RESUMO
PURPOSE: Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776. EXPERIMENTAL DESIGN: Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m(2) over 72 hours (667 mg/m(2)/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m(2)/dose. RESULTS: Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m(2)). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m(2) or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m(2), consistent with unrepaired DNA damage. CONCLUSIONS: These data support a randomized phase II trial of cytarabine +/- SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m(2)) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Quinase 1 do Ponto de Checagem , Citarabina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Histonas/metabolismo , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Fosforilação , Proteínas Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
A case of a patient with glenohumeral joint arthritis is presented which demonstrated the three-dimensional shoulder motion before and after total shoulder arthroplasty. Pre-operative shoulder motion differed compared to normal controls, while post-operatively her glenohumeral-to-scapulothoracic motion ratios were restored to near normal ratios.