Rescue of Schizosaccharomyces pombe from camptothecin-mediated death by a DNA topoisomerase I inhibitor, TAN-1518 A.

Abstract

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.

• Authors: T Horiguchi, S Tanida
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 49 Issue 10 Pg. 1395-401 (May 17 1995) ISSN: 0006-2952 [Print] England
• PMID: 7763282 (Publication Type: Journal Article)

Chemical References

• Tetracyclines
• Topoisomerase I Inhibitors
• TAN 1518 A
• Camptothecin

Topics

• Base Sequence
• Camptothecin (antagonists & inhibitors)
• Cell Count
• Cell Death
• DNA Damage
• Molecular Sequence Data
• Schizosaccharomyces (drug effects, genetics)
• Tetracyclines (pharmacology)
• Topoisomerase I Inhibitors