RESUMO
BACKGROUND: Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently metastasises to bone, SFK are also vital to the regulation of bone remodelling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone. METHODS: C4-2B CaP cells were injected into tibiae of SCID mice and treated with dasatinib, alone or in combination with docetaxel. Serum prostate-specific antigen levels, bone mineral density, radiographs and histology were analysed. RESULTS: Treatment with dasatinib alone significantly lowered sacrifice serum prostate-specific antigen levels compared to control, 2.3+/-0.4 vs 9.2+/-2.1 (P=0.004). Combination therapy improved efficacy over dasatinib alone (P=0.010). Dasatinib increased bone mineral density in tumoured tibiae by 25% over control tumoured tibiae (P<0.001). CONCLUSION: Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel. Additionally, dasatinib inhibits osteolysis associated with CaP. These data support further study of dasatinib in clinical trials for men with CaP bone metastases.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Osteólise/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Neoplasias Ósseas/sangue , Linhagem Celular Tumoral , Dasatinibe , Docetaxel , Humanos , Masculino , Camundongos , Camundongos SCID , Osteólise/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Taxoides/administração & dosagem , Tiazóis/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/antagonistas & inibidoresRESUMO
The outcome of high tibial osteotomy (HTO) deteriorates with time, and additional procedures may be required. The aim of this study was to compare the clinical and radiological outcomes between unicompartmental knee replacement (UKR) and total knee replacement (TKR) after HTO as well as after primary UKR. A total of 63 patients (63 knees) were studied retrospectively and divided into three groups: UKR after HTO (group A; n = 22), TKR after HTO (group B; n = 18) and primary UKR (group C; n = 22). The Oxford knee score (OKS), Knee Society score (KSS), hip-knee-ankle angles, mechanical axis and patellar height were evaluated pre- and post-operatively. At a mean of 64 months (19 to 180) post-operatively the mean OKS was 43.8 (33 to 49), 43.3 (30 to 48) and 42.5 (29 to 48) for groups A, B and C, respectively (p = 0.73). The mean KSS knee score was 88.8 (54 to 100), 88.11 (51 to 100) and 85.3 (45 to 100) for groups A, B and C, respectively (p = 0.65), and the mean KSS function score was 85.0 (50 to 100) in group A, 85.8 (20 to 100) in group B and 79.3 (50 to 100) in group C (p = 0.48). Radiologically the results were comparable for all groups except for patellar height, with a higher incidence of patella infra following a previous HTO (p = 0.02).