Amonafide, a topoisomerase II inhibitor, is unaffected by P-glycoprotein-mediated efflux.
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.
Chau
Mydoanh
M
Xanthus Pharmaceuticals, Inc., 300 Technology Square, Cambridge, MA 02139, United States.
Christensen
Jennifer L
JL
Ajami
Alfred M
AM
Capizzi
Robert L
RL
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