ABSTRACT
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.
Subject(s)
Drug Therapy, Combination , Epirubicin/administration & dosage , Hydroxamic Acids/administration & dosage , Indoles/administration & dosage , Sarcoma/drug therapy , Adult , Aged , Chromatin/drug effects , DNA Repair/drug effects , Dose-Response Relationship, Drug , Epirubicin/adverse effects , Female , Histone Deacetylase Inhibitors/administration & dosage , Humans , Hydroxamic Acids/adverse effects , Indoles/adverse effects , Male , Maximum Tolerated Dose , Middle Aged , Panobinostat , Sarcoma/genetics , Sarcoma/pathology , Topoisomerase II Inhibitors/administration & dosageABSTRACT
BACKGROUND: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points. METHODS: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. RESULTS: In all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response. CONCLUSION: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm , Estrogen Antagonists/administration & dosage , Histone Deacetylase Inhibitors/therapeutic use , Hydroxamic Acids/therapeutic use , Tamoxifen/therapeutic use , Acetylation , Adult , Aged , Breast Neoplasms/mortality , Female , Histone Deacetylase 2/analysis , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/adverse effects , Histones/metabolism , Humans , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/adverse effects , Middle Aged , Tamoxifen/administration & dosage , Tamoxifen/adverse effects , VorinostatABSTRACT
A total of 248 randomly selected subjects from urban, semiurban and rural areas of Calcutta was studied serologically for the prevalence of antibody to Toxoplasma gondii using latex agglutination technique. Fifty-nine (23.79%) out of these 248 subjects were found to possess anti-toxoplasma antibody. Seropositivity was found to be higher in females (25%) as compared to males (22.32%). Agewise highest positivity (30.5%) for toxoplasma antibody was observed in the third decade and lowest in the first decade of life, though all the age groups were involved by this protozoal infection. Sexwise distribution of anti-toxoplasma antibody showed highest positivity rate in the third decade in males and in the fourth decade in females. Twenty-five per cent of the subjects had history of contact with cat and/or soil and most of the subjects belonged to the middle and low income groups.
