Avaliação da interferência de imunossupressores no desenvolvimento de metástases em ratos inoculados com um fibro-histiocitoma maligno de baixo índice metastático

Abstract

Metastasis is responsible for death in the majority of cancer patients. Metastases are secondary tumors that grow out from heterogenous populations of primary malignant tumors, which possibly occurs when these cellular populations escape jfrom the immunologic surveillance and colonise at distant sites. The participation of the immune system is important in immunogenic tumors to reduce malignancy. Cyclosporme (CS) is a prototype of a generation of immunosuppressive drugs widely used in organ transplantation and autoimmune disease. CS acts by mhibitmg the function of T helper cells. The subject of this work was to determine the mfluence of C S m the development of metastasis fi-om a low metastatic tumor (fibrous histiocytoma T.E.G.S. 2047), maculated s.c. (suspension of 10 cells/rat). Comparison was made with other traditional immunosuppressant drugs: Azathioprin (AZA), methylprednisolone (MP), and with a new drug, Mycophenolate mofetil or CellCept (MMF). The latter is a pro dmg of mycophenolic acid, and mhibits specifically lymphocyte proliferation, and blocks the glycosylation of protems mvolved m the intercellular adhesion of lymphocytes and monocytes to endothelial cells. The study was performed on Wistar rats, 4-6 weeks old. Our results showed that in the ammals treated with CS (10 nig/Kg/day) the incidence of lung metastasis increased from 0% in our control groups (animals with tumors and without immunosuppressor treatment), to 72,72% (p<0,01). This value was significantly higher with respect to AZA or MP (p<0,01). CS also increased the tumor volume of the prmiary tumors with respect to the other groups. The animals treated with AZA (4 mg/Kg/day) and MP (1 mg/Kg/day) showed a significat mcrease m the mcidence of lung metastasis (p<0,05), 43,75% and 50%, respectively. With respect to MMF it did not cause any metastasis m our model, probably due to its effect on adhesion molecules. Hematological studies showed ymphopenia in the animals treated with CS and MP, and a lymphocytosis and neutrophilia m the ones treated with MMF. Our findmgs suggest the active participation of the dmgs used m the classic immunosuppressive scheme (CS/ AZA/ MP), mamly CS m the inhibition of mechanisms involved m the immunologic surveillance of this tumor. Our results with MMF may suggest a possible blockade at the level of adhesion molecules, could block another step m the metastatic cascade, the adhesion ofmetastatic cells to the endothelium.