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

  • Bull Exp Biol Med. 2024 May;177(1):30-34. doi: 10.1007/s10517-024-06125-9.
A K Zhanataev  1 ,  A V Kulakova  2 ,  O A Luzina  3 ,  T M Khomenko  3 ,  K P Volcho  3 ,  N F Salakhutdinov  3 ,  A D Durnev  2
Affiliations
  • 1. V. V. Zakusov Research Institute of Pharmacology, Moscow, Russia. [email protected].
  • 2. V. V. Zakusov Research Institute of Pharmacology, Moscow, Russia.
  • 3. N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
PMID: 38954304 DOI: 10.1007/s10517-024-06125-9
Abstract

Topotecan administered intraperitoneally at single doses of 0.25, 0.5, and 1 mg/kg induced chromosomal aberrations in bone marrow cells of F1(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.

Keywords
bone marrow; chromosomal aberrations; mice; topotecan; tyrosyl-DNA phosphodiesterase inhibitors.
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