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

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.Effects of exposure of A2780 cells to SN-38 (2 hours) were studied by assessing DNA/protein crosslinks, DNA damage and cytogenetic aberrations.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.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.