RESUMO
BACKGROUND: Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. OBJECTIVES: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). METHODS: Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. RESULTS: Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. CONCLUSIONS: Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.
Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Micose Fungoide/tratamento farmacológico , Síndrome de Sézary/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prurido/prevenção & controle , Retratamento , Resultado do TratamentoRESUMO
Two cDNA clones encoding rat mitochondrial adenine nucleotide translocator were isolated from libraries constructed from mRNAs of heart and liver. These two clones corresponded to the heart-skeletal muscle type (ANT1) and fibroblast type (ANT2), respectively. A genomic clone encoding rat ANT1 was also isolated and characterized.
Assuntos
DNA/isolamento & purificação , Isoenzimas/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Hepáticas/metabolismo , Translocases Mitocondriais de ADP e ATP/genética , Sequência de Aminoácidos , Animais , Clonagem Molecular , DNA/química , Biblioteca Gênica , Isoenzimas/química , Masculino , Translocases Mitocondriais de ADP e ATP/química , Dados de Sequência Molecular , RNA Mensageiro/química , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
Uncoupling protein has been thought to be expressed only in the brown adipose tissue mitochondria of mammals. However, mRNA encoding mitochondrial uncoupling protein was detected in the liver of newborn rats and adult rats after cold exposure, although not in the liver of untreated adult rats.