Nonproductive rearrangement of DNA topoisomerase I and II genes: correlation with resistance to topoisomerase inhibitors.
Topoisomerase inhibitors comprise an important group of agents that is used in cancer treatment. Because the development of resistance to cancer chemotherapeutic agents represents a major limitation of cancer chemotherapy, we investigated the mechanism of resistance by murine P388 leukemia to camptothecin (topoisomerase I inhibitor) or amsacrine (topoisomerase II inhibitor). The resistant cells contained reduced levels of topoisomerase activity and messenger RNA. The topoisomerase gene of these cells was rearranged (only in one allele) and hypermethylated. These topoisomerase gene alterations probably resulted in reduced transcription and, thus, enzyme production, which was correlated with resistance to the topoisomerase inhibitor.
Tan
K B
KB
Department of Cell Sciences, Smith Kline and French Laboratories, King of Prussia, PA 19406.
Mattern
M R
MR
Eng
W K
WK
McCabe
F L
FL
Johnson
R K
RK
D000483:Alleles; D000677:Amsacrine / Q000494:pharmacology*; D000818:Animals; D002166:Camptothecin / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000032:analysis / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D015321:Gene Rearrangement; D007941:Leukemia P388 / Q000201:enzymology*; D007942:Leukemia, Experimental / Q000201:enzymology*; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D008780:Methyltransferases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin