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

Autor(es)

Vivona, Douglas ^[1] ; Lima, Luciene Terezina ^[1] ; Rodrigues, Alice Cristina ^[2] ; Bueno, Carolina Tosin ^[1] ; Steinhorst Alcantara, Greyce Kelly ^[3] ; Ribeiro Barros, Luiza Saldanha ^[3] ; De Moraes Hungria, Vania Tiestsche ^[4] ; Chiattone, Carlos Sergio ^[4] ; Lopes Ferrari Chauffaille, Maria De Lourdes ^[5] ; Guerra-Shinohara, Elvira Maria ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin Toxicol & Bromatol Anal, BR-14040903 Ribeirao Preto - Brazil

^[4] Santa Casa Med Sch, Dept Hematol & Hemotherapy, BR-01223001 Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Clin & Expt Oncol, BR-04023900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Oncology Letters; v. 7, n. 4, p. 1313-1319, APR 2014.
• Citações Web of Science: 18

Resumo

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. (AU)

• Processo FAPESP: 09/54184-0 - Estudo da expressao de transportadores de membrana e sua relacao com marcadores de resposta ao mesilato de imatinibe em pacientes com leucemia mieloide cronica.
• Beneficiário: Elvira Maria Guerra Shinohara
• Modalidade de apoio: Auxílio à Pesquisa - Regular