Induction of Resistance to Etoposide and Adriamycin in a Human Glioma Cell Line Treated with Antisense Oligodeoxynucleotide Complementary to the Messenger Ribonucleic Acid of Deoxyribonucleic Acid Topoisomerase IIα

Abstract

Acquisition of resistance to anticancer agents is a serious problem for cancer chemotherapy. The present study analyzed the relationship between expression of the a isoform of deoxyribonucleic acid (DNA) topoisomerase II (topo IIα) and chemosensitivity to topo II inhibitors by modulating the level of topo IIα expression. A phosphorothioate analogue of an 18-nucleotide oligomer which is complementary to the translation initiation site of the human topo IIα messenger ribonucleic acid sequence was used to suppress the expression of topo IIα in a human glioma cell line (U373MG). The topo IIα activity of the treated cells was reduced to 1/3 of untreated cells in a decatenation assay using kinetoplast DNA. Antisense oligoDNA-treated cells showed mild resistance to the topo II inhibitors, etoposide and adriamycin, of about 2.0 fold and 1.5 fold, respectively, compared to control cells. Only partial reduction in the activity of topo IIα in the glioma cell line can cause a measurable resistance to topo II inhibitors, implying that the degree of topo II expression is correlated with chemosensitivity to topo II inhibitors.