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DNA topoisomerase II as the target for the anticancer drug TOP-53: mechanistic basis for drug action.

Byl JA, Cline SD, Utsugi T, Kobunai T, Yamada Y, Osheroff N
Biochemistry. 2001 40 (3): 712-8

PMID: 11170388 · DOI:10.1021/bi0021838

TOP-53 is a promising anticancer agent that displays high activity against non-small cell lung cancer in animal tumor models [Utsugi, T., et al. (1996) Cancer Res. 56, 2809-2814]. Compared to its parent compound, etoposide, TOP-53 is considerably more toxic to non-small cell lung cancer cells, is more active at generating chromosomal breaks, and displays improved cellular uptake and pharmacokinetics in animal lung tissues. Despite the preclinical success of TOP-53, several questions remain regarding its cytotoxic mechanism. Therefore, this study characterized the basis for drug action. Results indicate that topoisomerase II is the primary cytotoxic target for TOP-53. Furthermore, the drug kills cells by acting as a topoisomerase II poison. TOP-53 exhibits a DNA cleavage site specificity that is identical to that of etoposide. Like its parent compound, the drug increases the number of enzyme-mediated DNA breaks by interfering with the DNA religation activity of the enzyme. TOP-53 is considerably more efficient than etoposide at enhancing topoisomerase II-mediated DNA cleavage and exhibits high activity against human topoisomerase IIalpha and IIbeta in vitro and in cultured cells. Therefore, at least in part, the enhanced cytotoxic activity of TOP-53 can be attributed to an enhanced activity against topoisomerase II. Finally, TOP-53 displays nearly wild-type activity against a mutant yeast type II enzyme that is highly resistant to etoposide. This finding suggests that TOP-53 can retain activity against systems that have developed resistance to etoposide, and indicates that substituents on the etoposide C-ring are important for topoisomerase II-drug interactions.

MeSH Terms (17)

Antigens, Neoplasm Antineoplastic Agents, Phytogenic DNA, Fungal DNA-Binding Proteins DNA Damage DNA Ligases DNA Topoisomerases, Type II Etoposide Humans Hydrolysis Isoenzymes Mutagenesis, Site-Directed Recombinant Proteins Saccharomyces cerevisiae Structure-Activity Relationship Topoisomerase II Inhibitors Tumor Cells, Cultured

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