Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
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Da-125 a New Antitumor Agent, Inhibits Topoisomerase II as Topoisomerase Poison and DNA Intercalator Simultaneously

  • Seo, Jin-Wook (Department of Biotechnology, College of Industrial Science, Chung-Ang University) ;
  • Lee, Hak-Sung (Department of Biotechnology, College of Industrial Science, Chung-Ang University) ;
  • Lee, Min-Jun (Department of Biotechnology, College of Industrial Science, Chung-Ang University) ;
  • Kim, Mi-Ra (Department of Biotechnology, College of Industrial Science, Chung-Ang University) ;
  • Shin, Cha-Gyun (Department of Biotechnology, College of Industrial Science, Chung-Ang University)
  • Published : 2004.01.01
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Abstract

DA-125, a novel derivative of adriamycin, is known for its anti-cancer activity. In this study, the inhibitory mechanism of DA-125 on topoisomerase was investigated in the simian virus 40 (SV40) replicating CV-1 cell by studying the SV40 DNA replication intermediates and DNA-topoisomerase complexes. DNA-protein complexes that were formed in the drug-treated cells were quantitated by using a glass filter assay. SV40 DNA replication intermediates that were accumulated in the drug-treated CV-1 cell were analyzed in a high resolution gel. DA-125 did not accumulate B-dimers of SV40 DNA replication intermediates which were found in the adriamycin-treated CV-1 cells. DA-125 induced a dose-dependent formation of the DNA-protein complexes, while adriamycin did not. When adriamycin and etoposide (VP16) were added to the SV40-infected cells at the same time, adriamycin blocked the formation of the DNA-protein complexes induced by VP16 in a dose-dependent manner. However, DA-125 blocked the formation of the DNA-protein complexes induced by VP16 up to the maximum level of the DNA-protein complexes that were induced by DA-125 alone. Adriamycin and DA-125 did not inhibit the formation of the DNA-protein complexes that were caused by camptothecin, a known topoisomerase I poison. DA-125 is bifunctional in inhibiting topoisomerase II because it simultaneously has the properties of the topoisomerase II poison and the DNA intercalator. As a topoisomerase II poison, DA-125 alone induced dose-dependent formation of the DNA-protein complexes. However, as a DNA intercalator, it quantitatively inhibited the formation of the DNA-protein complexes induced by a strong topoisomerase II poison VP16. Furthermore considering that the levels of the DNA-protein complex induced by VP16 were decreased by DA-125 in terms of the topoisomerase II poison, we suggest that DA-125 has a higher affinity to the drug-binding sites of DNA than VP16 has.

Keywords

References

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