Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II.
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.
Nitiss
J L
JL
Cancer Pharmacology Section, Children's Hospital, Los Angeles, California 90027.
Liu
Y X
YX
Harbury
P
P
Jannatipour
M
M
Wasserman
R
R
Wang
J C
JC
D000677:Amsacrine / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D005800:Genes, Fungal / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics*; D012441:Saccharomyces cerevisiae
D000677:Amsacrine; D005047:Etoposide; D004250:DNA Topoisomerases, Type II