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

Background: SN-38 ir; the active metabolite of the topoisomerase-l (topo-I) inhibitor Irinotecan (CPT-II). Generally, topo-I inhibitors stabilize the complex between topo-I and DNA which collide with moving DNA replication fo rks, eventually leading to double stranded DNA damage. Therefore, topo-I in hibitors are regarded as S-phase specific. The present study investigated S -phase dependent and independent effects of SN-38. Materials and Methods: E ffects of exposure of A2780 cells to SN-38 (2 hours) were studied by assess ing DNA /protein crosslinks, DNA damage and cytogenetic aberrations Results : A close correlation (r(2)=0.97) was established between drug-induced DNA/ protein crosslinks and double stranded DNA breaks: Cytogenetic analysis rev ealed near maximum clastogenic effects already evident immediately followin g 2 hours drug exposure. However, qualitatively, chromatid breaks at 24 hou rs were different from those at 0 hours, in that at 24 hours they were asso ciated 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 da ta indicate two distinct interactions of SN-38 with DNA: immediate inductio n of chromatid breaks independent from DNA synthesis, and induction of chro matid breaks associated with radial chromosome configurations dependent on DNA synthesis.