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Cancer Pharmacology Section, Division of Hematology/Oncology, Children's Hospital of Los Angeles, Los Angeles, California 90027 [J. L. N., Y-X. L., M. J.]; Departments of Pediatrics and Biochemistry, University of Southern California Medical School, Los Angeles, California 90031 [J. L. N.]; and Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, Massachusetts 02138 [P. H., R. W., J. C. W.]
Increasing the cellular concentration of DNA topoisomerase II in yeast by expressing constitutively a plasmid-borne TOP2 gene encoding the enzyme greatly increases the sensitivity of the cells to amsacrine and etoposide (VP-16). This increased drug sensitivity at a higher intracellular DNA topoisomerase II level is observed in both RAD52+ repair-proficient strains and rad52 mutants that are defective in the repair of double-stranded breaks. These results provide strong support of the hypothesis that the cellular target of these drugs is DNA topoisomerase II, and that these drugs kill cells by converting DNA topoisomerase II into a DNA damaging agent.
1 This work was supported by grants from the NIH, the Martell Foundation for Leukemia, Cancer and AIDS, and a special fellowship to J. N. from the Leukemia Society of America.
Received 2/20/92. Accepted 6/ 3/92.
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