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Inhibition of Type II Topoisomerase by Fostriecin

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Date 1988 Nov 1
PMID 2847752
Citations 15
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Abstract

Fostriecin is a new antitumor antibiotic which is being developed further as an anticancer agent based on its marked activity in murine leukemias. Its mechanism of action, however, has thus far remained unknown. The present study demonstrates that fostriecin inhibits the catalytic activity of partially purified type II topoisomerase from Ehrlich ascites carcinoma. Under the experimental conditions employed, fostriecin completely inhibited the enzyme at 100 microM. A general kinetic analysis showed that fostriecin inhibited topoisomerase in an uncompetitive manner with a Ki,app of 110 microM and produced kinetics that were distinctly different from those of VM-26 which exhibited noncompetitive inhibition. Fostriecin did not cause DNA strand breaks in L1210 cells, suggesting that it did not stabilize a cleavable complex as do other known inhibitors of this enzyme. Fostriecin, however, did partially inhibit DNA strand breaks produced by amsacrine. An analysis by flow cytometry showed that L1210 cells exposed to 5 microM fostriecin for 12 hr caused a block in the G2 phase of the cell cycle. These studies thus suggest that the mechanism by which fostriecin produces its antitumor effects may be through inhibition of topoisomerase II and that the type of inhibition is markedly different from existing antitumor agents which inhibit this enzyme.

Citing Articles

Total and Formal Syntheses of Fostriecin.

Dong G, Li B, ODoherty G Org Chem Front. 2020; 7(22):3608-3615.

PMID: 33184589 PMC: 7654735. DOI: 10.1039/d0qo01121e.


Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products.

Trost B, Knopf J, Brindle C Chem Rev. 2016; 116(24):15035-15088.

PMID: 28027648 PMC: 5720176. DOI: 10.1021/acs.chemrev.6b00488.


Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death.

Theobald B, Bonness K, Musiyenko A, Andrews J, Urban G, Huang X Mol Cancer Res. 2013; 11(8):845-55.

PMID: 23671329 PMC: 3748177. DOI: 10.1158/1541-7786.MCR-13-0032.


Phase I and pharmacokinetic study of fostriecin given as an intravenous bolus daily for five consecutive days.

Le L, Erlichman C, Pillon L, Thiessen J, Day A, Wainman N Invest New Drugs. 2004; 22(2):159-67.

PMID: 14739664 DOI: 10.1023/B:DRUG.0000011792.13160.b0.


Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin.

de Jong R, Mulder N, Uges D, Sleijfer D, Hoppener F, Groen H Br J Cancer. 1999; 79(5-6):882-7.

PMID: 10070885 PMC: 2362650. DOI: 10.1038/sj.bjc.6690141.