Mutations in the gyrB domain of eukaryotic topoisomerase II can lead to partially dominant resistance to etoposide and amsacrine

JL Nitiss, PM Vilalta, H Wu and J McMahon

Cancer Pharmacology Section, Children's Hospital of Los Angeles, California 90027.

Anti-topoisomerase II agents represent a major class of anticancer therapeutic agents. Resistance to this class of agents can be mediated by several possible mechanisms. One mechanism may involve mutations in the structural gene(s) for topoisomerases, altering the drug sensitivity of the enzymes. Several mutations have been described in mammalian cell lines that were selected for resistance to topoisomerase II-targeting drugs such as Adriamycin, etoposide, or amsacrine. The difficulty of performing genetic analysis in mammalian cell lines has complicated the determination of whether the observed mutations are responsible for drug resistance. We have reconstructed, in the yeast topoisomerase II gene, the arginine to glutamine mutation at position 450 of human topoisomerase II alpha that was originally identified by Bugg et al. [Proc. Natl. Acad. Sci. USA 88:7654-7658 (1991)]. Mutation of Lys439, the equivalent amino acid in the yeast protein, to either glutamine or glutamic acid confers resistance to etoposide and amsacrine. Interestingly, in diploid yeast cells the heterozygous mutation can still confer partial drug resistance, compared with a diploid strain that is homozygous for wild-type topoisomerase II. Because mutations in the topoisomerase II gene that can confer dominant resistance to anti-topoisomerase II agents are relatively rare, mutations in the gyrB region may be important in the development of clinical drug resistance.

Volume 46, Issue 4, pp. 773-777, 10/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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