TY - JOUR T1 - Adva-27a, a Novel Podophyllotoxin Derivative Found to Be Effective against Multidrug Resistant Human Cancer Cells JF - Anticancer Research JO - Anticancer Res SP - 4423 LP - 4432 VL - 32 IS - 10 AU - ABDERRAZZAK MERZOUKI AU - MICHAEL D. BUSCHMANN AU - MYRIAM JEAN AU - REBECCA S. YOUNG AU - SI LIAO AU - SUSANNAH GAL AU - ZUOMEI LI AU - STEVE N. SLILATY Y1 - 2012/10/01 UR - http://ar.iiarjournals.org/content/32/10/4423.abstract N2 - 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. ER -