Enhancement of the Clastogenic Effects of Topotecan In Vivo by Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

• Published in: Bulletin of experimental biology and medicine Vol. 177; no. 1; pp. 30 - 34
• Main Authors: Zhanataev, A. K., Kulakova, A. V., Luzina, O. A., Khomenko, T. M., Volcho, K. P., Salakhutdinov, N. F., Durnev, A. D.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.05.2024; Springer Nature B.V
• Subjects: Acids; Animals; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bone Marrow Cells - drug effects; Cell Biology; Chromosome aberrations; Chromosome Aberrations - chemically induced; Chromosome Aberrations - drug effects; Chromosomes; Cytogenetics; DNA damage; DNA repair; Drug dosages; Enzymes; Experiments; Internal Medicine; Laboratory animals; Laboratory Medicine; Male; Mice; Mice, Inbred C57BL; Mutagens - toxicity; Pathology; Pharmacology; Pharmacology and Toxicology; Phosphodiesterase; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Research centers; Topoisomerase I Inhibitors - pharmacology; Topotecan; Topotecan - pharmacology; Usnic acid; chromosomal aberrations; tyrosyl-DNA phosphodiesterase inhibitors; mice; bone marrow; topotecan
• ISSN: 0007-4888; 1573-8221; 1573-8221
• DOI: 10.1007/s10517-024-06125-9

Topotecan administered intraperitoneally at single doses of 0.25, 0.5, and 1 mg/kg induced chromosomal aberrations in bone marrow cells of F 1 (CBA×C57BL/6) hybrid mice in a dose-dependent manner. A tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitor, an usnic acid derivative OL9-116 was inactive in a dose range of 20-240 mg/kg, but enhanced the cytogenetic effect of topotecan (0.25 mg/kg) at a dose of 40 mg/kg ( per os ). The TDP1 inhibitor, a coumarin derivative TX-2552 (at doses of 20, 40, 80, and 160 mg/kg per os ), increased the level of aberrant metaphases induced by topotecan (0.25 mg/kg) by 2.1-2.6 times, but was inactive at a dose of 10 mg/kg. The results indicate that TDP1 inhibitors enhance the clastogenic activity of topotecan in mouse bone marrow cells in vivo and are characterized by different dose profiles of the co-mutagenic effects.