Effect of 4β-Arylamino Derivatives of 4′-O-Demethylepipodophyllotoxin on Human DNA Topoisomerase II, Tubulin Polymerization, KB Cells, and Their Resistant Variants

Six 4β-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 μm. Tubulin polymerization was inhibited by these compounds to different degrees in the order: podophyllotoxin ≻ W73 ≻ W87 ≻ NPF ≻ NPC ≻ W68 ≻ W38 >≻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 spec-trums of antitumor activity.