title: Differential stabilization of eukaryotic DNA topoisomerase I cleavable complexes by camptothecin derivatives.
abstract: Camptothecins belong to a group of anticancer agents with a specific mechanism of action: stabilization and trapping of eukaryotic DNA topoisomerase I (top1) cleavable complexes. Two water-soluble camptothecin derivatives are in clinical trial, and their anticancer activity appears promising: topotecan and CPT-11. The latter is hydrolyzed to its active metabolite, SN-38. We have previously reported that SN-38 is among the most cytotoxic camptothecin derivatives and that the cleavable complexes induced by SN-38 are more stable than those induced by CPT in human colon carcinoma cells [Tanizawa et al. (1994) J. Natl. Cancer Inst, 86, 836-842]. Top1 inhibition was further investigated by determining the salt-induced religation rates of top1-cleavable complexes in fragments from the top1 cDNA. Religation depended on both the local DNA base sequence and the drug structure. Cleavable complexes induced by SN-38 and 10,11-methylenedioxycamptothecin were markedly more stable (less rapidly reversible) than those induced by CPT, topotecan, and 9-aminocamptothecin. The stability of 10-hydroxycamptothecin-induced cleavable complexes was intermediate to those of CPT and SN-38, indicating that both the 10-hydroxy and the 7-ethyl group of SN-38 probably interact with the drug binding site of top1-cleavable complexes. A DNA oligonucleotide containing a single top1 cleavage site was also used to compare the camptothecin derivatives. The salt stability of drug-induced cleavable complexes in the top1 oligonucleotide was correlated with the drug potencies to induce top1 cleavage. Cell killing requires that trapped cleavable complexes be converted to DNA damage as a result of replication fork collision.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tanizawa
authors.forename: K W
authors.initials: KW
authors.lastname: Kohn
authors.forename: G
authors.initials: G
authors.lastname: Kohlhagen
authors.forename: F
authors.initials: F
authors.lastname: Leteurtre
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004247:DNA; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004795:Enzyme Stability; D006868:Hydrolysis; D008969:Molecular Sequence Data; D009994:Osmolar Concentration; D012492:Salts; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D012492:Salts; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin