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REM sleep behavior disorder (RBD) is an early marker of Parkinson's disease (PD); however, it is still unclear which patients with RBD will eventually develop PD. Single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of alpha-synuclein (SNCA) have been associated with PD, but at present, no data is available about RBD. The 3'UTR hosts regulatory regions involved in gene expression control, such as microRNA binding sites. The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3'UTR in patients with "idiopathic" RBD (iRBD) and in patients with PD. We recruited 113 consecutive patients with a diagnosis of iRBD (56 patients) or PD (with or without RBD, 57 patients). Sequencing of SNCA-3'UTR was performed on genomic DNA extracted from peripheral blood samples. Bioinformatic analyses were carried out to predict the potential effect of the identified genetic variants on microRNA binding. We found three SNCA-3'UTR SNPs (rs356165, rs3857053, rs1045722) to be more frequent in PD patients than in iRBD patients (p = 0.014, 0.008, and 0.008, respectively). Four new or previously reported but not annotated specific genetic variants (KP876057, KP876056, NM_000345.3:c*860T>A, NM_000345.3:c*2320A>T) have been observed in the RBD population. The in silico approach highlighted that these variants could affect microRNA-mediated gene expression control. Our data show specific SNPs in the SNCA-3'UTR that may bear a risk for RBD to be associated with PD. Moreover, new genetic variants were identified in patients with iRBD.
Assuntos
Variação Genética/genética , Doença de Parkinson/genética , Transtorno do Comportamento do Sono REM/genética , alfa-Sinucleína/genética , Regiões 3' não Traduzidas , Idoso , Feminino , Expressão Gênica/genética , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Polimorfismo de Nucleotídeo Único/genética , Transtorno do Comportamento do Sono REM/etiologia , alfa-Sinucleína/metabolismoRESUMO
This study aimed to explore functional and regulatory polymorphisms and haplotypes at the HLA-G 3'UTR region in colorectal cancer development. The presence of nonpolymorphic variants was also evaluated. Three-hundred and eight patients with colorectal cancer and 294 healthy controls were analysed at the germinal level. We found an association with increased risk of colorectal cancer for +2960 14-bp INDEL, +3196 C>G SNPs and UTR-2 haplotype, and a 'protective' role for +3003 T>C, +3010 C>G polymorphisms and UTR-4 haplotype. We detected in 3 distinct patients, a novel nucleotide change (+3037 C>A) and 2 already described rare variants, +3032 G/C (EUR MAF = 0.1%) and +3092 G/T (EUR MAF = 0%). This is the first study showing associations between different polymorphisms in the HLA-G 3'UTR and colorectal cancer susceptibility.
Assuntos
Neoplasias Colorretais/genética , Estudos de Associação Genética , Antígenos HLA-G/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Alelos , Neoplasias Colorretais/patologia , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
The risk of severe irinotecan-induced neutropenia has been shown to be related to the UGT1 variant UGT1A1*28, which increases exposure to the potent metabolite SN-38. Our goal was to identify a novel UGT1 marker(s) using 28 haplotype-tagged single nucleotide polymorphisms genotyped by mass spectrometry. By characterizing the UGT1 sequence from a cohort of 167 Canadian metastatic colorectal cancer (mCRC) patients and a validation cohort of 250 Italian mCRC patients, we found rs11563250G, located in the intergenic region downstream of UGT1, to be significantly associated with reduced risk of severe neutropenia (odds ratio (OR)=0.21; P=0.043 and OR=0.27; P=0.036, respectively, and OR=0.31 when combined; P=0.001), which remained significant upon correction for multiple testing in the combined cohort (P=0.041). For the two-marker haplotype rs11563250G and UGT1A1*1 (rs8175347 TA6), the OR was of 0.17 (P=0.0004). Genetic testing of this marker may identify patients who might benefit from increased irinotecan dosing.
Assuntos
Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Glucuronosiltransferase/genética , Neutropenia/induzido quimicamente , Neutropenia/genética , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores Tumorais/genética , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Canadá , Feminino , Testes Genéticos/métodos , Haplótipos/genética , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131-1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P-value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Compostos Organoplatínicos/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Oxaliplatina , Prognóstico , Adulto JovemRESUMO
The discovery of pharmacogenomic markers in colorectal cancer (CRC) could be setting-specific. FOLFOX4 is employed in the adjuvant and metastatic setting in CRC. This prospective study is aimed to validate in the adjuvant setting the pharmacogenomic markers of toxicity reported in the metastatic setting (that is, GSTP1-rs947894, and -rs1138272; GSTM1-null genotype; AGXT-rs4426527, -rs34116584 and del-74 bp), and to discover additional markers. CRC patients (n=144) treated with adjuvant FOLFOX4 were genotyped for 57 polymorphisms in 29 genes. Grade ≥ 2 neurotoxicity was associated (false discovery rate-adjusted q-value <0.1) with single-nucleotide polymorphisms in ABCC1 (rs2074087: odds ratio=0.43(0.22-0.86)), and ABCC2 (rs3740066: 2.99(1.16-7.70); rs1885301: 3.06(1.35-6.92); rs4148396: 4.69(1.60-13.74); rs717620: 14.39(1.63-127.02)). hMSH6-rs3136228 was associated with grade 3-4 neutropenia (3.23(1.38-7.57), q-value=0.0937). XRCC3-rs1799794 was associated with grade 3-4 non-hematological toxicity (8.90(2.48-31.97), q-value=0.0150). The markers previously identified in metastatic CRC were not validated. We have identified new markers of toxicity in genes of transport and DNA repair. If validated in other studies, they could help to identify patients at risk of toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Reparo do DNA , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Síndromes Neurotóxicas/etiologia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
Background: Awareness about the importance of implementing DPYD pharmacogenetics in clinical practice to prevent severe side effects related to the use of fluoropyrimidines has been raised over the years. Since 2012 at the National Cancer Institute, CRO-Aviano (Italy), a diagnostic DPYD genotyping service was set up. Purpose: This study aims to describe the evolution of DPYD diagnostic activity at our center over the last 10 years as a case example of a successful introduction of pharmacogenetic testing in clinical practice. Methods: Data related to the diagnostic activity of in-and out-patients referred to our service between January 2012 and December 2022 were retrieved from the hospital database. Results: DPYD diagnostic activity at our center has greatly evolved over the years, shifting gradually from a post-toxicity to a pre-treatment approach. Development of pharmacogenetic guidelines by national and international consortia, genotyping, and IT technology evolution have impacted DPYD testing uptake in the clinics. Our participation in a large prospective implementation study (Ubiquitous Pharmacogenomics) increased health practitioners' and patients' awareness of pharmacogenetic matters and provided additional standardized infrastructures for genotyping and reporting. Nationwide test reimbursement together with recommendations by regulatory agencies in Europe and Italy in 2020 definitely changed the clinical practice guidelines of fluoropyrimidines prescription. A dramatic increase in the number of pre-treatment DPYD genotyping and in the coverage of new fluoropyrimidine prescriptions was noticed by the last year of observation (2022). Conclusion: The long path to a successful DPYD testing implementation in the clinical practice of a National Cancer Center in Italy demonstrated that the development of pharmacogenetic guidelines and genotyping infrastructure standardization as well as capillary training and education activity for all the potential stakeholders are fundamental. However, only national health politics of test reimbursement and clear recommendations by drug regulatory agencies will definitely move the field forward.
RESUMO
BACKGROUND: The main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations. METHODS: The survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted. RESULTS: We received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics. CONCLUSIONS: The EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.
Assuntos
Deficiência da Di-Hidropirimidina Desidrogenase , Humanos , Deficiência da Di-Hidropirimidina Desidrogenase/diagnóstico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Fluoruracila/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Estudos Retrospectivos , Di-Hidrouracila Desidrogenase (NADP)/genética , Europa (Continente)RESUMO
The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245C > G, which can affect radiosensitivity and MTHFR-677C > T, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRG ≤ 2 (OR = 0.46 95% CI 0.23-0.90, P = 0.024; and OR = 0.48 95% CI 0.24-0.96, P = 0.034; respectively). An association trend was observed for ABCB1-3435C > T, which is responsible for the multi-drug resistance (odds ratio (OR) = 1.96, 95% confidence interval (CI) 0.98-3.95, P = 0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene-gene and gene-environment interactions and a genetic signature associated with differential response, with hOGG1-1245C > G as the most predictive factor. Other significant variables were: ABCB1-3435C > T, MTHFR-677C > T, ERCC1-8092C > A, ABCC2-1249G > A, XRCC1-28152G > A, XRCC3-4541A > G and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRG ≤ 2 as compared with low profiles (OR = 4.12 95% CI 1.46-11.65, P < 0.001 and OR = 12.44, 95% CI 5.52-28.04, P < 0.0001, respectively). This study evidences a major role of hOGG1-1245C > G and MTHFR-677C > T polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene-gene and gene-environment interactions for complex phenotypes as tumor response.
Assuntos
Terapia Neoadjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Adulto , Idoso , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único/genética , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Neoplasias Retais/patologia , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Resultado do TratamentoRESUMO
Two common mutations, 677 C-->T and a1298 A-->C, in the methylenetetrahydrofolate reductase gene (MTHFR) reduce the activity of MTHFR and folate metabolism. Familial aggregation in a variable but significant proportion of gastric cancer (GC) cases suggests the importance of genetic predisposition in determining risk. In this study, we evaluate MTHFR polymorphisms in 57 patients with a diagnosis of GC, in 37 with a history of GC in first-degree relatives (GC-relatives), and in 454 blood donors. Helicobacter pylori (HP) infection was also determined. An increased risk was found for 677TT in GC patients with respect to blood donors (odds ratio (OR) = 1.98), and statistical significance was sustained when we compared sex-age-matched GC patients and donors (OR = 2.37). The 677TT genotype association with GC was found in women (OR = 3.10), while a reduction in the 667C allele frequency was present in both the sex. No statistically significant association was detected when 677-1298 genotype was stratified by sex and age. Men of GC-relatives showed a higher 1298C allele frequency than donors (OR = 4.38). Between GC and GC-relatives, HP infection frequency was similar. In conclusion, overall findings support the hypothesis that folate plays a role in GC risk. GC-relatives evidence a similar 677TT frequency to that found in the general population.
Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Família , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Neoplasias Gástricas/etiologiaRESUMO
Research into the molecular bases of malignant diseases has yielded the development of many novel agents with potential antitumor activity. Evidence for a causative role for the epidermal growth factor receptor (EGFR), which is now regarded as an excellent target for cancer chemotherapy in human cancer, leads to the development of EGFR inhibitors. Two classes of anti-EGFR agents are currently in clinical use: monoclonal antibodies directed at the extracellular domain of the receptor, and the low-molecular-weight receptor tyrosine kinase inhibitors acting intracellularly by competing with adenosine triphosphate for binding to the tyrosine kinase portion of the EGFR. The effect on the receptor interferes with key biological functions including cell cycle arrest, potentiation of apoptosis, inhibition of angiogenesis and cell invasion and metastasis. Cetuximab, a monoclonal antibody, and the receptor tyrosine kinase inhibitors gefitinib and erlotinib are currently approved for the treatment of patients with cancer. New agents with clinical activity are entering the clinic, and new combinatorial approaches are being explored with the aim of improving the potency and pharmacokinetics of EGFR inhibition, to increase the synergistic activity in combination with chemotherapy and overcome resistance to the EGFR inhibitors.
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Anticorpos Monoclonais/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Aminoquinolinas , Compostos de Anilina , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Cetuximab , Cloridrato de Erlotinib , Gefitinibe , Humanos , Isoxazóis/farmacologia , Lapatinib , Leflunomida , Morfolinas/farmacologia , Compostos Orgânicos/farmacologia , Panitumumabe , Piperidinas/farmacologia , Purinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Quinolinas/farmacologiaRESUMO
The adoption of a preemptive UGT1A1*28 genotyping to increase irinotecan safety in clinical practice is still limited. This is the first actual study of costs associated with the management of irinotecan-related toxicities, and their association with UGT1A1*28 genotype. A retrospective analysis of the cost of toxicity management was conducted on 243 metastatic colorectal cancer patients enrolled in a clinical trial and treated with standard of care FOLFIRI (5-fluorouracil combined with irinotecan). The mean predicted cost per patient was higher for *28/*28 (4,886), vs. *1/*1 (812), (regression coefficient 1.79, 95% confidence interval (CI) = 1.31-2.28; P < 0.001) and for *1/*28 (1,119) vs. *1/*1 (regression coefficient 0.32, 95% CI = 0.04-0.60; P = 0.024). This is consistent with a different grade 4 toxicity profile among the three genotypes, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele. A differential toxicity management cost by *28 genotype is herein demonstrated, representing a first step towards the demonstration of the test clinical utility.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Glucuronosiltransferase/genética , Irinotecano , Testes Farmacogenômicos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Análise Custo-Benefício , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/economia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/farmacocinética , Itália , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Administração dos Cuidados ao Paciente/economia , Administração dos Cuidados ao Paciente/métodos , Testes Farmacogenômicos/economia , Testes Farmacogenômicos/métodos , Variantes Farmacogenômicos/genética , Estudos Retrospectivos , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacocinéticaRESUMO
Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.
Assuntos
Testes Farmacogenômicos/métodos , Testes Farmacogenômicos/estatística & dados numéricos , Projetos de Pesquisa , Biomarcadores , Análise Custo-Benefício , Registros Eletrônicos de Saúde/organização & administração , Europa (Continente) , Genótipo , Humanos , Testes Farmacogenômicos/economia , Testes Farmacogenômicos/tendências , Guias de Prática Clínica como Assunto , Medicina de Precisão/métodos , Estudos Prospectivos , Resultado do TratamentoRESUMO
Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Hidrolases de Éster Carboxílico/genética , Sistema Enzimático do Citocromo P-450/genética , Glucuronosiltransferase/genética , Humanos , Inativação Metabólica/genética , Irinotecano , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Polimorfismo Genético , Inibidores da Topoisomerase IRESUMO
Glycosylated hemoglobin (Hb AI) is commonly accepted as a parameter of the last 2-3 months metabolism of the glucides; therefore its growth must be proportionate to the metabolic unbalance [1]. We observed that chronic alcoholics often had significantly increased levels of Hb AI when compared with normal controls, although with a normal oral glucose tolerance test (OGTT); we therefore tried to correlate other metabolic factors with glycosylated hemoglobin: uricemia, triglyceridemia, cholesterolemia and high density lipoprotein (HDL)-cholesterol.
Assuntos
Alcoolismo/sangue , Hemoglobinas Glicadas/metabolismo , Adulto , Idoso , Glicemia/metabolismo , Teste de Tolerância a Glucose , Humanos , Triglicerídeos/sangue , Ácido Úrico/sangueRESUMO
CYP1B1 is the enzyme with the highest efficiency of conversion of estradiol to 4-hydroxyestradiol in humans. This metabolite has a well-known carcinogenic effect interacting with genomic DNA and has been hypothesized to be partly responsible for the role played by estrogens in ovarian cancer development. A polymorphism has been described for this enzyme causing a Leu to Val substitution in position 432 (CYP1B1*3). The Val432 allele has a higher efficiency of conversion of estradiol to 4-hydroxyestradiol and has been reported to increase the risk of ovarian cancer. A previous study reported a higher, significant prevalence of CYP1B1*3 polymorphism in ovarian cancer patients of mixed ethnicity. The aim of this study was to investigate the role of CYP1B1*3 polymorphism as a risk factor for ovarian cancer in a Caucasian population. The polymorphism frequency was determined in 223 cases of ovarian cancer and compared with that of 280 healthy female blood donors. Genetic analysis was performed on genomic DNA from PBMC and RFLP methods were used for mutation detection. No significant difference between cases and controls was found. These results do not support a favoring role of CYP1B1*3 in ovarian cancer development in our population.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias Ovarianas/genética , Polimorfismo Genético , Alelos , Citocromo P-450 CYP1B1 , Feminino , Frequência do Gene , Homozigoto , Humanos , Leucina/química , Leucócitos Mononucleares/metabolismo , Razão de Chances , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Valina/química , População BrancaRESUMO
C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been suggested to affect susceptibility to malignant lymphoma, possibly by altering DNA methylation. The DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in diffuse large B-cell lymphomas (DLBCL). We analyzed the MTHFR677 and MTHFR1298 genotypes in 111 DLBCL patients and 465 controls. No significant difference in the frequency of MTHFR polymorphisms between patients and controls and no significant association between MTHFR677 or MTHFR1298 genotypes and methylation of MGMT promoter were observed. These results indicate that MTHFR variants are not related to DLBCL development and MGMT hypermethylation.
Assuntos
Genótipo , Linfoma Difuso de Grandes Células B/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , Alelos , Estudos de Casos e Controles , Metilação de DNA , Reparo do DNA , Humanos , Polimorfismo Genético , Regiões Promotoras Genéticas , Transcrição GênicaRESUMO
Sixty patients with end stage chronic renal failure (CRF) enrolled in a dialysis program underwent studies of serum thyroid hormones and carbohydrate metabolic state. The aim of the study was: 1) to evaluate whether the glucose intolerance per se represents a factor for the alteration of circulating thyroid hormones; and 2) to explore the potential usefulness of specific thyroid hormones and particularly reverse T3 (RT3) as indicators for predicting glucose intolerance. Forty-two patients received hemodialysis and 18 were on intermittent peritoneal dialysis (IPD). CRF patients had reduced serum total T4 and T3 levels, slightly decreased RT3 and TBG concentrations and normal TSH values. There was no significant difference in serum thyroid hormone indices between HD and IPD patients. Glucose intolerance was found in 25 patients. Ten had fasting hyperglycemia and diabetic response to oral glucose tolerance test (OGTT), 15 had an impaired glucose tolerance according to the criteria of the National Diabetes Data Group. In CRF patients with glucose intolerance, serum T3 and T3/T4 molar ratio were significantly lower than in those with a normal OGTT response, whereas serum RT3 and RT3/T4 molar ratio were found to be higher. In the whole group of CRF patients these serum thyroid hormones closely correlated with glucose tolerance indices. To investigate the usefulness of serum RT3 assay in predicting glucose intolerance we compared the outcome of the OGTT and serum RT3 values. Using the results of the OGTT as the true diagnosis of glucose intolerance, serum RT3 assay showed a diagnostic specificity of 94.2% and a sensitivity of 100%. In conclusion these results suggest that: 1) the glucose intolerance, which frequently occurs in uremia, may influence circulating thyroid hormones probably leading to a shift in the peripheral tissue conversion of T4 from T3 to RT3; and 2) serum RT3 assay could assume a clinical interest in assessing carbohydrate metabolic state in treated end stage renal failure independently of the type of dialysis therapy.
Assuntos
Glicemia/análise , Teste de Tolerância a Glucose , Diálise Renal/efeitos adversos , Tri-Iodotironina Reversa/sangue , Uremia/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Uremia/terapiaRESUMO
Pharmacogenetics could be a useful tool for performing tailored anticancer chemotherapy. Several polymorphisms potentially affecting enzymes responsible for metabolism, transport and mechanism of action of irinotecan, fluoropyrimidines and antifolate agents have been investigated and sometimes associated with toxicity and response. In particular, uridine diphosphoglucuronosyl transferase 1A1 (UGT1A1) enzyme is responsible for detoxification of irinotecan active metabolite, SN38. A polymorphic structure in the promoter region (UGT1A1*28) may affect irinotecan toxicity and SN38 plasma level. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate cycle, presenting two common polymorphisms (677C>T and 1298 A>C) which have impact on toxicity and efficacy of methotrexate and 5-fluorouracil.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/análogos & derivados , Glucuronosiltransferase/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Neoplasias/tratamento farmacológico , Farmacogenética , Polimorfismo Genético , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Neoplasias/genética , Sensibilidade e Especificidade , ToxicogenéticaRESUMO
In chronic renal failure both HbA1 and HbA1c levels have been reported to be elevated. In order to investigate the causes of such increase we measured HbA1 (cation-exchange chromatography), blood urea nitrogen, arterial blood pH, plasma bicarbonate, phosphatemia, serum iron and serum ferritin before dialysis in 60 uremic patients receiving long term hemodialysis. The increased levels of HbA1 do not correlate with glucose intolerance, phosphatemia, blood urea nitrogen, time averaged concentration of urea, serum iron and serum ferritin. On the contrary the presence of a highly significant correlation between HbA1 and arterial blood pH (p less than 0.001) and between HbA1 and plasma bicarbonate (p less than 0.001) seems to emphasize a major role for acidosis in increasing the HbA1 levels in uremic patients on long term hemodialysis.
Assuntos
Hemoglobinas Glicadas/análise , Hemoglobina A/análogos & derivados , Falência Renal Crônica/sangue , Acidose/sangue , Adulto , Idoso , Feminino , Teste de Tolerância a Glucose , Hemoglobina A/análise , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Uremia/sangueRESUMO
We evaluated survival and risk factors in 86 elderly patients (pts) who underwent dialysis at one center throughout the last 10 years. Thirty-five pts received hemodialysis (HD), 32 intermittent peritoneal dialysis (IPD), and 19 continuous peritoneal dialysis (CAPD). Risk factors included: treatment, age, sex, underlying disease, heart failure (HF), peripheral vascular disease (PVD), diabetes mellitus (DM) and malignancy. Median age was 65 years for both HD and CAPD, and 69 for IPD (p less than 0.05). Survival evaluation demonstrated a longer life span for HD vs. IPD (p = 0.02) for CAPD vs. IPD (p = 0.03) and no difference between HD and CAPD pts. Cox analysis showed higher death odds ratio (OR = 2.4) for IPD vs. HD and lower ratio for CAPD vs. IPD (OR = 0.3). Other OR positive risk factors were: HF, PVD, DM and malignancy. The median value of risk factors for each group was higher for both IPD and CAPD vs. HD. Both life span and death OR for CAPD were equal to HD in spite of higher risk factors in CAPD group. The lower survival of the IPD group may be due to its older age. CAPD should represent the elective treatment for elderly uremics while HD or IPD should be reserved for selected patients.