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Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia

Leukemia volume 22, pages 2110–2115 (2008)Cite this article

Secondary acute myeloid leukemia (sAML; following a hematologic disorder such as antecedent myelodysplastic syndrome or therapy-related AML) responds poorly to treatment. P-glycoprotein (Pgp; multidrug resistance 1 (MDR1); ABCB1), an efflux pump for chemotherapy drugs used to treat AML including the topoisomerase 2 (topo 2) inhibitors daunorubicin, mitoxantrone, etoposide and, to a lesser extent, idarubicin is frequently overexpressed in de novo AML and sAML and is associated with treatment failure,1 as are other MDR proteins, including the ABC proteins multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2).2

Amonafide L-malate (Xanafide; Xanthus Pharmaceuticals Inc., Cambridge, MA, USA), the malate salt of the imide naphthalic acid derivative amonafide, a DNA intercalating agent and non-ATP-dependent topo 2 inhibitor, is currently undergoing phase III testing in sAML based on promising phase II activity.3, 4 Amonafide L-malate was found not to be a Pgp substrate in cell lines.5 Here, we studied transport of amonafide L-malate in cell lines overexpressing Pgp, MRP-1 and BCRP and in blasts from sAML patients, and cytotoxicity of amonafide L-malate and its active metabolite N-acetyl amonafide, in relation to other topo 2 inhibitors used in AML treatment.

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References

  1. Mahadevan D, List AF . Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. Blood 2004; 104: 1940–1951.

    Article  CAS  PubMed  Google Scholar 

  2. Steinbach D, Legrand O . ABC transporters and drug resistance in leukemia: was Pgp nothing but the first head of the Hydra? Leukemia 2007; 21: 1172–1176.

    Article  CAS  PubMed  Google Scholar 

  3. Allen SL, Kolitz JE, Lundberg AS, Capizzi RL, Budman DR . Clinical and cytogenetic responses to amonafide in secondary acute myeloid leukemia (AML). J Clin Oncol 2006; 24: 6584 (abstract).

    Google Scholar 

  4. Erba HP, Rizzieri DA, O'Donnell MR, Lundberg AS, Ajami AM, Rampersad AD et al. Amonafide and ara-C treatment for secondary acute myeloid leukemia (sAML). J Clin Oncol 2007; 25: 7065 (abstract).

    Google Scholar 

  5. Chau M, Christensen JL, Ajami AM, Capizzi RL . Amonafide, a topoisomerase II inhibitor, is unaffected by P-glycoprotein-mediated efflux. Leuk Res 2008; 32: 465–473.

    Article  CAS  PubMed  Google Scholar 

  6. Suvannasankha A, Minderman H, O'Loughlin KL, Nakanishi T, Greco WR, Ross DD et al. Breast cancer resistance protein in acute myeloid leukemia: discordance between expression and function. Leukemia 2004; 18: 1252–1257.

    Article  CAS  PubMed  Google Scholar 

  7. Qadir M, O'Loughlin KL, Fricke SM, Williamson NA, Greco WR, Minderman H et al. Cyclosporin A is a broad-spectrum multidrug resistance modulator. Clin Cancer Res 2005; 11: 2320–2326.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA

    M Burcu & M R Baer

  2. Laboratory of Flow Cytometry, Roswell Park Cancer Institute, Buffalo, NY, USA

    K L O'Loughlin & M R Baer

  3. Clinical Research Services, Roswell Park Cancer Institute, Buffalo, NY, USA

    L A Ford

Authors
  1. M Burcu
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  2. K L O'Loughlin
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  3. L A Ford
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  4. M R Baer
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Correspondence to M R Baer.

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Burcu, M., O'Loughlin, K., Ford, L. et al. Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia 22, 2110–2115 (2008). https://doi.org/10.1038/leu.2008.87

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