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


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.


CONCLUSIONS
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.
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
Abderrazzak
A
Merzouki
Michael D
MD
Buschmann
Myriam
M
Jean
Rebecca S
RS
Young
Si
S
Liao
Susannah
S
Gal
Zuomei
Z
Li
Steve N
SN
Slilaty
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D017611:Fluorine Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D006027:Glycosides; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009005:Monosaccharides / Q000737:chemistry / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000201:enzymology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
C577284:Adva-27a podophyllotoxin; D000970:Antineoplastic Agents; C438934:C-glycoside; D017611:Fluorine Compounds; D006027:Glycosides; D009005:Monosaccharides; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011034:Podophyllotoxin