RESUMO
Members of the histone deacetylase (HDAC) family exhibit great promise as potential drug targets in pediatric tumors including neuroblastoma, medulloblastoma, ependymoma and Ewing's sarcoma. HDAC inhibitors of various structural classes have shown anti-tumoral effects in pre-clinical pediatric tumor models as single agents or in combination treatments. Suberoylanilidehydroxamic acid (SAHA=vorinostat) is the most clinical advanced compound of the class and was approved by the US FDA in October 2006 for the treatment of refractory cutaneous T-cell lymphoma. In this phase I/II trial, pediatric patients with relapsed solid tumors, lymphoma or leukemias are treated according to an individualized dose escalation concept ensuring each individual patient to receive his optimal dose with respect to toxicity and efficacy. The study is accompanied by an extensive pharmacokinetic, pharmacodynamic and biomarker program.
Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Administração Oral , Adolescente , Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Ácidos Hidroxâmicos/farmacocinética , Leucemia/sangue , Assistência de Longa Duração , Linfoma/sangue , Masculino , Recidiva Local de Neoplasia/sangue , Neoplasias/sangue , VorinostatRESUMO
Left ventricular biopsies from 38 patients with hypertrophic cardiomyopathy (HOCM 28, HNCM 10) were investigated to evaluate possible correlations between morphological and clinical parameters. No correlation was found between the degree of myocardial hypertrophy (muscle cell diameter), nuclear size of the myocytes, fibrous tissue content and various clinical data such as pressure gradient, left ventricular end-diastolic pressure, Sokolow index and heart volume. In 11 patients with HOCM, a second biopsy was performed after medical therapy (verapamil, n = 9; propranolol, n = 2) over 33 +/- 12 months. Increasing myocardial hypertrophy (cell diameter 16.2 +/- 4.4 mu vs. 20.3 +/- 4.2 mu) was observed in all 11 patients. The interstitial fibrous tissue content increased from 5.7 +/- 6.3 to 12.7 +/- 6.8%. The volume fraction of myofibrils decreased (48.8 +/- 2.7 vs. 43.6 +/- 5.3%). The morphological changes were observed regardless of the clinical outcome which was improved in four, unchanged in five and worsened in two cases. The underlying hypertrophic process in HCM seems to be slowly progressive in most patients and cannot be influenced by medical treatment.