Rescue of Schizosaccharomyces pombe from camptothecin-mediated death by a DNA topoisomerase I inhibitor, TAN-1518 A.
TAN-1518 A is a cytotoxic agent with suppressive activity against Meth A fibrosarcoma in vivo. This compound inhibits calf thymus DNA topoisomerase I (Topo I) but does not stimulate cleavable complex formation in the nuclei of Chinese hamster ovary (CHO)-K1 cells, suggesting that it inhibits Topo I in a manner different from that of camptothecin (CPT). To clarify the mode of action of TAN-1518 A, we examined its effects on the eukaryotic microorganism Schizosaccharomyces pombe (S. pombe), which does not require Topo I as an essential factor for growth. TAN-1518 A inhibited purified S. pombe Topo I as potently as did CPT. TAN-1518 A, unlike CPT, did not stimulate Topo I-induced DNA cleavage; instead, it inhibited CPT-induced cleavable complex formation. We constructed a S. pombe strain, IR9, that produced excess Topo I. IR9 was hypersensitive to CPT, but its growth was not affected by TAN-1518 A. The CPT-mediated death of IR9 cells was reduced dramatically in the presence of TAN-1518 A. These findings clearly demonstrate that TAN-1518 A is a specific inhibitor of Topo I in eukaryotic cells and also suggest that this agent inhibits some earlier step(s) that occurs before the formation of cleavable complex on DNA strands in the catalytic cycle of this enzyme.
Horiguchi
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T
Discovery Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
Tanida
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S
D001483:Base Sequence; D002166:Camptothecin / Q000037:antagonists & inhibitors*; D002452:Cell Count; D016923:Cell Death; D004249:DNA Damage; D008969:Molecular Sequence Data; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics; D013754:Tetracyclines / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
D013754:Tetracyclines; D059004:Topoisomerase I Inhibitors; C088527:TAN 1518 A; D002166:Camptothecin