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Anticancer Res. 2012 Oct;32(10):4423-32.

Adva-27a, a novel podophyllotoxin derivative found to be effective against multidrug resistant human cancer cells.

Author information

1
Department of Chemical Engineering, École Polytechnique, Institute of Biomedical Engineering, PO Box 6079, Station Centre-ville, Montréal, Québec, Canada H3C 3A7. abderrazzak.merzouki@polymtl.ca

Abstract

BACKGROUND/AIM:

Multidrug resistance poses a serious challenge in cancer therapy. To address this problem, we designed and synthesized Adva-27a, a novel non-ester GEM-difluorinated C-glycoside derivative of podophyllotoxin.

MATERIALS AND METHODS:

Adva-27a activity was evaluated in a variety of assays including inhibition of topoisomerase IIα, cytotoxic activity in drug-sensitive and drug-resistant cancer cell lines, metabolic stability in human liver microsomes and pharmacokinetic properties in rats.

RESULTS:

Adva-27a exhibited dose-dependent human topoisomerase IIα inhibitory activity and dose-dependent growth inhibitory activity in several drug-sensitive and two multidrug-resistant cancer cell lines. In the multidrug-resistant cell lines, MCF-7/MDR (breast cancer) and H69AR (small-cell lung cancer), Adva-27a was significantly more potent than etoposide. The metabolic stability of Adva-27a in human liver microsomes and its pharmacokinetic properties in rats were better than those of etoposide.

CONCLUSION:

Our studies have identified Adva-27a as a novel topoisomerase II inhibitor with superior cytotoxic activity against multidrug-resistant human cancer cells and more desirable pharmacokinetic properties than etoposide.

PMID:
23060568
[Indexed for MEDLINE]
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