We examined the chemoprotective effects of
KF41399, a novel derivative of
carbazole compounds, on severe
thrombocytopenia induced by
nimustine (
ACNU, 45 mg/kg administered for 2 consecutive days intravenously) in mice. Administration schedule studies revealed that pretreatment of mice with
KF41399 was necessary to improve
thrombocytopenia.
Oral administration of
KF41399 ameliorated
thrombocytopenia induced by
ACNU and accelerated the rate of platelet recovery in a dose-dependent fashion. In addition,
KF41399 pretreatment improved the decrease in
body weight and spleen weight and in the colony-forming activity of bone marrow mononuclear cells (MNC).
Oral administration of
KF41399 to normal mice induced G(0)/G(1)-phase accumulation of MNC as well as hematopoietic progenitor cells (lineage negative cells [Lin(-)]) and reduced the colony-forming activity of MNC. In Lin(-) cells derived from KF41399-treated mice, up-regulation of Bcl-2 and down-regulation 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
kinase 2 (Cdk2), Cdk4, and Cdk6. More important,
KF41399 did not affect the antitumor 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 reduction of the antitumor activity of
ACNU without inducing
thrombocytopenia. These results suggest that
KF41399 might be useful as a chemoprotective agent to improve
chemotherapy-induced
thrombocytopenia and types of other toxicity. (Blood. 2000;95:3771-3780)