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Laboratory of Biochemistry, Aichi Cancer Center Research Institute [R. I., T. A.] and Department of Pharmacy, Aichi Cancer Center Hospital [M. H.], Chikusa-Ku, Nagoya 464, Japan; Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, Massachusetts 02138 [R. A. W., J. C. W.]; and Molecular Pharmacology Department, St. Jude Children's Research Hospital, Memphis, Tennessee 38101 [J. L. N.]
Bisdioxopiperazines such as ICRF-159 and ICRF-193 have been shown to inhibit DNA topoisomerase II. To determine the molecular target of these compounds in vivo, we utilized a yeast genetic system in which the topoisomerase II activity can be modulated. To reduce topoisomerase II activity, we used top2-1 mutant yeast cells that have normal DNA topoisomerase II activity at 25°C but greatly reduced enzyme activity at 30°C, a temperature that is semipermissive for growth. At 25°C top2-1 cells are as sensitive to the ICRF compounds as the wild-type strain; at 30°C the cells became hypersensitive to these agents. In contrast, top2-1 strains become very resistant to the class of topoisomerase II inhibitors such as amsacrine and etoposide, which stabilize the covalent enzyme-DNA intermediate of the enzyme reaction. Overexpression of topoisomerase II from a plasmid-born TOP2 gene results in lower susceptibility to ICRF compounds and higher susceptibility to amsacrine than the parental strain exhibits. These results support the hypothesis that the main cellular target of ICRF compounds is DNA topoisomerase II, and that these compounds, unlike amsacrine and etoposide, inhibit topoisomerase II activity without stabilizing an enzyme-DNA covalent complex.
1 This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture (R. I., T. A.) and the Ministry of Health and Welfare of Japan (T. A.), and by National Cancer Institute Grants CA47958 (J. C. W.) and CA52814 (J. L. N.).
2 To whom requests for reprints should be addressed, at Aichi Cancer Center Research Institute, Laboratory of Biochemistry, Chikusa-Ku, Nagoya 464, Japan.
Received 1/30/95. Accepted 4/17/95.
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