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1.
Antioxid Redox Signal ; 34(7): 505-516, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32438819

RESUMO

Aims: TNF receptor-associated protein 1 (TRAP1), the mitochondrial paralog of the heat shock protein 90 (Hsp90) family of molecular chaperones, is required for neoplastic growth in several tumor cell models, where it inhibits succinate dehydrogenase (SDH) activity, thus favoring bioenergetic rewiring, maintenance of redox homeostasis, and orchestration of a hypoxia-inducible factor 1-alpha (HIF1α)-mediated pseudohypoxic program. Development of selective TRAP1 inhibitors is instrumental for targeted development of antineoplastic drugs, but it has been hampered up to now by the high degree of homology among catalytic pockets of Hsp90 family members. The vegetal derivative honokiol and its lipophilic bis-dichloroacetate ester, honokiol DCA (HDCA), are small-molecule compounds with antineoplastic activity. HDCA leads to oxidative stress and apoptosis in in vivo tumor models and displays an action that is functionally opposed to that of TRAP1, as it induces both SDH and the mitochondrial deacetylase sirtuin-3 (SIRT3), which further enhances SDH activity. We investigated whether HDCA could interact with TRAP1, inhibiting its chaperone function, and the effects of HDCA on tumor cells harboring TRAP1. Results: An allosteric binding site in TRAP1 is able to host HDCA, which inhibits TRAP1 but not Hsp90 ATPase activity. In neoplastic cells, HDCA reverts TRAP1-dependent downregulation of SDH, decreases proliferation rate, increases mitochondrial superoxide levels, and abolishes tumorigenic growth. Innovation: HDCA is a potential lead compound for the generation of antineoplastic approaches based on the allosteric inhibition of TRAP1 chaperone activity. Conclusions: We have identified a selective TRAP1 inhibitor that can be used to better dissect TRAP1 biochemical functions and to tailor novel tumor-targeting strategies.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lignanas/farmacologia , Mitocôndrias/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/química , Compostos de Bifenilo/química , Linhagem Celular , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lignanas/química , Mitocôndrias/metabolismo , Modelos Moleculares , Estrutura Molecular , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
2.
Cancer Chemother Pharmacol ; 83(3): 493-500, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30542768

RESUMO

PURPOSE: This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms. METHODS: Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints. RESULTS: Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r2 = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r2 = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms. CONCLUSIONS: Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Vinorelbina/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração Metronômica , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Estudos de Viabilidade , Feminino , Seguimentos , Meia-Vida , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Curva ROC , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento , Vinorelbina/efeitos adversos , Vinorelbina/farmacocinética
3.
Invest New Drugs ; 36(5): 927-932, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29956056

RESUMO

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Vinorelbina/administração & dosagem , Administração Metronômica , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Feminino , Humanos , Masculino , Resultado do Tratamento , Vinorelbina/efeitos adversos , Vinorelbina/farmacocinética
4.
Cancer Chemother Pharmacol ; 73(3): 517-24, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24442033

RESUMO

PURPOSE: Pegylated liposomal doxorubicin (PLD) is often used in elderly people, due to its improved tolerability. However, clinical and pharmacological data in the subset of patients over 70 are scanty. METHODS: PLD safety was evaluated in 35 patients (aged ≥70 years) who were treated with PLD as a single agent for 165 cycles. Doxorubicin plasma levels, leukocyte DNA breaks and monocyte count variations were measured as markers of drug exposure, DNA repair capability and reticuloendothelial system activation, respectively. A correlation between these markers and age was sought. RESULTS: Treatment was generally well tolerated. Skin erythrodysesthesia was the most frequent side effect, and no severe (G4) toxicity occurred. PLD plasma half-life generally correlated with age (P < 0.001) and was particularly prolonged in octogenarians (P = 0.005). Doxorubicin clearance significantly declined up to 70 % at cycle 7. DNA breaks increased over the first two cycles (P = 0.007) and were inversely correlated with age (P = 0.007) and directly with clearance (P = 0.006). Pre-treatment monocyte counts increased over cycles (P < 0.001) and were associated with an increase in clearance at cycle 3 (P = 0.015). The hand-foot-skin syndrome was significantly more severe in patients of advanced age or longer PLD half-life. CONCLUSIONS: This study showed (1) increased systemic drug exposure over subsequent cycles; (2) association of age with increased drug exposure, reduced DNA repair capability and worse skin toxicity; (3) a relation between monocyte count and drug clearance.


Assuntos
Doxorrubicina/análogos & derivados , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Ensaio Cometa , Dano ao DNA , Reparo do DNA , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética
5.
Br J Clin Pharmacol ; 71(3): 437-44, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21284703

RESUMO

AIM: Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance. METHODS: Forty-seven patients received GEM 1000-1250mgm(-2) i.v. over 30min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA. RESULTS: Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration-time curve from time 0 to infinity (AUC(0,∞)) (r(2) = 0.77). CONCLUSIONS: Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Citidina Desaminase/genética , Transportador Equilibrativo 1 de Nucleosídeo/genética , Neoplasias/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Citidina Desaminase/metabolismo , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/genética , Polimorfismo Genético , População Branca , Gencitabina
6.
Nutrition ; 19(6): 510-4, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12781850

RESUMO

OBJECTIVE: Bioelectrical impedance vector analysis allows non-invasive evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements. METHODS: Whole-body impedance measurements were made with a single frequency (50 kHz) analyzer (BIA-101, Akern/RJL Systems) in 148 adult, white, male subjects 45 to 85 y old: 56 healthy control subjects, 31 cancer patients after surgical procedure (without disease), and 61 patients with locally advanced (30 patients) or disseminated (31 patients) disease with the same body mass index and age. All patients were free from antineoplastic treatment and active nutritional intervention. RESULTS: Mean vectors of cancer groups without disease and locally advance disease versus the control group were characterized by a comparable normalized resistance component with a reduced reactance component (separate 95% confidence limits, P < 0.05), indicating a comparable ionic conduction (hydration) with loss of dielectric mass (cell membranes and tissue interfaces) of soft tissues. Overlapping 95% confidence limits of their mean vectors indicated comparable electrical tissue properties in less versus more advanced disease. CONCLUSION: Monitoring vector displacement trajectory toward the reference target vector position may represent useful feedback in support therapy planning of individual patients.


Assuntos
Composição Corporal , Impedância Elétrica , Neoplasias/complicações , Neoplasias/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Caquexia/etiologia , Caquexia/fisiopatologia , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/fisiopatologia , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/fisiopatologia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/fisiopatologia , Pessoa de Meia-Idade
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