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

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

Author Vivona, Douglas Google Scholar
Lima, Luciene Terezina Google Scholar
Rodrigues, Alice Cristina Google Scholar
Bueno, Carolina Tosin Google Scholar
Steinhorst Alcantara, Greyce Kelly Google Scholar
Ribeiro Barros, Luiza Saldanha Google Scholar
De Moraes Hungria, Vania Tiestsche Google Scholar
Chiattone, Carlos Sergio Google Scholar
Chauffaille, Maria de Lourdes Lopes Ferrari Autor UNIFESP Google Scholar
Guerra-Shinohara, Elvira Maria Google Scholar
Institution Universidade de São Paulo (USP)
Santa Casa Med Sch
Universidade Federal de São Paulo (UNIFESP)
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 mu g/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.
Keywords ABCB1
imatinib mesylate
chronic myeloid leukemia
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
National Council for Scientific and Technological Development, Brazil
Grant number FAPESP: 09/54184-0
Date 2014-04-01
Published in Oncology Letters. Athens: Spandidos Publ Ltd, v. 7, n. 4, p. 1313-1319, 2014.
ISSN 1792-1074 (Sherpa/Romeo, impact factor)
Publisher Spandidos Publ Ltd
Extent 1313-1319
Origin http://dx.doi.org/10.3892/ol.2014.1857
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000334311900076
URI http://repositorio.unifesp.br/handle/11600/37583

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