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Differential expression of ABCB1 and SLC22A1 genes and their relationship with response markers to imatinib mesylate in patients with chronic myeloid leukemia

Grant number: 11/06253-2
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2011
Effective date (End): February 28, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Elvira Maria Guerra Shinohara
Grantee:Douglas Vivona
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Chronic myeloid leukemia (CML) is a clonal expansion of the hematopoietic progenitor cell, representing myeloid hyperplasia, leukocytosis, neutrophilia, basophilia and splenomegaly. The Philadelphia chromosome is peculiar on the disease, being the result of the translocation t(9; 22) (q34; q11), leading on the fusion of the ABL and BCR genes. This merger creates a hybrid gene that produces a protein with high activity of tyrosine kinase that is the main pathogenesis of CML. The Imatinib mesylate (IM) is a fenilaminopirimidine derivative which inhibits the ABL protein-tyrosine kinase in vitro and in vivo. MI interacts with membrane transporters efflux, as the ATP binding cassette B1 (ABCB1, MDR1) and ATP binding cassette G2 (MXR, BCRP) and influx, such as Organic cation transporter 1 (hOCT1). This study aims to investigate the relationship of gene expression of ABCB1 and SLC22A1 with response markers to treatment with MI in individuals with CML, and determine the predisposing factors of response to MI.118 patients with CML were included and divided in two groups. Group 1: 70 patients with complete cytogenetic response and a standard dose of IM (400 mg / day IM) for up to 18 months. Group 2: 48 patients without a complete cytogenetic response and initial dose of 400 mg / day IM or whith response lost throughout the treatment. Blood samples were obtained for: quantification of BCR-ABL1, total RNA extraction and band G cytogenetic analysis. Total RNA will be used to evaluate the number of BCR-ABL1 transcripts by RT-PCR and for assessment of gene expression and by real time PCR. Response to treatment will be evaluated according to criteria of the European LeukemiaNet. The result of this study is expected to contribute to a better understanding of the mechanisms that lead to variability in response to MI in patients with CML, by combining the values of gene expression of ABCB1 and SLC22A1 as markers of response to treatment, thereby elucidating the pharmacokinetic possible causes that still remain unclear in patients that not responding to standard dose IM (400 mg / day).

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