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

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dc.contributor.authorVivona, Douglas
dc.contributor.authorLima, Luciene Terezina
dc.contributor.authorRodrigues, Alice Cristina
dc.contributor.authorBueno, Carolina Tosin
dc.contributor.authorSteinhorst Alcantara, Greyce Kelly
dc.contributor.authorRibeiro Barros, Luiza Saldanha
dc.contributor.authorDe Moraes Hungria, Vania Tiestsche
dc.contributor.authorChiattone, Carlos Sergio
dc.contributor.authorChauffaille, Maria de Lourdes Lopes Ferrari [UNIFESP]
dc.contributor.authorGuerra-Shinohara, Elvira Maria
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionSanta Casa Med Sch
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2016-01-24T14:35:29Z
dc.date.available2016-01-24T14:35:29Z
dc.date.issued2014-04-01
dc.description.abstractDespite 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.en
dc.description.affiliationUniv São Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508900 São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Fac Pharmaceut Sci, Dept Clin Toxicol & Bromatol Anal, BR-14040903 Ribeirao Preto, Brazil
dc.description.affiliationSanta Casa Med Sch, Dept Hematol & Hemotherapy, BR-01223001 São Paulo, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Clin & Expt Oncol, BR-04023900 São Paulo, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Clin & Expt Oncol, BR-04023900 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipNational Council for Scientific and Technological Development, Brazil
dc.description.sponsorshipIDFAPESP: 09/54184-0
dc.format.extent1313-1319
dc.identifierhttp://dx.doi.org/10.3892/ol.2014.1857
dc.identifier.citationOncology Letters. Athens: Spandidos Publ Ltd, v. 7, n. 4, p. 1313-1319, 2014.
dc.identifier.doi10.3892/ol.2014.1857
dc.identifier.issn1792-1074
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/37583
dc.identifier.wosWOS:000334311900076
dc.language.isoeng
dc.publisherSpandidos Publ Ltd
dc.relation.ispartofOncology Letters
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectABCB1en
dc.subjectimatinib mesylateen
dc.subjectchronic myeloid leukemiaen
dc.titleABCB1 haplotypes are associated with P-gp activity and affect a major molecular response in chronic myeloid leukemia patients treated with a standard dose of imatiniben
dc.typeinfo:eu-repo/semantics/article
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