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Effect of 4ß-Arylamino Derivatives of 4'-O-Demethylepipodophyllotoxin on Human DNA Topoisomerase II, Tubulin Polymerization, KB Cells, and Their Resistant Variants¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 [J-Y. C, F-S. H., S-Y. L, Y-C.C.], and School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599 [Z-Q. W., K-H. L.]

Six 4ß-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 derivatives to have different spectrums of antitumor activity.

¹ This study is supported by Grants CA44358 and CH370-C from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Dept. of Pharmacology, Yale University School of Medicine, Sterling Hall of Medicine, P. O. Box 3333, New Haven, CT 06510-8066.

Received 9/21/90. Accepted 1/15/91.

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