Desenvolvimento do modelo experimental de mielossupressão induzida pela carboplatina: papel do óxido nítrico e da interleucina-17

Abstract

Myelosuppression is an important and dose-limiting side effect in cancer therapy, whose pathophysiology is not completely understood. Carboplatin (CB) is a platinum derivative with high myelotoxicity. This study aims to develop a short-term experimental murine model of CB-induced myelosuppression and to evaluate changes in peripheral blood, bone marrow and spleen. It also aims to validate the experimental model by investigating the role of nitric oxide and IL-17 in myelosuppression and post-CB hematopoietic recovery. 126 male Swiss mice (Mus musculus), aged 6 to 8 weeks, weighing between 22-26 g were used. First, the kinetics and dose-response curve were evaluated with different doses of CB, 100, 120 and 150 mg/kg intraperitoneal (i.p.). Considering myelosuppression and recovery, a dose of 120 mg/kg of CB was chosen. The mice were sacrificed at 1 st , 2 nd, 3rd, 4th and 6th day of the beginning of the experiment. To assess the effects of nitric oxide and IL-17, NOS inhibitors (L-Name, aminoguanidine or 1400W) or IL-17 were administered i.p. 60 minutes before CB and daily until the animal was sacrificed on the third day of the experiment. Haematological changes were assessed by blood count with reticulocytes, myelograms, splenograms and histopathological study of the bone marrow. CB-induced myelosuppression is time and dosedependent, with nadir between two and three days and recovery from hematopoiesis in about four to six days. The NOS inhibitors used stimulated granulopoiesis causing an increase in neutrophils in peripheral blood. L-Name, a non-selective NOS inhibitor, caused an increase in total cellularity with granulocytic medullary hyperplasia and splenic lymphocytic hyperplasia, demonstrating an inhibitory effect of nitric oxide on myelopoiesis. The L-Name had a suppressive effect on megakaryopoiesis. IL-17 stimulated granulopoiesis with increased total cellularity with medullary and splenic granulocytic hyperplasia, with a consequent increase in neutrophils in peripheral blood. It is concluded that the experimental model of short-term myelosuppression induced by CB is reversible and reproducible. This model adequately displays the course of hematological changes in CB-induced myelosuppression. Nitric oxide inhibits myelopoiesis and stimulates megakarypoiesis. IL-17 stimulates myelopoiesis with elevation of leukocytes and neutrophils in peripheral blood and medullary and splenic granulocytic hyperplasia, as well as reducing the recovery time from CB-induced myelosuppression.