Chemoprotective effects of KF41399, a derivative of carbazole compounds, on nimustine-induced thrombocytopenia
| Autor: | Fumihiko Kanai, Shiro Akinaga, Hideaki Mizoguchi, Kinya Yamashita, Chikara Murakata, Yoji Ikuina, Tatsuya Tamaoki, Yukimasa Shiotsu, Masanao Teramura |
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| Rok vydání: | 2000 |
| Předmět: |
Chemoprotective agent
Male Cyclin E Lung Neoplasms Cell Survival Cyclin A Transplantation Heterologous Immunology Carbazoles Administration Oral Mice Nude Bone Marrow Cells Pharmacology Adenocarcinoma Biochemistry Colony-Forming Units Assay chemistry.chemical_compound Mice Oral administration Medicine Animals Humans Sarcoma 180 Mice Inbred BALB C biology business.industry Platelet Count Nimustine Cell Cycle Cell Biology Hematology Hematopoietic Stem Cells Thrombocytopenia medicine.anatomical_structure chemistry Toxicity Chemoprotective biology.protein Leukocytes Mononuclear Bone marrow business K562 Cells Spleen |
| Zdroj: | Blood. 95:3771-3780 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v95.12.3771 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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