Multidrug resistance genes in infant acute lymphoblastic leukemia: Ara-C is not a substrate for the breast cancer resistance protein

Stam, Ronald W.; Heuvel‐Eibrink, Marry M. van den; Boer, Monique L. den; Ebus, Marli E.; Janka‐Schaub, Gritta; Allen, John D.; Pieters, Rob

doi:10.1038/sj.leu.2403168

Cited by 50 publications

(33 citation statements)

References 28 publications

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“…As in AML, high ABCG2 expression has been correlated with resistance to the cytotoxic agent cytarabine, a non-ABCG2 substrate (Stam et al, 2004). Many common drugs used to treat ALL are not ABCG2 substrates, but this latter observation suggests that in both AML and ALL, ABCG2 expression may be a marker of resistance, as opposed to a mechanism that is Steinbach et al, 2002 59 Untreated AML, 9 relapse samples Median ABCG more than 10Â higher in patients who did not achieve remission compared with responders.…”

Section: Significance Of Abcg2 In Cancermentioning

confidence: 99%

Molecular Pharmacology of ABCG2 and Its Role in Chemoresistance

2013

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Section: Significance Of Abcg2 In Cancermentioning

confidence: 99%

Molecular Pharmacology of ABCG2 and Its Role in Chemoresistance

2013

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“…In preclinical studies, Symadex has shown cytotoxic activity apparently via several mechanisms of action. Whereas Hyzy et al (2005) showed that Symadex cytotoxicity is exerted through a prolonged G 2 arrest followed by mitotic catastrophe, recent reports reveal that Symadex is a potent and selective FLT3 receptor tyrosine kinase inhibitor (Stam et al, 2004;Goodman et al, 2008). Specifically, Symadex is currently undergoing phase II clinical trials as a novel anticancer drug, including colorectal cancer (Alami et al, 2007).…”

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Structural Determinants of Imidazoacridinones Facilitating Antitumor Activity Are Crucial for Substrate Recognition by ABCG2

Bram

Adar²,

Mesika³

et al. 2009

Mol Pharmacol

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Symadex is the lead acridine compound of a novel class of imidazoacridinones (IAs) currently undergoing phase II clinical trials for the treatment of various cancers. Recently, we have shown that Symadex is extruded by ABCG2-overexpressing lung cancer A549/K1.5 cells, thereby resulting in a marked resistance to certain IAs. To identify the IA residues essential for substrate recognition by ABCG2, we here explored the ability of ABCG2 to extrude and confer resistance to a series of 23 IAs differing at defined residue(s) surrounding their common 10-azaanthracene structure. Taking advantage of the inherent fluorescent properties of IAs, ABCG2-dependent efflux and drug resistance were determined in A549/K1.5 cells using flow cytometry in the presence or absence of fumitremorgin C, a specific ABCG2 transport inhibitor. We find that a hydroxyl group at one of the R1, R2, or R3 positions in the proximal IA ring was essential for ABCG2-mediated efflux and consequent IA resistance. Moreover, elongation of the common distal aliphatic side chain attenuated ABCG2-dependent efflux, thereby resulting in the retention of parental cell sensitivity. Hence, the current study offers novel molecular insight into the structural determinants that facilitate ABCG2-mediated drug efflux and consequent drug resistance using a unique platform of fluorescent IAs. Moreover, these results establish that the IA determinants mediating cytotoxicity are precisely those that facilitate ABCG2-dependent drug efflux and IA resistance. The possible clinical implications for the future design of novel acridines that overcome ABCG2-dependent multidrug resistance are discussed.

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“…They were cross-resistant to mitoxantrone, daunorubicin, doxorubicin, bisantrene, and topotecan. Daunorubicin was also shown to be a BCRP substrate in AML cells (14), and Ara-C was not a BCRP substrate in infant acute lymphoblastic leukemia (15). The specificity of BCRP binding to its substrate could be modified by changes in its amino acid sequence (16).…”

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MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia

Benderra

Faussat

Sayada

et al. 2005

Clinical Cancer Research

136

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Purpose: P-Glycoprotein (Pgp) is associated with poor outcome in acute myeloid leukemia (AML). We have investigated other ATP-binding cassette proteins such as BCRP, MRP1, MRP2, MRP3, and MRP5 for their potential implication in chemoresistance. Experimental Design and Results: Eighty five AML patient samples were analyzed in this study. First, MRP3 function was higher in patients which had a high level of leukocytes (P = 0.01), a M5 FAB subtype (P = 0.04), and an intermediate or poor cytogenesis (P = 0.05). BCRP activity was not correlated with clinical or biological variables, but high Pgp activity was correlated with the following variables: CD34 expression (P = 0.002), FAB subtype (P = 0.002), intermediate or poor cytogenesis (P = 0.02), and elderly patients (P = 0.03). Second, Pgp, MRP3, and BCRP activities were correlated with complete remission (P = 0.02, P = 0.04, and P = 0.04, respectively), disease-free survival (P = 0.02, P = 0.03, and P = 0.25, respectively), and overall survival (P = 0.04, P = 0.04, and P = 0.05, respectively) in multivariate analysis.The patient samples expressing one or none of these Pgp, MRP3, or BCRP functional proteins have a better prognosis than the patients expressing two or three of these functional proteins (complete remission, P = 0.02; disease-free survival, P = 0.01; overall survival, P < 0.001).Conclusions: BCRP and MRP3 may also be involved in chemoresistance in AML, especially MRP3 in patients with M5 FAB. Additional modulation of BCRP or MRP3 to Pgp modulation may be necessary in some patients in order to improve the treatment outcome.

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Multidrug resistance genes in infant acute lymphoblastic leukemia: Ara-C is not a substrate for the breast cancer resistance protein

Cited by 50 publications

References 28 publications

Molecular Pharmacology of ABCG2 and Its Role in Chemoresistance

Molecular Pharmacology of ABCG2 and Its Role in Chemoresistance

Structural Determinants of Imidazoacridinones Facilitating Antitumor Activity Are Crucial for Substrate Recognition by ABCG2

MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia

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