Journal article
Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis
Anticancer research, Vol.18(5A), pp.3499-3505
1998
PMID: 9858931
Abstract
Background: SN-38 is the active metabolite of the topoisomerase-I (topo-I) inhibitor Irinotecan (CPT-11). Generally, topo-I inhibitors stabilize the complex between topo-I and DNA which collide with moving DNA replication forks, eventually leading to double stranded DNA damage. Therefore, topo-I inhibitors are regarded as S-phase specific. The present study investigated S-phase dependent and independent effects of SN-38.
Materials and methods: Effects of exposure of A2780 cells to SN-38 (2 hours) were studied by assessing DNA/protein crosslinks, DNA damage and cytogenetic aberrations.
Results: A close correlation (r2 = 0.97) was established between drug-induced DNA/protein crosslinks and double stranded DNA breaks. Cytogenetic analysis revealed near maximum clastogenic effects already evident immediately following 2 hours drug exposure. However, qualitatively, chromatid breaks at 24 hours were different from those at 0 hours, in that at 24 hours they were associated with radial chromosome configurations and sister chromatid exchanges.
Conclusion: The data corroborate that the S-phase dependent mechanism of action of topo-I inhibitors is also applicable to SN-38. The cytogenetic data indicate two distinct interactions of SN-38 with DNA: immediate induction of chromatid breaks independent from DNA synthesis, and induction of chromatid breaks associated with radial chromosome configurations dependent on DNA synthesis.
Details
- Title: Subtitle
- Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis
- Creators
- W Voigt - Visiting Scientist from Dept. Haematology/Oncology, the Martin-Luther Universitaet Halle-Wittenberg, 06120 Halle/Saale, GermanyS Matsui - Roswell Park Cancer InstituteM. B Yin - Roswell Park Cancer InstituteW. C Burhans - Roswell Park Cancer InstituteH Minderman - Roswell Park Cancer InstituteY. M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Anticancer research, Vol.18(5A), pp.3499-3505
- Publisher
- International Institute of Anticancer Research
- PMID
- 9858931
- ISSN
- 0250-7005
- eISSN
- 1791-7530
- Language
- English
- Date published
- 1998
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359903302771
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