Asunto(s)
Algoritmos , Biomarcadores , Causalidad , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Interpretación Estadística de Datos , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Humanos , Reproducibilidad de los Resultados , Seguridad , Estados Unidos , United States Food and Drug AdministrationRESUMEN
The use of transgenic rodents may overcome many limitations of traditional cancer studies. Regulatory perspectives continue to evolve as new models are developed and validated. The transgenic mouse, K6/ODC, develops epidermal tumors when exposed to genotoxic carcinogens. In this study, K6/ODC mice were evaluated for model fitness and health robustness in a 36-week study to determine oncogenic risk of residual DNA in vaccines from neoplastic cell substrates. K6/ODC and C57BL/6 mice were treated with T24-H-ras expression plasmid, carrier vector DNA, or saline topically or by subcutaneous injection. One group of K6/ODC mice received 7,12-dimethylbenz-[a]anthracene [DMBA] dermally. Only DMBA-treated mice developed papillomas by six weeks, increasing in incidence to 25 weeks. By week 11, many K6/ODC mice showed severe dehydration and dermal eczema. By week 32, (6/8) surviving K6/ODC mice showed loss of mobility and balance. Microscopic evaluation of tissues revealed dermal/sebaceous gland hyperplasia, follicular dystrophy, splenic atrophy, and amyloid deposition/neutrophilic infiltration within liver, heart, and spleen, in all K6/ODC mice. Pathology was not detected in C57BL/6 mice. Progressive adverse health, decreased survival, and failure to develop papillomas to the H-ras plasmid suggest that K6/ODC mice may be an inappropriate alternative model for detection of oncogenic DNA and pharmaceutical carcinogenicity testing.
Asunto(s)
Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Queratina-6/genética , Ornitina Descarboxilasa/genética , Neoplasias Cutáneas/inducido químicamente , 9,10-Dimetil-1,2-benzantraceno/administración & dosificación , Animales , Pruebas de Carcinogenicidad/métodos , Carcinógenos/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Virus del Sarcoma Murino/genética , Neoplasias Cutáneas/patología , Bazo/efectos de los fármacos , Bazo/patología , TransfecciónRESUMEN
Toxicology studies in animals are required by regulatory authorities worldwide to provide assurances that clinical testing of pharmaceutical candidates can be conducted safely. Safety concerns from animal studies account for over 20% of attritions from drug development. As discordance between humans and animals is expected, two goals of safe and efficient drug development must be (1) to improve the human relevance of animal testing with new models and technologies, and (2) to advance quickly to clinical testing armed with improved safety biomarker tools.