Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors

Molecular Cancer Therapeutics
Laetitia MarziY Pommier

Abstract

Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135), and NSC 779134 (LMP134). We tested the induction and stability of TOP1 cleavage complexes (TOP1cc), and the induction and persistence of DNA damage measured by histone H2AX phosphorylation (γH2AX) compared with their parent compounds LMP744 and LMP776 in leukemia CCRF-CEM and colon carcinoma HCT116 cells. The fluoroindenoisoquinolines induced TOP1cc and γH2AX at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. The fluoroindenoisoquinoline LMP135 showed greater antitumor activity than topotecan in small-cell lung cancer cell H82 xenografts. It was also more potent than topotecan in the NCI-60 cancer cell line panel. Bioinformatics tools (http://discover.nci.nih.gov/cellm...Continue Reading

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Citations

Feb 23, 2020·Science Translational Medicine·Florence CoussyElisabetta Marangoni
Nov 28, 2019·Oxidative Medicine and Cellular Longevity·Cristiano TrindadeJoão A P Henriques
Oct 12, 2019·F1000Research·Mary-Ann Bjornsti, Scott H Kaufmann
May 21, 2020·Molecular Cancer Therapeutics·Laetitia MarziYves Pommier
Apr 1, 2021·British Journal of Cancer·Tsuyoshi TakashimaWataru Yasui

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