Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3771-3780
Chemoprotective effects of KF41399, a derivative of carbazole
compounds, on nimustine-induced thrombocytopenia
Yukimasa Shiotsu,
Kinya Yamashita,
Fumihiko Kanai,
Yoji Ikuina,
Chikara Murakata,
Masanao Teramura,
Hideaki Mizoguchi,
Tatsuya Tamaoki, and
Shiro Akinaga
From Kyowa Hakko Kogyo Pharmaceutical Laboratories, Shizuoka, and
the Department of Hematology, Tokyo Women's Medical University, Tokyo,
Japan.
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
G0/G1-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.
