ABCB1 haplotypes are associated with P‑gp activity and affect a major molecular response in chronic myeloid leukemia patients treated with a standard dose of imatinib

Vivona,Douglas; Lima,Luciene Terezina; Rodrigues,Alice Cristina; Bueno,Carolina Tosin; Alcantara,Greyce Kelly Steinhorst; Barros,Luiza Saldanha Ribeiro; Hungria,Vania Tiestsche De Moraes; Chiattone,Carlos Sérgio; Chauffaille,Maria De Lourdes Lopes Ferrari; Guerra‑Shinohara,Elvira Maria

doi:10.3892/ol.2014.1857

ABCB1 haplotypes are associated with P‑gp activity and affect a major molecular response in chronic myeloid leukemia patients treated with a standard dose of imatinib

Authors:
- Douglas Vivona
- Luciene Terezina Lima
- Alice Cristina Rodrigues
- Carolina Tosin Bueno
- Greyce Kelly Steinhorst Alcantara
- Luiza Saldanha Ribeiro Barros
- Vania Tiestsche De Moraes Hungria
- Carlos Sérgio Chiattone
- Maria De Lourdes Lopes Ferrari Chauffaille
- Elvira Maria Guerra‑Shinohara
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Affiliations: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Science, University of São Paulo, São Paulo 05508‑900, Brazil, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo 05508‑900, Brazil, Department of Clinical, Toxicological and Bromatological Analyses, Faculty of Pharmaceutical Science, University of São Paulo, Ribeirão Preto 14040‑903, Brazil, Department of Hematology and Hemotherapy, Santa Casa Medical School, São Paulo 01223-001, Brazil, Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo 04023-900, Brazil
Published online on: February 7, 2014 https://doi.org/10.3892/ol.2014.1857
Pages: 1313-1319

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Abstract

Despite the high efficacy of imatinib mesylate (IM) treatment for chronic myeloid leukemia (CML) patients, some individuals develop resistance due to impaired bioavailability. It has been previously demonstrated that the haplotypes for ATP‑binding cassette subfamily B member 1 (ABCB1)with c.1236C>T, c.3435C>T and c.2677G>T/A polymorphisms markedly affect the secondary structure of ABCB1 mRNA and its activity. These modifications may affect efflux transporter activity and response to treatment with IM. The aim of the present study was to investigate the influence of ABCB1 haplotypes on P‑glycoprotein (P‑gp) activity, IM plasma levels and IM response. In total, 28 chronic‑phase CML patients treated with a standard dose of IM (400 mg/day) were studied. The patients were selected according to the haplotypes of ABCB1, with c.1236C>T, c.3435C>T and c.2677G>T polymorphisms, and were classified into two groups based on the presence of the mutated allele in each genotype for the three ABCB1 polymorphisms. In addition, expression of P‑gp and breakpoint cluster region‑abelson 1 (BCR‑ABL1), ABCB1 and solute carrier family 22 member 1 (SLC22A1) mRNA were evaluated. The P‑gp activity in the wild‑type group was found to be higher than that in the mutated group (59.1 vs. 38.3%; P=0.001). Furthermore, the patients who did not achieve major molecular response (MMR) showed a higher rate of efflux mediated by P‑gp when compared with individuals who achieved MMR (64.7 vs. 45.7%; P=0.001). All patients without MMR demonstrated effluxes of >60%. In addition, patients without MMR exhibited lower plasma concentrations of IM compared with those with MMR (0.51 vs. 1.42 µg/ml; P=0.001). Higher levels of SLC22A1 mRNA were observed in patients who achieved MMR and complete molecular response (P<0.05). In conclusion, the ABCB1 1236CT/3435CT/2677GT and 1236TT/3435TT/2677TT haplotypes are associated with reduced P‑gp activity and MMR in chronic‑phase CML patients treated with a standard dose of IM.

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