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Molecular Pharmacology

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Abstract

Podophyllotoxin analogs: effects on DNA topoisomerase II, tubulin polymerization, human tumor KB cells, and their VP-16-resistant variants.

S Y Liu, B D Hwang, M Haruna, Y Imakura, K H Lee and Y C Cheng
Molecular Pharmacology July 1989, 36 (1) 78-82;
S Y Liu
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B D Hwang
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M Haruna
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Y Imakura
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K H Lee
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Y C Cheng
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Abstract

Several derivatives of podophyllotoxin with modifications at the C-4 position of ring C, in addition to demethylation at the C-4' position of ring E, were examined for inhibitory activity against DNA topoisomerase II and tubulin polymerization, generation of protein-linked DNA breaks, and cytotoxicity against KB cells and VP-16-resistant KB variants. Substitution of podophyllotoxin with a group in the beta configuration at the C-4 position of ring C resulted in compounds with greater inhibitory activity against DNA topoisomerase II and lower inhibitory activity against tubulin polymerization than those with an alpha configuration. These active analogs exhibited the same mechanism of DNA topoisomerase II inhibition as the epipodophyllotoxin derivative VP-16, which causes protein-linked DNA breaks in vitro as well as in cells. Two analogs selectively inhibited DNA topoisomerases II to a greater extent than tubulin polymerization. These analogs were cytotoxic towards KB cells in addition to VP-16-resistant KB cell lines, which indicated limited cross-resistance with VP-16 in VP-16-resistant KB variants.

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Molecular Pharmacology
Vol. 36, Issue 1
1 Jul 1989
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Abstract

Podophyllotoxin analogs: effects on DNA topoisomerase II, tubulin polymerization, human tumor KB cells, and their VP-16-resistant variants.

S Y Liu, B D Hwang, M Haruna, Y Imakura, K H Lee and Y C Cheng
Molecular Pharmacology July 1, 1989, 36 (1) 78-82;

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Abstract

Podophyllotoxin analogs: effects on DNA topoisomerase II, tubulin polymerization, human tumor KB cells, and their VP-16-resistant variants.

S Y Liu, B D Hwang, M Haruna, Y Imakura, K H Lee and Y C Cheng
Molecular Pharmacology July 1, 1989, 36 (1) 78-82;
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