RESUMO
BACKGROUND: Treatment options for sarcoma are limited. Histone deacetylase inhibitors increase the efficacy of topoisomerase II inhibitors by promoting access to chromatin and by down-regulating DNA repair. Thus, combined panobinostat and epirubicin therapy was evaluated to treat refractory sarcoma. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled in a 3 + 3 dose-escalation phase I trial of panobinostat given on days 1, 3, and 5 followed by 75 mg/m(2) of epirubicin on day 5 in 21-day cycles, with a dose expansion at maximum tolerated dose (MTD) in 20 sarcoma patients. Peripheral blood mononucleocyte histone acetylation was also evaluated. RESULTS: Forty patients received 20-60 mg panobinostat. Dose-limiting toxicities included thrombocytopenia, febrile neutropenia, and fatigue at 60 mg, defining a panobinostat MTD at 50 mg. Four responses were seen in 37 assessable patients, all after progression on prior topoisomerase II inhibitors. For those with sarcoma, 12 of 20 derived clinical benefit (1 partial response and 11 stable disease, median overall survival 8.3 months), including 8 of 14 previously progressed on topoisomerase II therapy. Treatment benefits correlated with increased histone acetylation and decreased neutrophil count on day 5. CONCLUSIONS: Panobinostat and epirubicin treatment is well tolerated and may reverse anthracycline resistance. Changes in histone acetylation and associated decrease in neutrophil count correlated with clinical benefit and warrant investigation as predictive biomarkers. CLINICAL TRIAL: This trial is registered at www.Clinicaltrials.gov, Identifier: NCT00878904.
Assuntos
Quimioterapia Combinada , Epirubicina/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Indóis/administração & dosagem , Sarcoma/tratamento farmacológico , Adulto , Idoso , Cromatina/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Epirubicina/efeitos adversos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Indóis/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Panobinostat , Sarcoma/genética , Sarcoma/patologia , Inibidores da Topoisomerase II/administração & dosagemRESUMO
Endemic goiter involves about 15% of the population of Vietnam. To define the role of various factors which contribute to endemic goiter in Vietnam, we surveyed 935 people in Vancon, a lowland commune with goiter appearing only in the past decade, and 619 people in Dich Giao, a highland commune with endemic goiter treated erratically with iodized salt. In Dich Giao, cassava, a goitrogenic food, constitutes half of the dietary caloric intake. The prevalence of goiter was 45% in Vancon and 28% in Dich Giao. Laboratory studies were carried out in a subgroup of 63 subjects in Vancon, 52 subjects in Dich Giao, and a control group of 46 women in Hanoi. The mean serum TSH levels were 1.4 +/- 0.1 (+/- SE) microU/ml in Hanoi, 3.6 +/- 0.5 microU/ml in Vancon (P less than 0.001), and 2.4 +/- 0.2 microU/ml in Dich Giao (P less than 0.05). The mean serum T4 concentrations were similar in the three groups, but the mean free T4 concentration was low in Vancon. Serum T3 levels and the T3 to T4 ratios were significantly elevated in the goitrous regions. The mean serum thyroglobulin (Tg) concentrations were 27 +/- 3 ng/ml in Hanoi, 101 +/- 20 ng/ml in Vancon (P less than 0.01), and 44 +/- 5 ng/ml in Dich Giao (P less than 0.01). The 4-h thyroid uptake was higher in Vancon than in Hanoi. The urinary iodine concentration was low in both goitrous regions, and urinary thiocyanate was increased in Dich Giao, reflecting the ingestion of cassava. For all regions combined, there was a direct correlation between serum TSH and T3 and between serum TSH and Tg. In Vancon, where iodine deficiency was more severe, there was an inverse correlation between thyroid uptake and the urinary iodine concentration; thyroid uptake correlated directly with serum T3, the T3 to T4 ratio, and serum Tg. In Dich Giao, there was no correlation between urinary thiocyanate and thyroid uptake or urinary iodine levels. The data show that low iodine intake is a major factor in the causation of goiter in Vancon, where iodine deficiency had not been suspected. The ingestion of cassava in Dich Giao did not cause a major change in thyroid hormone economy even though iodine intake was marginally low; the data suggest that the goitrogenic effect of cassava is easily overcome by supplementary iodine, even when it is ingested irregularly.