |
Abstract | 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. |
Alternate Journal | Mol. Pharmacol. |
PubMed ID | 1311406 |
Grant List | CA18856 / CA / NCI NIH HHS / United States |