Navegando por Palavras-chave "ABCB1"

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    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
    (Spandidos Publ Ltd, 2014-04-01) Vivona, Douglas; Lima, Luciene Terezina; Rodrigues, Alice Cristina; Bueno, Carolina Tosin; Steinhorst Alcantara, Greyce Kelly; Ribeiro Barros, Luiza Saldanha; De Moraes Hungria, Vania Tiestsche; Chiattone, Carlos Sergio; Chauffaille, Maria de Lourdes Lopes Ferrari [UNIFESP]; Guerra-Shinohara, Elvira Maria; Universidade de São Paulo (USP); Santa Casa Med Sch; Universidade Federal de São Paulo (UNIFESP)
    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.
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    Association between ABCB1 Immunohistochemical Expression and Overall Survival in Gastric Cancer Patients
    (Asian Pacific Organization Cancer Prevention, 2014-01-01) Oliveira, Juliana de [UNIFESP]; Felipe, Aledson Vitor [UNIFESP]; Artigiani Neto, Ricardo [UNIFESP]; Oshima, Celina Tizuko Fujiyama [UNIFESP]; Silva, Marcelo de Souza [UNIFESP]; Forones, Nora Manoukian [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Gastric cancer (GC) is one of the most common malignancies worldwide. the ABCB1 protein, a member of the ATP-binding cassette (ABC) transporter family, encoded by the ABCB1 gene, considerably influences the distribution of drugs across cell membranes as well as multidrug resistance (MDR) of antineoplastic drugs. in contrast to the extensive knowledge on the pharmacological action of ABCB1 protein, the correlation between the clinical-pathological data and ABCB1 protein expression in patients with GC remains unclear. the aim was to investigate association between ABCB1 expression and overall survival in GC patients. Human tumor fragments from 57 GC patients were examined by immunohistochemistry assay. We observed lower survival rate of patients with GC who were positive for ABCB1 expression (p=0.030). Based on these observations, we conclude that GC patients with positive ABCB1 protein immunohistochemical expression in their tumors suffer shorter overall survival.
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    Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients
    (Frontiers Media Sa, 2018) Tavares, Leticia C.; Marcatto, Leiliane R.; Soares, Renata A. G.; Krieger, Jose Eduardo [UNIFESP]; Pereira, Alexandre C.; Santos, Paulo C. J. L. [UNIFESP]
    The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan((R)) genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309)
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    Establishment and Partial Characterization of an Epirubicin-Resistant Gastric Cancer Cell Line with Upregulated ABCB1
    (Asian Pacific Organization Cancer Prevention, 2014-01-01) Felipe, Aledson Vitor [UNIFESP]; Moraes, Andrea Aparecida Fátima Souza [UNIFESP]; Oliveira, Juliana de [UNIFESP]; Silva, Tiago Donizetti da [UNIFESP]; Forones, Nora Manoukian [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Univ Nove de Julho
    Multidrug resistance (MDR) is a major impediment to successful chemotherapy of gastric cancer. Our aim was to establish an epirubicin-resistant cell subline (AGS/EPI) and to elucidate the mechanisms involved in acquired EPI resistance. the AGS/EPI cell subline developed by exposing parental AGS cells to stepwise increasing concentrations of EPI demonstrated 2.52-fold resistance relative to the AGS cell line, and mRNA expression of the ATP-dependent drug-efflux pump P-glycoprotein (Pgp), more recently known as ABCB1 protein, was similarly upregulated. An AGS/EPI cell subline could thus be effectively established, and MDR mechanism of these cells was shown to be related to the overexpression of mRNA of the ABCB1 gene.
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    Estudo de associação entre polimorfismos dos genes ERCC1 e ABCB1 e nefro-hepatotoxicidade à quimioterapia com Paclitaxel/Carboplatina em pacientes com câncer ginecológico
    (Universidade Federal de São Paulo (UNIFESP), 2020-03-05) Costa Junior, Luiz Carlos Da [UNIFESP]; Santos, Paulo Caleb Junior De Lima [UNIFESP]; Vianna-Jorge, Rosane [UNIFESP]; http://lattes.cnpq.br/7806610722907256; http://lattes.cnpq.br/7270343730265469; http://lattes.cnpq.br/1669800539285831; Universidade Federal de São Paulo
    Background: Paclitaxel/carboplatin combination is the standard chemotherapeutic protocol for gynecological cancers, but severe toxicities such as nephro and hepatotoxicity may compromise treatment. There is great interindividual variability regarding the incidence and severity of toxicities, which may be accounted to single nucleotide polymorphisms (SNPs) affecting drug transport or cellular sensitivity. Objective: To evaluate the impact of selected SNPs in ERCC1 and ABCB1 genes on the incidence of nephro- and hepatotoxicity in patients with gynecological cancer treated with paclitaxel/carboplatin. Methods: A cohort of 507 gynecological cancer patients receiving paclitaxel/carboplatin from the Brazilian National Cancer Institute (INCA-Brazil). Clinical data were obtained during routine consults or at electronic medical records. Hepatic and renal toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Genotyping was performed using real-time PCR. Results: ABCB1 c.1236C>T was associated with moderate to severe (grades 2- 4) nephrotoxicity (OR: 2.40; 95% CI 1.39–4.15), whereas ERCC1 c.118C>T was associated with moderate to severe hepatotoxicity (OR 3.71; 95% CI 1.08– 12.77). Conclusions: ABCB1 c.1236C>T and ERCC1 c.118C>T can be potential biomarkers for the risk of nephro- and hepatotoxicity to carboplatin/paclitaxel chemotherapy of gynecological cancers.
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    Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients
    (Lippincott Williams & Wilkins, 2016) Genvigir, Fabiana D. V.; Salgado, Patricia C.; Felipe, Claudia Rosso [UNIFESP]; Luo, Elena Y. F.; Alves, Camila; Cerda, Alvaro; Tedesco-Silva Junior, Hélio [UNIFESP]; Pestana, Jose Osmar Medina [UNIFESP]; Oliveira, Nagilla Ione de [UNIFESP]; Rodrigues, Alice C.; Doi, Sonia Q.; Hirata, Mario H.; Hirata, Rosario D. C.
    BackgroundPolymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.ObjectiveThe aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.Material and methodsBrazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.ResultsFrequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).ConclusionThe results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.
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    Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients
    (Future Medicine Ltd, 2011-09-01) Santoro, Ana; Felipe, Claudia Rosso [UNIFESP]; Tedesco-Silva, Helio [UNIFESP]; Medina-Pestana, Jose O. [UNIFESP]; Struchiner, Claudio J.; Ojopi, Elida B.; Suarez-Kurtz, Guilherme; Inst Nacl Canc; Universidade Federal de São Paulo (UNIFESP); Fundacao Oswaldo Cruz; Universidade de São Paulo (USP)
    Aim: Polymorphisms in the CYP3A5 and ABCB1 genes have been investigated as modulators of the pharmacokinetics and clinical effects of cyclosporine (CSA) and tacrolimus (TAC) in European, North American and Asian populations, with controversial results. the extensive variation in worldwide frequency distribution of CYP3A5 and ABCB1 polymorphisms is a caveat against the extrapolation of these data to the heterogeneous and admixed Brazilian population. We investigated the effect of CYP3A5 and ABCB1 polymorphisms on CSA and TAC dose-adjusted trough concentration (C(0)/dose) in Brazilian renal transplant recipients, during the first 3 months post-transplantation. Materials & methods: Patients receiving CSA (n = 150) or TAC (n = 151) were genotyped for CYP3A5(star)3 (rs776746, 6986A>G), (star)6(rs10264272, 14690G>A) and (star) 7 (rs41303343, 27131-27132insT) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. We explored the effects of CYP3A5 and ABCB1 polymorphisms, clinical and demographical characteristics on CSA and TAC C(0)/dose under a two-step data ana-lysis strategy by fitting a longitudinal mixed-effects model to the data; first to select the important covariates under a univariate setting and then to fit the final multivariate model. Results: C(0)/dose of TAC was associated with the number of CYP3A5-defective alleles, in a gene-dose manner, throughout the observation period, whereas C0/dose of CSA was associated with body surface area and prednisone dosing. No other significant associations were detected. Conclusion: Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5(star)3, (star)6 and (star)7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials. Original submitted 5 April 2011; Revision submitted 4 May 2011