Rol del polimorfismo del gen MDR-1 de resistencia múltiple a drogas en la evolución y respuesta al tratamiento con inhibidores de tirosina kinasa en leucemia mieloide crónica en Argentina
The chronic myeloid leukemia (CML) is characterized by the activation of the tyrosine kinase (TK) BCR-ABL. Such TK (ITKs) inhibitors, are the therapy of choice for CML, but 20% of the patients develop resistance ITKs, by amplification, mutations of BCR-ABL, or overexpression of the gene MDR-1 (P-gp)...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2016
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_1324 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_1324.dir/1324.PDF |
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| Sumario: | The chronic myeloid leukemia (CML) is characterized by the activation of the tyrosine kinase (TK) BCR-ABL. Such TK (ITKs) inhibitors, are the therapy of choice for CML, but 20% of the patients develop resistance ITKs, by amplification, mutations of BCR-ABL, or overexpression of the gene MDR-1 (P-gp). We studied the resistance to Imatinib in K562 cells (BCR-ABL-positive), and verify whether polymorphisms (SNPs) in the gene MDR-1 (exons 12, 21 and 26), play a predictive role of evolution and/or therapeutic response in CML. Against Imatinib cell growth with and without inhibitor of P-gp was tested. We studied the SNPs in 24 patients CML (chronic phase 22 and 2 blast crisis) and 25 controls. Therapeutic responses according to the haplotypes and administered treatments were evaluated. The K562 line, above expressed P-gp, and reversed the CyA (81%) resistance to Imatinib. 16 haplotypes were found variants-T, which were observed in controls (100%), and patients (75%) who achieved optimal molecular (93,75%) response. The haplotype exclusive wt in patients, showed lack of response in 4/6 cases (p < 0.001). Conclusions: 1 - the inhibition of P-gp increases the efficacy of Imatinib in vitro. 2 - the haplotype-wt, would serve as a marker for risk of CML, and/or poor prognosis of clinic-terapeutic evolution. |
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