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1.
Invest New Drugs ; 40(5): 1080-1086, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35763178

RESUMO

BACKGROUND: Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs. METHODS: Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report. RESULTS: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1-6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7-1.5 months), and median overall survival was 2.9 months 95% CI (1.5-4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. CONCLUSIONS: This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Cisplatino/uso terapêutico , Dissulfiram/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico
2.
Free Radic Res ; 47(8): 624-34, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23710677

RESUMO

Crohn's disease (CD) is a nonspecific, chronic inflammatory disease of the gastrointestinal tract. It is supposed that in etiopathogenesis oxidative stress (OS) plays a role. However, its precise role in the active and non-active states of disease is not known yet. We conducted a pilot study focusing on the relationship between OS of CD in remission and the possibility to influence clinical parameters and markers of OS by polyphenolic extract, Pycnogenol® (Pyc). Compared to 15 healthy controls 15 pediatric CD patients (all were in remission according to their disease activity index - PCDAI) had reduced the activity of Cu/Zn-superoxide dismutase (SOD) and increased the oxidative damage to proteins. We found negative correlations between markers of inflammation (calprotectin, CRP) as well as between PCDAI and total antioxidant capacity (TAC). Activities of antioxidant enzymes, SOD, and glutathione peroxidase (GPX) negatively correlated with calprotectin and PCDAI. Pyc (2 mg/kg) positively influenced the parameters of OS in CD patients after 10 weeks of administration.


Assuntos
Doença de Crohn/metabolismo , Flavonoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adolescente , Amina Oxidase (contendo Cobre)/metabolismo , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Criança , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Feminino , Flavonoides/administração & dosagem , Humanos , Inflamação/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Mesalamina/administração & dosagem , Mesalamina/uso terapêutico , Projetos Piloto , Extratos Vegetais
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