RESUMO
Lens-epithelium-derived growth-factor (LEDGF/p75)-binding site on HIV-1 integrase (IN), is an attractive target for antiviral chemotherapy. Small-molecule compounds binding to this site are referred as LEDGF-IN inhibitors (LEDGINs). In this study, compound libraries were screened to identify new inhibitors of LEDGF/p75-IN interaction. Ebselen (2-phenyl-1,2-benzisoselenazol-3-one), a reported anti-HIV-1 agent, was identified as a moderate micromolar inhibitor of LEDGF/p75-IN interaction. Ebselen inhibited the interaction by binding to LEDGF/p75 and the ability of ebselen to inhibit the interaction could be reversed by dithiothreitol (DTT). BLI experiment showed that ebselen probably formed selenium-sulphur bonds with reduced thiols in LEDGF/p75. To the best of our knowledge, we showed for the first time that small-molecule compound, ebselen inhibited LEDGF/p75-IN interaction by directly binding to LEDGF/p75. The compound discovered here could be used as probe compounds to design and develop new disrupter of LEDGF/p75-IN interaction.
Assuntos
Fármacos Anti-HIV/farmacologia , Azóis/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Compostos Organosselênicos/farmacologia , Fármacos Anti-HIV/química , Azóis/química , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores de Integrase de HIV/química , Humanos , Isoindóis , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organosselênicos/química , Relação Estrutura-AtividadeRESUMO
<p><b>OBJECTIVE</b>To assess the therapeutic effect of percutaneous intratumoral injection with lipiodol emulsion of chemotherapie agents (CALE) on implanted VX2 tumor in rabbits.</p><p><b>METHODS</b>Twelve New Zealand rabbits with implanted VX2 tumor (24 models) were divided into lipiodol group, chemotherapeutic agent group and CALE group with intratumoral injections of the corresponding agents. The pathological changes of all the lesions were observed and the expression of proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) were evaluated 7 days after the operation.</p><p><b>RESULTS</b>Compared with the lipiodol group and chemotherapie agent group, intratumoral injection of CALE resulted in the highest tumor necrosis rate and greatest tumor necrosis (P<0.01). The labeling indices of PCNA and VEGF expressions in CALE group were markedly lower than those in the other two groups (P<0.01).</p><p><b>CONCLUSION</b>Percutaneous intratumoral injection of CALE is an effective ablation approach for treatment of malignant solid tumors.</p>
Assuntos
Animais , Coelhos , Emulsões , Injeções Intralesionais , Óleo Iodado , Usos Terapêuticos , Neoplasias Experimentais , Metabolismo , Patologia , Terapêutica , Antígeno Nuclear de Célula em Proliferação , Metabolismo , Fator A de Crescimento do Endotélio Vascular , MetabolismoRESUMO
<p><b>OBJECTIVE</b>To evaluate the effectiveness and safety of fluoroscopy-guided percutaneous intratumor injection of pingyangmycin lipiodol emulsion (PLE) in the management of recurrent sacrococcygeal chordomas.</p><p><b>METHODS</b>Seven patients with recurrent sacrococcygeal chordomas presenting with severe local pain with visual analogue score (VAS)≥8 received treatment sessions of fluoroscopy-guided percutaneous intratumor injection of PLE. The patients were followed up every 3 months after the last session to assess their clinical responses and observe the changes in the tumor size measured by computed tomography. The changes in the VAS, tumor necrosis and pain relief as well as the adverse events were recorded.</p><p><b>RESULTS</b>A total of 22 sessions of fluoroscopy-guided percutaneous intratumoral PLE injection was performed in these cases (3 or 4 sessions in each case). The total average pingyangmycin dose delivered was 48.0 mg and the average lipiodol dose was 40.0 ml in each case. Five patients showed low fever and vomiting 48 after the injection. During the follow-up (median time of 21.7 months, range 10-26 months), all the patients showed obviously reduced tumor size and VAS, and partial remission was achieved in 6 patients and stable disease (SD) in 1 patient. None of the patients had complications during the follow-up.</p><p><b>CONCLUSION</b>Fluoroscopy-guided percutaneous intratumoral injection of PLE can be effective and safe and may serve as a alternative for treatment of recurrent sacrococcygeal chordomas.</p>