RESUMO
BACKGROUND: The objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. PATIENTS AND METHODS: Dose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs). RESULTS: Thirty patients treated at one of five doses (10-80 mg/day) received 79 cycles of SB939 (range, 1-12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (C(max)) and area under the concentration-time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and C(max). Stable disease was seen in several tumor types treated at ≥40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose. CONCLUSIONS: SB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939.
Assuntos
Benzimidazóis/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Histona Desacetilases/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/metabolismoRESUMO
Molecular determinants of FlA1 fluorinase specificity were probed using 5'-chloro-5'-deoxyadenosine (5'-ClDA) analogs as substrates and FlA1 active site mutants. Modifications at F213 or A279 residues are beneficial towards these modified substrates, including 5'-chloro-5'-deoxy-2-ethynyladenosine, ClDEA (>10-fold activity improvement), and conferred novel activity towards substrates not readily accepted by wild-type FlA1.
Assuntos
Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sondas Moleculares/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Proteínas de Bactérias/química , Cladribina/química , Cladribina/metabolismo , Modelos Moleculares , Sondas Moleculares/química , Mutação , Conformação de Ácido Nucleico , Oxirredutases/química , Streptomyces/enzimologia , Especificidade por SubstratoRESUMO
Two methods of podophyllin application, namely hospital-application (regimen A) and self-application (regimen B) of 25% podophyllin in tincture of benzoin compound for the treatment of penile condylomata were compared. The objective was to compare the response and safety of self-application with traditional hospital-application. A total of 100 men were selected, of which 64 were valid for evaluation of response. At six weeks' follow-up 66% and 72% of patients treated with regimen A and B, respectively were cured. Patients treated with regimen A were less compliant making only 58% of the required number of applications as compared with those treated with regimen B who made 92% of the applications. Of the patients successfully treated, 43% and 20% of those treated with regimens A and B, respectively were cured after only one or two applications (p greater than 0.1). Three patients--two treated with regimen A and one treated with regimen B suffered local reactions to the first application of podophyllin. All these patients recovered without sequelae. Self-application of podophyllin can therefore be used safely and effectively in selected men with penile condyloma acuminata.