Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis.
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.


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.


CONCLUSIONS
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.
Voigt
W
W
Dept. Haematology/Oncology, Martin-Luther Universitaet Halle-Wittenberg, Halle/Saale, Germany.
Matsui
S
S
Yin
M B
MB
Burhans
W C
WC
Minderman
H
H
Rustum
Y M
YM
D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002842:Chromatids / Q000187:drug effects*; D002869:Chromosome Aberrations; D004249:DNA Damage; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D016196:S Phase; D012854:Sister Chromatid Exchange; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin