Chemoprotective effects of KF41399, a derivative of carbazole compounds, on nimustine-induced thrombocytopenia

We examined the chemoprotective effects of KF41399, a novel derivative of c arbazole compounds, on severe thrombocytopenia induced by nimustine (ACNU, 45 mg/kg administered for 2 consecutive days intravenously) in mice. Admini stration schedule studies revealed that pretreatment of mice with KF41399 w as necessary to improve thrombocytopenia, Oral administration of KF41399 am eliorated thrombocytopenia induced by ACNU and accelerated the rate of plat elet recovery in a dose-dependent fashion. In addition, KF41399 pretreatmen t improved the decrease in body weight and spleen weight and in the colony- forming activity of bone marrow mononuclear cells (MNC). Oral administratio n of KF41399 to normal mice induced G(0)/G(1)-phase accumulation of MNC as well as hematopoietic progenitor cells (lineage negative cells [Lin(-)]) an d reduced the colony-forming activity of MNC. In Lin(-) cells derived from KF41399-treated mice, up-regulation of Bcl-2 and downregulation of cyclin E and cyclin A proteins were observed. In the same cells, a decrease in the phosphorylated form of Rb protein and an increase in the p130 protein were observed without changes in the protein level of cell cycle-dependent kinas e 2 (Cdk2), Cdk4, and Cdk6, More important, KF41399 did not affect the anti tumor activity of ACNU against mouse Sarcoma180 and human lung cancer LC-6, However, 25-mg/kg KF41399 treatment reduced the antitumor activity of ACNU against human lung cancer Lu-65, and 5 mg/kg KF41399 caused a slight reduc tion of the antitumor activity of ACNU without inducing thrombocytopenia. T hese results suggest that KF41399 might be useful as a chemoprotective agen t to improve chemotherapy-induced thrombocytopenia and types of other toxic ity. (C) 2000 by The American Society of Hematology.