Abstract
BE‐22179, a novel cyclic depsipeptide antibiotic having two 3‐hydroxyquinoline moieties, inhibited the DNA‐relaxing activity of L1210 topoisomerase II completely at 0.08 μM. This effect was far stronger than that of VP‐16. However, it did not show any marked effect on topoisomerase II‐mediated DNA cleavage. BE‐22179 was ineffective in inhibiting the DNA relaxation by topoisomerase I at concentrations up to 10 μM, but showed DNA‐intercalating ability (DNA unwinding) at 30 μM. The structure of BE‐22179 is quite novel for a topoisomerase II inhibitor. Echinomycin, a quinoxaline antibiotic structurally related to BE‐22179, interfered with DNA relaxation by topoisomerase II, though the effect was not due to inhibition of the catalytic activity of topoisomerase II but to conformational change of DNA based on its intercalation into DNA. Therefore, the potent inhibitory activity on topoisomerase II might not be a common activity of quinoxaline antibiotics, but might rather be specific to BE‐22179. BE‐22179 prevented DNA synthesis as well as RNA synthesis in L1210 cells and inhibited the growth of the cells. However, it remains unclear to what extent the topoisomerase II inhibition was responsible for the cytotoxicity of BE‐22179.
Keywords: Topoisomerase II, DNA relaxation, Cyclic depsipeptide, Quinoxaline antibiotic, Antitumor agent
Full Text
The Full Text of this article is available as a PDF (328.9 KB).
REFERENCES
- 1. ) Sutcliff , J. A. , Goots , T. D. and Barrett , J. F.Biochemical characteristics and physiological significance of major DNA topoisomerases . Antimicrob. Agents Chemother. , 33 , 2027 – 2033 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. ) Lock , R. B. and Ross , W. E.DNA topoisomerases in cancer therapy . Anti-Cancer Drug Des. , 2 , 151 – 164 ( 1987. ). [PubMed] [Google Scholar]
- 3. ) Liu , L. F.DNA topoisomerase poisons as antitumor drugs . Annu. Rev. Biochem. , 58 , 351 – 375 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Okada , H. , Suzuki , H. , Yoshinari , T. , Arakawa , H. , Okura , A. , Suda , H. , Yamada , H. and Uemura , D.A new topoisomerase II inhibitor, BE‐22179, produced by a Streptomycetes. I. Producing strain, fermentation, isolation, and biological activity . J. Antibiot. , in press . [DOI] [PubMed] [Google Scholar]
- 5. ) Waring , M. J. and Fox , K. M.Molecular aspects of the interaction between quinoxaline antibiotics and nucleic acids . In “ Molecular Aspects of Anticancer Drug Action ,” ed. Neidle S. and Waring M. J. , pp. 127 – 156 ( 1983. ). Verlag Chemie; , Basel . [Google Scholar]
- 6. ) Foster , B. L. , Clagett‐Carr , K. , Shoemaker , D. D. , Suffness , M. , Plowman , J. A. , Trissel , L. A. , Grieshaber , C. K. and Leyland‐Jones , B.Echinomycin: the first bifunctional intercalating agent in clinical trials . Invest. New Drugs , 3 , 404 – 410 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Pazdur , R. , Haas , C. D. , Backer , L. H. , Leichman , C. G. and Decker , D.Phase I study of echinomycin . Cancer Treat. Rep. , 71 , 1217 – 1219 ( 1987. ). [PubMed] [Google Scholar]
- 8. ) Wang , A. H.‐J. , Ughetto , G. , Quigley , G. J. , Hakoshima , T. , van der Marel , G. A. , van Boom , J. H. and Rich , A.The molecular structure of a DNA‐triostin A complex . Science , 225 , 1115 – 1121 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Gause , G. G. , Dudnik , Y. V. , Loshgareva , N. P. and Zbarsky , I. B.Inhibition of RNA synthesis by antibiotic 6270 from echinomycin group in bacterial and tissue cells . Antibiotiki , 11 , 426 – 429 ( 1966. ). [PubMed] [Google Scholar]
- 10. ) Drake , F. H. , Zimmerman , J. P. , MacCabe , F. L. , Bartus , H. F. , Per , S. R. , Sallivans , D. M. , Ross , W. E. , Mattern , M. R. , Johnson , R. K. , Crooke , S. T. and Mirabelli , C. K.Purification of topoisomerase II from amsacrine‐resistant P388 leukemia cells . J. Biol. Chem. , 262 , 16739 – 16747 ( 1987. ). [PubMed] [Google Scholar]
- 11. ) Chen , G. L. , Yang , L. , Rowe , T. C. , Halligan , B. D. , Tewey , K. M. and Liu , L. F.Nonintercalative antitumor drugs interfere with the breakage‐reunion reaction of mammalian DNA topoisomerase II . J. Biol. Chem. , 259 , 13560 – 13566 ( 1984. ). [PubMed] [Google Scholar]
- 12. ) Rubinstein , L. V. , Shoemaker , R. H. , Paull , K. D. , Simon , R. M. , Tosini , S. , Skehan , P. , Scudiero , D. A. , Monks , A. and Boyd , M. R.Comparison of in vitro anticancer‐drug‐screening data generated with a tetrazolium assay versus a protein assay against diverse panel of human tumor cell lines . J. Natl. Cancer Inst. , 82 , 1113 – 1118 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Yoshinari , T. , Yamada , A. , Uemura , D. , Nomura , K. , Arakawa , H. , Kojiri , K. , Yoshida , E. , Suda , H. and Okura , A.Inhibition of topoisomerase I‐mediated DNA cleavage by a new indolocarbazole, ED‐110 . Cancer Res. , 53 , 490 – 494 ( 1993. ). [PubMed] [Google Scholar]
- 14. ) Tewey , K. M. , Rowe , T. C. , Yang , L. , Halligan , B. D. and Liu , L. F.Adriamycin‐induced DNA damage mediated by mammalian DNA topoisomerase II . Science , 226 , 466 – 468 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Tewey , K. M. , Chen , G. L. , Nelson , E. M. and Liu , L. F.Intercalative antitumor drugs interfere with the breakagereunion reaction of mammalian DNA topoisomerase II . J. Biol. Chem. , 259 , 9182 – 9187 ( 1984. ). [PubMed] [Google Scholar]