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1.
Pharmacogenet Genomics ; 25(12): 573-83, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26352872

RESUMO

OBJECTIVE: Irinotecan is a cytotoxic agent used widely for the treatment of solid tumors, particularly for metastatic colorectal cancers. Treatment with this drug frequently results in severe neutropenia and diarrhea that can markedly impact the course of treatment and patients' quality of life. Pharmacogenomic tailoring of irinotecan-based chemotherapy has been the subject of several investigations, but with limited data on ATP-binding cassette (ABC) and solute carrier (SLC) transporter genes. MATERIALS AND METHODS: In this study, we aimed to discover toxicity-associated markers in seven transporter genes participating in irinotecan pharmacokinetics involving the ABC transporter genes ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, and ABCG2 and the solute carrier organic anion transporter gene SLCO1B1 and using a haplotype-tagging single-nucleotide polymorphisms (n=210 htSNPs) strategy. The profiles of 167 metastatic colorectal cancer Canadian patients treated with FOLFIRI-based regimens were examined and the findings were replicated in an independent cohort of 250 Italian patients. RESULTS: In combined cohorts, a two-marker ABCC5 rs3749438 and rs10937158 haplotype (T-C) predicted lower risk of severe diarrhea [odds ratio (OR) of 0.43; P=0.001]. The co-occurrence of ABCG1 rs225440T and ABCC5 rs2292997A predicted the risk of severe neutropenia (OR=5.93; P=0.0002), which was further improved when incorporating the well-known risk marker UGT1A1*28 rs8175347 (OR=7.68; P<0.0001). In contrast, carriers of one protective marker (UGT1 rs11563250G) but none of these risk alleles experienced significantly less severe neutropenia (8.2 vs. 34.0%; P<0.0001). CONCLUSION: This combination of predictive genetic markers could potentially lead to better risk assessment and may thus improve personalized treatment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos Fitogênicos/toxicidade , Camptotecina/análogos & derivados , Neoplasias Colorretais/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Camptotecina/toxicidade , Neoplasias Colorretais/tratamento farmacológico , Diarreia/induzido quimicamente , Diarreia/genética , Feminino , Marcadores Genéticos/genética , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Neutropenia/induzido quimicamente , Neutropenia/genética , Estudos Prospectivos
2.
J Pharmacol Exp Ther ; 345(1): 95-101, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23386248

RESUMO

Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate markers across the gene (n = 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3'untranscribed region (3'UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) = 2.43; P = 0.004]. The inclusion of a 3'UTR single-nucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR = 0.55; P = 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3'UTR SNP allowed the identification of a protective HI (OR = 0.50; P = 0.048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P ≤ 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias Colorretais/genética , Glucuronosiltransferase/genética , Haplótipos , Neutropenia/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/toxicidade , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Fluoruracila/toxicidade , Marcadores Genéticos , Humanos , Irinotecano , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/toxicidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutropenia/genética , Estudos Prospectivos , Índice de Gravidade de Doença
3.
BMC Cancer ; 4: 11, 2004 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-15040806

RESUMO

BACKGROUND: Fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluoro-2'deoxyuridine (FUDR) are among the most effective chemotherapeutic agents for treatment of metastatic colorectal cancer (CRC). Increased expression of thymidylate synthetase (TS) in CRC metastases has been proposed to be an important mechanism of resistance to fluoropyrimidine-based chemotherapy. METHODS: The present study investigated whether TS mRNA levels in liver metastases of 20 CRC patients before treatment with FUDR by hepatic arterial infusion (HAI) correlated with frequency of clinical response or survival duration. RESULTS: Median survival duration of patients with TS mRNA levels above and below the median was 15 and 18 months, respectively (p > 0.05). Clinical response was achieved in 40% of patients with low TS mRNA levels, but in only 20% of patients with high TS mRNA levels (p = 0.01). TS mRNA levels were also measured for liver metastases of 7 of the patients that did not achieve a clinical response. A statistically significant increase in expression of TS mRNA was observed for liver metastases resistant to chemotherapy (21 +/- 14) in comparison to liver metastases of the same patients before chemotherapy (8 +/- 4) (p = 0.03). CONCLUSION: This is the first report to demonstrate increased TS expression in liver metastases from CRC patients resistant to fluoropyrimidine based chemotherapy. These findings are consistent with previous studies indicating that increased TS expression is associated with resistance to fluoropyrimidine-based chemotherapy.


Assuntos
Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas , Proteínas de Neoplasias/análise , Timidilato Sintase/análise , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Feminino , Floxuridina/administração & dosagem , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise
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