Amonafide, a topoisomerase II inhibitor, is unaffected by P-glycoprotein-mediated efflux
| Autor: | Jennifer L. Christensen, Robert L. Capizzi, MyDoanh Chau, Alfred M. Ajami |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Daunorubicin Organophosphonates Biology Pharmacology Imides Mice hemic and lymphatic diseases Cyclosporin a Cell Line Tumor polycyclic compounds medicine Idarubicin Animals Humans Topoisomerase II Inhibitors Doxorubicin ATP Binding Cassette Transporter Subfamily B Member 1 Enzyme Inhibitors Etoposide P-glycoprotein Mitoxantrone Adenine Amonafide Hematology Isoquinolines Drug Resistance Multiple Naphthalimides Oncology biology.protein medicine.drug |
| Zdroj: | Leukemia research. 32(3) |
| ISSN: | 0145-2126 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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