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Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [Y. P., A. O., K. W. K.], and Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 94403 Vitry-sur-Seine Cedex, France [J-F. R.]
Amsacrine and demethylepipodophyllotoxins (etoposide and teniposide) are potent topoisomerase II inhibitors which have optimum activity in different cancers. To investigate whether these differences are due to different activity on cellular oncogenes, drug-induced topoisomerase II cleavage sites were mapped and sequenced in the human c-myc protooncogene. In the presence of purified murine L1210 topoisomerase II, amsacrine induces prominent cleavage in the P2 promoter (site 2499/2502). Footprinting experiments indicate that topoisomerase II binds to the entire promoter region (
20 base pairs on the sides of the P2 site). In the case of teniposide or etoposide, cleavage is more diffuse and markedly less at the P2 site. Mapping of cleavage sites in human small cell lung carcinoma cells (NCI N417) also shows that cleavage in the P2 promoter region is induced preferentially by amsacrine but not by demethylepipodophyllotoxins. Thus, selective gene damage among topoisomerase II inhibitors may contribute to differential anticancer activity.
1 To whom requests for reprints should be addressed, at Bldg. 37, Rm. 5C27, National Institutes of Health, Bethesda, MD 20892.
Received 12/27/91. Accepted 3/24/92.
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