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1.
Artigo em Inglês | MEDLINE | ID: mdl-34477275

RESUMO

AIM: This pilot study aimed to compare the pharmacokinetic profiles of oral (PO) and intravenous (IV) ibuprofen for treatment of patent ductus arteriosus (PDA) in preterm neonates. METHODS: In a single-centre, parallel, randomised open-label trial, neonates ≤35 weeks, weight <1800 g with haemodynamically significant PDA during the first week of life were recruited between June 2017 and February 2019 and randomised to receive either PO or IV ibuprofen at standard dosage of 10, 5 and 5 mg/kg every 24 h for three consecutive days. Plasma concentrations of ibuprofen were quantified using a validated high-performance liquid chromatography method and pharmacokinetic parameters were calculated. Treatment outcomes were recorded. RESULTS: Eleven neonates participated in the trial, six and five patients receiving PO and IV ibuprofen, respectively. Pharmacokinetic analysis reveals similar ibuprofen exposure levels in treatment groups. Median dose- and weight-normalised Cmax values of PO and IV groups were 2.12 and 2.53 g/mL respectively (P = 0.082) and median AUC0-24 levels were comparable (PO: 34.6 g*h/mL vs. IV: 50.7.6 g*h/mL, P = 0.25). CONCLUSION: This exploratory study demonstrates comparable pharmacokinetics of PO and IV formulations of ibuprofen in preterm neonates. Larger prospective studies are required to validate these findings.

2.
Nat Nanotechnol ; 16(6): 734-742, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33686255

RESUMO

Current technologies to measure drug-target interactions require complex processing and invasive tissue biopsies, limiting their clinical utility for cancer treatment monitoring. Here we develop an analytical platform that leverages circulating extracellular vesicles (EVs) for activity-based assessment of tumour-specific drug-target interactions in patient blood samples. The technology, termed extracellular vesicle monitoring of small-molecule chemical occupancy and protein expression (ExoSCOPE), utilizes bio-orthogonal probe amplification and spatial patterning of molecular reactions within matched plasmonic nanoring resonators to achieve in situ analysis of EV drug dynamics. It measures changes in drug occupancy and protein composition in molecular subpopulations of EVs. When used to monitor various targeted therapies, the ExoSCOPE revealed EV signatures that closely reflected cellular treatment efficacy. We further applied the technology for clinical cancer diagnostics and treatment monitoring. Using a small volume of blood, the ExoSCOPE accurately classified disease status and rapidly distinguished between targeted treatment outcomes, within 24 h after treatment initiation.


Assuntos
Antineoplásicos/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/sangue , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Receptores ErbB/genética , Cloridrato de Erlotinib/sangue , Cloridrato de Erlotinib/uso terapêutico , Vesículas Extracelulares/química , Estudos de Viabilidade , Humanos , Neoplasias Pulmonares/sangue , Razão Sinal-Ruído
3.
Cancer Res ; 81(7): 1802-1812, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33547160

RESUMO

Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is a key to tumor progression. Here, we deconvoluted bulk tumor transcriptomes to infer cross-talk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. This approach recovered known transcriptional hallmarks of cancer and stromal cells and was concordant with single-cell, in situ hybridization and IHC data. Inferred autocrine cancer cell interactions varied between tissues but often converged on Ephrin, BMP, and FGFR-signaling pathways. Analysis of immune checkpoints nominated interactions with high levels of cancer-to-immune cross-talk across distinct tumor types. Strikingly, PD-L1 was found to be highly expressed in stromal rather than cancer cells. Overall, our study presents a new resource for hypothesis generation and exploration of cross-talk in the TME. SIGNIFICANCE: This study provides deconvoluted bulk tumor transcriptomes across multiple cancer types to infer cross-talk in the tumor microenvironment.


Assuntos
Neoplasias , Receptor Cross-Talk/fisiologia , Microambiente Tumoral , Comunicação Autócrina/fisiologia , Comunicação Celular/genética , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Genômica/métodos , Humanos , Ligantes , Masculino , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Microambiente Tumoral/genética , Sequenciamento Completo do Exoma
4.
Clin Pharmacol Ther ; 108(3): 661-670, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32578187

RESUMO

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared with elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing.


Assuntos
Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Modelos Teóricos , Obesidade/complicações , Tamoxifeno/análogos & derivados , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/sangue , Peso Corporal , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Simulação por Computador , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/sangue , Variantes Farmacogenômicos , Tamoxifeno/administração & dosagem , Tamoxifeno/sangue , Tamoxifeno/farmacocinética , Adulto Jovem
5.
Pharmacogenomics J ; 20(3): 505-515, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31813937

RESUMO

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Grupo com Ancestrais do Continente Asiático/genética , Azatioprina/efeitos adversos , Variação Genética/genética , Doenças Inflamatórias Intestinais/genética , Íntrons/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/etnologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/etnologia , Leucopenia/induzido quimicamente , Leucopenia/etnologia , Leucopenia/genética , Masculino , Mercaptopurina/efeitos adversos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/etnologia , Neutropenia/genética , Estudos Retrospectivos , Adulto Jovem
6.
Pharmacogenomics ; 19(1): 31-43, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29210335

RESUMO

BACKGROUND: Genetic variants of TPMT and NUDT15 have been reported to predict the inter-patient variability in response and toxicity profiles of patients receiving thiopurine therapy. However, the clinical utility of TPMT genotyping in guiding thiopurine doses has been questionable, in part due to underlying differences in the prevalence of TPMT variants in both Caucasian and Asian populations. Several NUDT15 variants have been associated with thiopurine-induced leukopenia, particularly in Asian cohorts. So far, none have been reported in a multiethnic Asian population. AIM: To investigate the associations between TPMT and NUDT15 variants with thiopurine-induced myelotoxicity in 129 Asian inflammatory bowel disease patients. MATERIALS & METHODS: Pyrosequencing was performed to screen for TPMT and NUDT15 variants. Intracellular steady-state metabolite concentrations were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: Significant declines in nadir white blood cell, absolute neutrophil count and platelet counts were observed with increasing copy numbers of the risk T allele at NUDT15 c.415C>T locus (overall p < 0.05) within 4, 8 and 12 weeks and 6 months after thiopurine initiation. Patients with low and intermediate NUDT15 activity, as inferred from haplotype pairs, had significantly higher risks of leukopenia (p = 0.000253) and neutropenia (p = 0.002) compared with patients with normal NUDT15 activity. CONCLUSION: These findings highlight the critical relevance of NUDT15 pharmacogenetics in predicting for thiopurine-induced myelotoxicity and confirm the lack of significance of TPMT variants in Asian inflammatory bowel disease patients.


Assuntos
Azatioprina/efeitos adversos , Variação Genética/genética , Doenças Inflamatórias Intestinais/genética , Pirofosfatases/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Azatioprina/uso terapêutico , Feminino , Haplótipos/genética , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Leucopenia/induzido quimicamente , Leucopenia/genética , Masculino , Metiltransferases/genética , Neutrófilos/efeitos dos fármacos , Farmacogenética/métodos , Contagem de Plaquetas/métodos , Fatores de Risco
7.
Nat Med ; 23(10): 1167-1175, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28920960

RESUMO

Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , RNA Longo não Codificante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Feminino , Gefitinibe , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/genética , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias Bucais/genética , Isoformas de RNA , Splicing de RNA , Carcinoma de Células Escamosas de Cabeça e Pescoço , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Front Pharmacol ; 8: 582, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28955222

RESUMO

Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual's capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings. Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin. Robust coefficients of determination (R2) were estimated for endoxifen (E) or metabolic ratio endoxifen/desmethyl-TAM (E/DMT) as dependent and different CYP2D6 phenotype assignments as independent variables. Allele activity scores (ASs) were modified with respect to a reduced ∗10 allele activity. Predictability of endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL was investigated by receiver operating characteristic (ROC) analysis. Results: CYP2D6 diplotypes (N = 898) were strongly associated with E and E/DMT independent of age (P < 10-15). Across all ethnicities, 68-82% inter-patient variability of E/DMT was explained by CYP2D6 diplotype, while plasma endoxifen was predictable by 39-58%. The previously used codeine specific phenotype classification showed worse prediction for both endpoints particularly in Asians (median R2< 20%; P < 10-9). Downgrading of ∗10 activity slightly improved the explanatory value of metabolizer phenotype (P < 0.002). Endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL were achieved in 82.3% of patients and were predictable (96% sensitivity, 57% specificity) by CYP2D6 diplotypes with AS > 0.5, i.e., omitting PM/PM and PM/IM patients. Conclusion: The CYP2D6 explanatory power for active drug level assessment is maximized by TAM-specific phenotype assignments while a genotype cutoff that separates PM/PM and PM/IM from the remaining patients may improve clinical benefit via increased endoxifen concentrations.

9.
Sci Rep ; 7(1): 1540, 2017 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-28484248

RESUMO

Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR 19del , but not the EGFR L858R . In the current study we use modelling and simulations to show that structural constraints in EGFR 19del deletion result in significantly attenuated flexibilities in the binding pocket resulting in strong hydrogen and halogen bonds with afatinib in the EGFR 19del ; these constraints are modulated by buried water and result in the differential affinities of afatinib for the different mutants. SNP analysis of residues surrounding the buried water points to the likelihood of further differential effects of afatinib and provides a compelling case for investigating the effects of the SNPs towards further stratification of patients for ensuring the most effective use of afatinib.


Assuntos
Afatinib/farmacologia , Receptores ErbB/antagonistas & inibidores , Mutação/genética , Água/química , Sítios de Ligação , Ativação Enzimática , Humanos , Ligantes , Simulação de Dinâmica Molecular
10.
Pharmacogenet Genomics ; 27(3): 120-123, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28059867

RESUMO

The critical role of lysine demethylase 4A (KDM4A), in regulating chromatin structure and consequently in driving cellular proliferation and oncogenesis has been the focus of recent studies. Non-small-cell lung cancer (NSCLC) patients with adenocarcinoma histology who were homozygous for KDM4A single nucleotide polymorphism (SNP)-A482 (rs586339) were recently shown to have significantly worse overall survival (OS) compared with patients with the wild-type or the heterozygous genotype at this locus (hazard ratio=1.68, P=0.042). In the current study, we investigated the association between the same polymorphism with OS in our Asian NSCLC-adenocarcinoma patients comprising Chinese (N=572), Malays (N=50), and Indians (N=22). KDM4A SNP-A482 genotype status was determined by Sanger sequencing. OS was calculated from the date of diagnosis to date of death or censored at the date of last follow-up. Kaplan-Meier analysis, log-rank test, and Cox regression methods were utilized to evaluate OS outcomes. KDM4A SNP-A482 had a minor allele (C) frequency of 18.8% and a major allele (A) frequency of 81.2% in our Asian NSCLC (adenocarcinoma) patients. However, the OS in our Asian NSCLC patients homozygous for KDM4A SNP-A482 was not significantly different from those who were wild type or heterozygous at this locus [CC vs. AA/AC: median OS (95% confidence interval): 40.2 (18.7-61.6) vs. 29.6 (26.9-32.3) months; P=0.858]. The results remained statistically nonsignificant even after adjustment for epidermal growth factor receptor mutational status, suggesting that KDM4A SNP-A482 does not significantly influence OS in Asian NSCLC patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Carcinoma Pulmonar de Células não Pequenas/genética , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/etnologia , Feminino , Estudos de Associação Genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Análise de Sobrevida
11.
J Thorac Oncol ; 12(3): 529-538, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27908825

RESUMO

INTRODUCTION: Activating mutations in the EGFR gene have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced NSCLC. However, wide interpatient variability in treatment outcomes in response to EGFR tyrosine kinase inhibitors in these patients remains unaccounted for. This study aimed to evaluate the influence of EGFR mutation types and subtypes on survival outcomes in advanced Asian patients with NSCLC receiving first-line gefitinib therapy. METHODS: Patients with stage IIIB or IV NSCLC who were harboring EGFR mutations, receiving first-line gefitinib treatment, and of Asian descent (N = 383) were evaluated. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Log-rank tests and Cox proportional hazards models were implemented to evaluate the differences in PFS and OS. RESULTS: Significant differences in PFS were observed between patients carrying EGFR mutations in exons 18, 19, 20, and 21, with patients carrying EGFR exon 19 mutations having the longest median PFS (overall p = 8.88 × 10-15). Comparison of PFS among the five different exon 19 mutation subtypes and among the two exon 19 deletion start codons did not reveal any significant differences. No significant difference was observed in OS among patients carrying EGFR mutations on different exons (overall p = 0.054); however, OS was found to be significantly different among the various subtypes of exon 19 mutations, with the 15-nucleotide deletion "non-ELREA" group having the shortest OS of 11.3 months (overall p = 0.025). CONCLUSIONS: EGFR mutation types and subtypes significantly influence survival outcomes in patients with advanced NSCLC who are receiving first-line gefitinib treatment.


Assuntos
Adenocarcinoma/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Neoplasias Pulmonares/mortalidade , Mutação , Quinazolinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Seguimentos , Gefitinibe , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Taxa de Sobrevida
12.
Cancer Lett ; 388: 328-333, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28003122

RESUMO

Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema.


Assuntos
Administração Metronômica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Humanos
13.
Pharmacogenomics ; 17(17): 1941-1955, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27804783

RESUMO

The use of imatinib in the treatment of BCR-ABL-positive chronic myeloid leukemia and gastrointestinal stromal tumors has significantly improved survival outcomes in patients afflicted by these malignancies. However, a substantial proportion of imatinib-treated patients still experience treatment failure. Suboptimal concentrations of imatinib have been postulated to contribute at least partially to the development of resistance against imatinib. Indeed, variations in the genes encoding drug transporters have been reported to markedly influence imatinib disposition and treatment outcomes in various populations. This review aims to consolidate and critically assess the studies conducted to date which have investigated the influence of pharmacogenetic variants in drug transporters on the disposition of imatinib and treatment outcomes in Asians and other populations.

14.
Drugs R D ; 16(4): 317-326, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27681888

RESUMO

Des-aspartate-angiotensin I (DAA-I) is an endogenous angiotensin peptide and a prototype angiotensin receptor agonist (ARA). It acts on the angiotensin AT1 receptor and antagonises the deleterious actions of angiotensin II. DAA-I attenuates animal models of human disease in which angiotensin II has been implicated, such as cardiac hypertrophy, neointima formation, arteriosclerosis, renal failure, post-infarction injuries, diabetes, viral infection, chemical-induced inflammation, heat stroke, cancer, and gamma radiation lethality. DAA-I crosses Caco-2 cells and is effective at sub-nanomolar concentrations. These two properties are responsible for its oral efficacy. A single dose-escalation study was conducted to evaluate the safety, tolerability and pharmacokinetics of orally administered DAA-I in 18 healthy subjects. DAA-I was safe and well tolerated by the subjects, who were administered either 0.08, 0.70 or 1.50 mg/kg of the compound. The heart rate and systolic and diastolic blood pressures determined at each post-dose measurement remained within the clinically acceptable range. Across all cohorts, DAA-I had no substantial effect on blood pressures compared with placebo. Electrocardiographs (ECGs) were normal, and none of the subjects complained of chest discomfort. All clinical laboratory tests obtained before and after DAA-I and placebo treatment were normal. Pharmacokinetic analysis over a 12-h period following DAA-I administration did not show any increase of its level beyond basal concentration. This is in line with studies showing that intravenously administered DAA-I is rapidly metabolized and has a short half-life. We postulate that, during its short systemic sojourn, DAA-I exerts its actions via biased agonism on the angiotensin AT1 receptor.The ClinicalTrial.gov assignment number for this study is NCT02666196.


Assuntos
Angiotensina I/análogos & derivados , Administração Oral , Adulto , Angiotensina I/administração & dosagem , Angiotensina I/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Drug Metab Rev ; 48(4): 502-540, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27546072

RESUMO

Drug efflux and influx transporters play critical roles in regulating the cellular drug disposition and modulating the pharmacokinetics and pharmacodynamics of anti-cancer agents, which may potentially alter treatment outcomes. The efficiency of drug transport is often dependent on the expression and activity of these membrane-bound proteins, factors which have been shown to be regulated by genes that are known to be highly polymorphic in different ethnic populations. The role of drug transporters becomes even more critical for anti-cancer agents due to the narrow therapeutic windows that separate treatment response and toxicities for these agents. Moreover, high inter-individual variability in the disposition of anti-cancer agents often results in variable treatment outcomes among patients receiving standard doses of the same drug. Such variability has been attributed at least in part to polymorphisms in genes encoding drug-metabolizing enzymes and transporter. To date, numerous pharmacogenetic studies have investigated the associations between variants in the ABC and SLC transporters genes with drug disposition, treatment outcomes and drug-induced toxicities. However, the strengths of these associations and their clinical relevance in different ethnic populations have not been critically examined. This review aims to summarize and evaluate the implications of pharmacogenetic variants in the ABC and SLC transporters genes on the pharmacokinetics and clinical outcomes of three anti-cancer agents: irinotecan, docetaxel and doxorubicin in Caucasian and Asian patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Camptotecina/análogos & derivados , Doxorrubicina/farmacocinética , Grupo com Ancestrais do Continente Europeu/genética , Neoplasias/genética , Neoplasias/metabolismo , Taxoides/farmacocinética , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Docetaxel , Doxorrubicina/uso terapêutico , Humanos , Irinotecano , Polimorfismo Genético/genética , Proteínas Carreadoras de Solutos/genética , Taxoides/uso terapêutico , Resultado do Tratamento
16.
Lancet Oncol ; 17(9): 1240-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27470079

RESUMO

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS: We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS: Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION: To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING: Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Linfoma Extranodal de Células T-NK/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Estudos de Casos e Controles , China , Feminino , Seguimentos , Humanos , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Adulto Jovem
17.
PLoS One ; 11(5): e0154316, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27135612

RESUMO

PURPOSE: This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). METHODS: This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. RESULTS: The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. CONCLUSIONS: Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT00702182.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Vimblastina/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Esquema de Medicação , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/farmacocinética , Vimblastina/uso terapêutico , Vinorelbina
18.
Clin Pharmacokinet ; 55(10): 1239-1250, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27098059

RESUMO

Tamoxifen (TAM) is an established endocrine treatment for all stages of oestrogen receptor (ER)-positive breast cancer. Its complex metabolism leads to the formation of multiple active and inactive metabolites. One of the main detoxification and elimination pathways of tamoxifen and its active metabolites, 4-hydroxytamoxifen (4-OHT) and endoxifen, is via glucuronidation catalysed by uridine 5'-diphospho-glucuronosyltransferases (UGTs). However, few studies have comprehensively examined the impact of variations in the genes encoding the major hepatic UGTs on the disposition of tamoxifen and its metabolites. In the present study, we systematically sequenced exons, exon/intron boundaries, and flanking regions of UGT1A4, UGT2B7 and UGT2B15 in 240 healthy subjects of different Asian ethnicities (Chinese, Malays and Indians) to identify haplotype tagging single nucleotide polymorphisms. Subsequently, 202 Asian breast cancer patients receiving tamoxifen were genotyped for 50 selected variants in the three UGT genes to comprehensively investigate their associations with steady-state plasma levels of tamoxifen, its active metabolites and their conjugated counterparts. The UGT1A4 haplotype (containing variant 142T>G, L48 V defining the *3 allele) was strongly associated with higher plasma levels of TAM-N-glucuronide, with a twofold higher metabolic ratio of TAM-N-glucuronide/TAM observed in carriers of this haplotype upon covariate adjustment (P < 0.0001). Variants in UGT2B7 were not associated with altered O-glucuronidation of both 4-OHT and endoxifen, while UGT2B15 haplotypes had a modest effect on (E)-endoxifen plasma levels after adjustment for CYP2D6 genotypes. Our findings highlight the influence of UGT1A4 haplotypes on tamoxifen disposition in Asian breast cancer patients, while genetic variants in UGT2B7 and UGT2B15 appear to be of minor importance.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/tratamento farmacológico , Glucuronosiltransferase/genética , Tamoxifeno/farmacocinética , Tamoxifeno/uso terapêutico , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/etnologia , Neoplasias da Mama/etnologia , Citocromo P-450 CYP2D6/genética , Grupos Étnicos , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único , Tamoxifeno/análogos & derivados , Tamoxifeno/sangue , Tamoxifeno/metabolismo
19.
Br J Clin Pharmacol ; 81(6): 1142-52, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26799162

RESUMO

AIM: The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer. METHODS: Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatography­mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic­phenotypic associations and haplotypic effects of the SNPs. RESULTS: CYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C19*2 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C19*2 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA: 1.51 (0.38­3.28) vs. 1.28 (0.30­3.36) vs. 1.15 ng ml−1 (0.26­2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27­28.35) vs. 8.15 (2.67­18.9) vs. 6.06 (4.47­14.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA: 2.75 (0.62­6.26) vs. 2.43 (0.96­4.18) vs. 1.75 (1.10­2.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND. CONCLUSION: These data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.


Assuntos
Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/metabolismo , Citocromo P-450 CYP2C19/genética , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacocinética , Adulto , Idoso , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Biotransformação , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Feminino , Frequência do Gene , Haplótipos , Voluntários Saudáveis , Humanos , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único , Tamoxifeno/sangue , Tamoxifeno/uso terapêutico
20.
PLoS One ; 10(8): e0134102, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26244574

RESUMO

Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in FLT3, ABCB1, VEGFR2, ABCG2 and BIM with patient toxicities, response, and survival. We observed a stronger association of FLT3 738T genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; P=0.03). We observed significant associations of FLT3 738T (OR=2.7), ABCB1 1236T (OR=0.3), ABCB1 3435T (OR=0.1), ABCB1 2677T (OR=0.4), ABCG2 421A (OR=0.3) alleles and ABCB1 3435, 1236, 2677 TTT haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype. In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between FLT3 738T and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Pirróis/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma de Células Renais/etnologia , Carcinoma de Células Renais/genética , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Indóis/efeitos adversos , Neoplasias Renais/etnologia , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirróis/efeitos adversos , Singapura , Sunitinibe , Resultado do Tratamento , Adulto Jovem
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