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: Mydoanh Chau, Jennifer L Christensen, Alfred M Ajami, Robert L Capizzi
• Journal: Leukemia research (Leuk Res) Vol. 32 Issue 3 Pg. 465-73 (Mar 2008) ISSN: 0145-2126 [Print] England
• PMID: 17826829 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Enzyme Inhibitors
• Imides
• Isoquinolines
• Naphthalimides
• Organophosphonates
• Topoisomerase II Inhibitors
• amonafide
• Adenine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism, pharmacology)
• Adenine
• Animals
• Cell Line, Tumor
• Drug Resistance, Multiple
• Enzyme Inhibitors (pharmacology)
• Humans
• Imides (pharmacology)
• Isoquinolines (pharmacology)
• Mice
• Naphthalimides (pharmacology)
• Organophosphonates
• Topoisomerase II Inhibitors