title: Effect of 4 beta-arylamino derivatives of 4'-O-demethylepipodophyllotoxin on human DNA topoisomerase II, tubulin polymerization, KB cells, and their resistant variants.
abstract: Six 4 beta-arylamino derivatives of 4'-O-demethylepipodophyllotoxin were examined for inhibitory activity against human DNA topoisomerase II and tubulin polymerization, their ability to generate protein-linked DNA breaks in cells, and their cytotoxicity toward the KB cell line and its VP-16- and vincristine-resistant variants. Five of these derivatives were 5- to 10-fold more potent than VP-16 as inhibitors of DNA topoisomerase II in vitro, and all of these derivatives could generate the same amount of or more protein-linked DNA breaks in cells than VP-16 at 1-20 microMs. Tubulin polymerization was inhibited by these compounds to different degrees in the order: podophyllotoxin greater than W73 greater than W87 greater than NPF greater than NPC greater than W68 greater than W38 greater than VP-16. These analogues were cytotoxic not only to KB cells but also to their VP-16-resistant and vincristine-resistant variants which showed decreased cellular uptake of VP-16 and a decrease in DNA topoisomerase II content or overexpression of MDR1 phenotype. These characteristics may cause these derivatives to have different spectrums of antitumor activity.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: J Y
authors.initials: JY
authors.lastname: Chang
authors.forename: F S
authors.initials: FS
authors.lastname: Han
authors.forename: S Y
authors.initials: SY
authors.lastname: Liu
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Wang
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D004249:DNA Damage; D004351:Drug Resistance; D005047:Etoposide / Q000737:chemistry / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D059005:Topoisomerase II Inhibitors; D014404:Tubulin; D005047:Etoposide; D011034:Podophyllotoxin