title: Amonafide, a topoisomerase II inhibitor, is unaffected by P-glycoprotein-mediated efflux.
abstract: Over-expression of P-glycoprotein (Pgp+) has been related to resistance to classical Topo II inhibitors used in the treatment of AML and is common in patients with poor-prognosis, such as those with secondary AML (sAML). Since clinical trials with amonafide, a unique ATP-independent Topo II inhibitor, in combination with cytarabine, have shown significant efficacy for remission induction in patients with sAML, we compared the cytotoxic effect of amonafide (amonafide l-malate, Xanafide) to the classical Topo II inhibitors (daunorubicin, doxorubicin, idarubicin, etoposide, and mitoxantrone) in K562 leukemia cells and in the MDR subline, K562/DOX. Pgp expression was found to be approximately 6.5-fold greater in K562/DOX and causes the rapid efflux of these drugs from the leukemia cell. As a consequence, the LC(50) values for the classical Topo II inhibitor drugs tested were each increased up to 3 log units. A similar result was also observed in murine P388 and P388/ADR leukemia cells. Addition of cyclosporin A reversed K562/DOX resistance for the classical Topo II inhibitors, decreasing their LC(50) values to the levels observed with wild type cells but had no effect on amonafide potency in Pgp+ or wild type cells. Further examination of amonafide in bidirectional Caco-2 and MDR1-MDCK models confirmed that amonafide is neither a substrate nor inhibitor of Pgp. These observations suggest that amonafide is a promising therapeutic candidate directed toward bypassing this common mechanism of drug resistance encountered in the treatment of patients with AML, and possibly in other resistant hematological malignancies as well.
authors.affiliation: Xanthus Pharmaceuticals, Inc., 300 Technology Square, Cambridge, MA 02139, United States.
authors.forename: Mydoanh
authors.initials: M
authors.lastname: Chau
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Christensen
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Ajami
authors.forename: Robert L
authors.initials: RL
authors.lastname: Capizzi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000494:pharmacology; D000225:Adenine; D000818:Animals; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007094:Imides / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D053644:Naphthalimides / Q000494:pharmacology*; D063065:Organophosphonates; D059005:Topoisomerase II Inhibitors