RESUMO
The utilization of adenosine 5'-triphosphate (ATP) infusions to inhibit the growth of some human and animals tumors was based on the anticancer activity observed in in vitro and in vivo experiments, but contradictory results make the use of ATP in clinical practice rather controversial. Moreover, there is no literature regarding the use of ATP infusions to treat hepatocarcinomas. The purpose of this study was to investigate whether ATP prevents in vivo oncogenesis in very-early-stage cancer cells in a well characterized two-stage model of hepatocarcinogenesis in the rat. As we could not preclude the possible effect due to the intrinsic properties of adenosine, a known tumorigenic product of ATP hydrolysis, the effect of the administration of adenosine was also studied. Animals were divided in groups: rats submitted to the two stage preneoplasia initiation/promotion model of hepatocarcinogenesis, rats treated with intraperitoneal ATP or adenosine during the two phases of the model and appropriate control groups. The number and volume of preneoplastic foci per liver identified by the expression of glutathione S-transferase placental type and the number of proliferating nuclear antigen positive cells significantly increased in ATP and adenosine treated groups. Taken together, these results indicate that in this preneoplastic liver model, ATP as well as adenosine disturb the balance between apoptosis and proliferation contributing to malignant transformation.
Assuntos
Trifosfato de Adenosina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Glutationa Transferase/análise , Fígado/efeitos dos fármacos , Fígado/enzimologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Coelhos , Ratos , Ratos WistarRESUMO
The utilization of adenosine 5´-triphosphate (ATP ) infusions to inhibit the growth of some human and animals tumors was based on the anticancer activity observed in in vitro and in vivo experiments, but contradictory results make the use of ATP in clinical practice rather controversial. Moreover, there is no literature regarding the use of ATP infusions to treat hepatocarcinomas. The purpose of this study was to investigate whether ATP prevents in vivo oncogenesis in very-early-stage cancer cells in a well characterized two-stage model of hepatocarcinogenesis in the rat. As we could not preclude the possible effect due to the intrinsic properties of adenosine, a known tumorigenic product of ATP hydrolysis, the effect of the administration of adenosine was also studied. Animals were divided in groups: rats submitted to the two stage preneoplasia initiation/promotion model of hepatocarcinogenesis, rats treated with intraperitoneal ATP or adenosine during the two phases of the model and appropriate control groups. The number and volume of preneoplastic foci per liver identified by the expression of glutathione S-transferase placental type and the number of proliferating nuclear antigen positive cells significantly increased in ATP and adenosine treated groups. Taken together, these results indicate that in this preneoplastic liver model, ATP as well as adenosine disturb the balance between apoptosis and proliferation contributing to malignant transformation.
La utilización de adenosina 5´-trifosfato (ATP ) para inhibir el crecimiento de algunos tumores en humanos y en animales se basa en la actividad anticancerígena observada en experimentos in vitro e in vivo. El uso del ATP en la práctica clínica es discutido debido a resultados contradictorios. Por otra parte, no existen antecedentes del uso de ATP en el tratamiento de hepatocarcinomas. El objetivo del presente estudio fue determinar si el ATP previene la oncogénesis in vivo en un modelo de preneoplasia hepática murina de dos etapas. Para determinar la probable contribución de la adenosina, producto de la hidrólisis de ATP y descrita como tumorigénica, se estudió también el efecto del nucleósido exógeno sobre los focos preneoplásicos. Los animales se dividieron en grupos: ratas sometidas al modelo de preneoplasia de iniciación/promoción, ratas tratadas con ATP o adenosina intraperitonealmente durante las dos fases del modelo y los correspondientes grupos controles. El número y el volumen de focos preneoplásicos por hígado, identificados por la expresión de la forma placentaria de la glutation S- transferasa de rata y el número de células positivas para el antígeno nuclear proliferante, aumentaron significativamente en los grupos tratados con ATP y adenosina. Los resultados en su conjunto indican que en este modelo preneoplásico, el ATP y la adenosina alteran el balance entre apoptosis y proliferación, contribuyendo a la transformación maligna.