RESUMO
Previous studies have drawn attention to dendritic cell (DC) vaccines; particularly the application of the tumor-associated antigen-targeted DC vaccine. The present study analyzed DCs derived from a normal individual and pulsed the cells with heat shock protein 70 peptide (Hsp70) and/or hepatitis B virus x antigen (HBxAg), a hepatocellular carcinoma (HCC)-associated antigen. It was then investigated whether this method of vaccination induced strong therapeutic antitumor immunity. The results revealed that the Hsp70/HBxAg complex-activated phenotype improves the functional maturation of DCs compared with using Hsp70 or HBxAg alone. Compared with either Hsp70 or HBxAg alone, matured DCs pulsed with the Hsp70/HBxAg complex stimulated a high level of autologous T-cell proliferation and induced HCC-specific cytotoxic T lymphocytes, which specifically killed HCC cells through a major histocompatibility complex class I mechanism. These results indicated that a vaccination therapy using DCs co-pulsed with the Hsp70/HBxAg complex is an effective strategy for immunotherapy and may offer a useful approach to protect against HCC.
Assuntos
Carcinoma Hepatocelular/imunologia , Células Dendríticas/imunologia , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Hepáticas/imunologia , Transativadores/imunologia , Animais , Antígenos Virais/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/virologia , Morte Celular , Diferenciação Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Citometria de Fluxo , Células Hep G2 , Humanos , L-Lactato Desidrogenase/metabolismo , Camundongos Nus , Camundongos SCID , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T Citotóxicos/imunologia , Transativadores/genética , Transfecção , Proteínas Virais Reguladoras e Acessórias , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1. METHODS: A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m(2), po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, t1/2, AUC0-t, and AUC0-∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and Cmax of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews. RESULTS: The mean values of Cmax, AUC0-t, and AUC0-∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found. CONCLUSION: The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m(2)) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.
