RESUMO
Anticancer drug discovery and development in cancer are currently undergoing of fast transformation. The selection of a therapeutic and effective dose using conventional cytotoxic agents has been based on the consecution of the maximally tolerated dose. However, this principle does not apply for new targeted therapies, where the definition of the optimal biologic dose (OBD) should be preferred. The definition of OBD might be established based on pharmacokinetic endpoints and, ideally, on pharmacodynamic assays by demonstrating directly the biological effect on the target and its downstream molecules in normal or tumor tissues. Normal tissues, such as peripheral blood mononuclear cells, skin or mucosa, may be excellent surrogates for explore the exposure of a drug and the dynamic target inhibition in vivo. In addition, tumor pharmacodynamic assays may determine the biologic effects of a therapy because tumor cells respond in a different way to targeted drugs than normal tissues, and to identify biomarkers that would permit to predict the individual response. In conclusion, these studies provide demonstration of proof of concept for biological and molecular mechanisms of selected drug, to select the appropriate population to be treated, to help the interpretation of clinical data, to inform the identification of optimal dose and schedule, to evaluate the clinical response and to contribute to take decisions for final approval by authorities.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias/metabolismo , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Systemic infections caused by opportunistic fungi have shown an increased frequency in the past 10 years, particularly in immunocompromised patients. Hansenula anomala is an ascosporogenous yeast of the Ascomycetes class found in the skin, throat, and digestive tract transient normal flora. This study was conducted to compare the pathogenicity of H. anomala and Candida albicans in a model of immunocompromised mice. Thirty-eight Swiss mice were divided into two groups as follows: 30 animals received an intraperitoneal (i.p.) injection of cyclophosphamide (200 mg/kg) four days before the induction of infection with H. anomala (1 x 10(6) yeasts/mL), and 8 animals received 100 mg/kg of cyclophosphamide at 3-day intervals during 3 weeks before inoculation of 1 x 10(7) yeasts/mL. All animals were treated with amoxicillin/clavulanic acid (40 mg/kg) four days before induction of infection. A group of mice inoculated with C. albicans (ATCC 64548) served as control. Tissue samples from the lung, spleen, liver, and kidney for histological and mycologic studies were obtained at necropsy. In each animal, the number of viable yeasts per gram of kidney was determined. The organs most frequently infected by H. anomala were the kidneys and the liver (20%), and the lung (10%). However, in conditions of sustained immunosuppression, H. anomala was found in 65.5% of the organs examined. It is concluded that in an experimental model of immunocompromised mice, the pathogenicity of H. anomala was low.