RESUMEN
To establish the pharmacological profile of a molecule with anti-cancer potential, it seems essential to add an in vivo approach to the first pharmacological experiments carried out in vitro. The present study aims to characterize the degree of sensitivity of seven syngeneic models (two leukemias and five solid tumors) to eleven molecules which have proven to be clinically reliable. We also used some of these models to investigate whether the molecular effects on the extent of growth in a subcutaneously grafted experimental model correlate with the effects of the same drug on the survival of the animals so grafted. Our data show that all the molecules demonstrated significant anti-tumor activities in two mouse leukemia models (with some discrepancies between the two). Two lymphoma models displayed weaker chemosensitivity profiles than the two leukemia models from which they were developed. Two other models, namely the MXT-HS mammary carcinoma and the B16 melanoma, appeared to be rather chemoresistant. However, a direct relationship was evident between the drug-induced decrease in the tumor growth rate and the increase observed in the survival periods of the MXT tumor-bearing mice. This relationship was also observed in the L1210_LYM lymphoma, though to a lesser extent, and was completely absent from the B16 melanoma model. Finally, our data indicated that we had developed a pair of metastasizing, as opposed to non-metastasizing, lymphoma and mammary carcinoma models. In conclusion, the present study shows that syngeneic mouse tumor models can be used as valuable in vivo experimental models for the screening of potential anti-cancer agents.
Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales/métodos , Neoplasias Experimentales/tratamiento farmacológico , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/estadística & datos numéricos , Femenino , Leucemia L1210/tratamiento farmacológico , Leucemia L1210/patología , Leucemia P388/tratamiento farmacológico , Leucemia P388/patología , Masculino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Neoplasias Experimentales/patología , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Nonsmall cell lung carcinomas (NSCLCs) are associated with very dismal prognoses, and adjuvant chemotherapy, including irinotecan, taxanes, platin, and vinca alkaloid derivatives, offer patients only slight clinical benefits. Part of the chemoresistance of NSCLC results from the expression in NSCLC cells of a very large set of endogenous proteins, which antagonize chemotherapy-mediated attacks on these tumor cells. METHODS: The authors set up an orthotopic model of a human NSCLC by grafting A549 cells into the lungs of nude mice. They tried treating these A549 NSCLC orthotopic xenograft-bearing nude mice on the basis of various chemotherapeutic protocols, including chronic administrations of taxol, oxaliplatin, and irinotecan. A cyclooxygenase-2 (COX-2) inhibitor (NS-398) also was assayed in combination with taxol. The immunohistochemical expression levels of COX-2, prostaglandin E synthetase (PGES), ornithine decarboxylase (ODC), the lung-related resistance protein (LRP), and glutathione-S-transferase-alpha (GST-alpha), GST-mu, and GST-pi were quantitatively determined by means of computer-assisted microscopy in control and drug-treated NSCLC orthotopic xenografts. RESULTS: The orthotopic A549 xenograft model developed in 100% of the grafted mice, leading to brain metastases in approximately 61% mice and to liver metastases in approximately 40% of mice. The model was resistant to taxol and oxaliplatin and was only weakly sensitive to irinotecan. High levels of chemoresistant markers (i.e., COX-2, PGES, ODC, LRP, GST-alpha, GST-mu, and GST-pi) were observed in the nontreated A549 xenografts, although with dramatic variations in individual expression. Taxol and oxaliplatin significantly increased the levels of expression of COX-2, PGES, GST-mu, and GST-pi in a number of different experimental protocols. CONCLUSIONS: The A549 orthotopic xenograft model could be used to evaluate investigational chemotherapeutic agents to identify drugs rapidly that are more active than the drugs currently in use in hospitals.