title: Alchemix: a novel alkylating anthraquinone with potent activity against anthracycline- and cisplatin-resistant ovarian cancer.
abstract: Chloroethylaminoanthraquinones are described with intercalating and alkylating capacity that potentially covalently cross-link topoisomerase II (topo II) to DNA. These compounds have potent cytotoxic activity (IC(50) = 0.9-7.6 nM) against the A2780 human ovarian carcinoma cell line. Hydroxyethylaminoanthraquinones also reported in this paper have similar IC(50) values (0.7-1.7 nM) in the same cell line. Alchemix (ZP281M, 1-(2-[N,N-bis(2-chloroethyl)amino]ethylamino)-4-(2-[N,N-(dimethyl)amino]ethylamino)-5,8-dihydroxy-9,10-anthracenedione), an alkylating anthraquinone, retains excellent antitumor activity in Adriamycin-resistant (2780AD) and cisplatin-resistant (2780/cp70) cell lines in vitro and in vivo. This indicates that Alchemix can evade both P-glycoprotein efflux pump and DNA mismatch repair-mediated resistance. In treated cells, Alchemix was shown to preferentially induce drug-stabilized covalent bound topo IIalpha-DNA complexes over topo IIbeta-DNA complexes.
authors.affiliation: Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, London WC1N 1AX, United Kingdom.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pors
authors.forename: Zennia
authors.initials: Z
authors.lastname: Paniwnyk
authors.forename: Paul
authors.initials: P
authors.lastname: Teesdale-Spittle
authors.forename: Jane A
authors.initials: JA
authors.lastname: Plumb
authors.forename: Elaine
authors.initials: E
authors.lastname: Willmore
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Austin
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Patterson
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D000880:Anthraquinones / Q000627:therapeutic use*; D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C483940:Alchemix; D018943:Anthracyclines; D000880:Anthraquinones; D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D004247:DNA; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin