CHARACTERIZATION OF A CHINESE-HAMSTER OVARY CELL-LINE WITH ACQUIRED-RESISTANCE TO THE BISDIOXOPIPERAZINE DEXRAZOXANE (ICRF-187) CATALYTIC INHIBITOR OF TOPOISOMERASE-II

A Chinese hamster ovary (CHO) cell line highly resistant to the non cl eavable complex-forming topoisomerase II inhibitor dexrazoxane (ICRF-1 87, Zinecard(R)) was selected. The resistant cell line (DZR) was 1500- fold resistant (IC50 = 2800 vs 1.8 mu M) to continuous dexrazoxane exp osure. DZR cells were also cross-resistant (8- to 500-fold) to other b isdioxopiperazines (ICRF-193, ICRF-154, and ICRF-186), and somewhat cr oss resistant (4- to 14-fold) to anthracyclines (daunorubicin, doxorub icin, epirubicin, and idarubicin) and etoposide (8.5-fold), but not to the other non cleavable complex-forming topoisomerase II inhibitors s uramin and merbarone. The cytotoxicity of dexrazoxane to both cell lin es was unchanged in the presence of the membrane-active agent verapami l. DZR cells were 9-fold resistant to dexrazoxane-mediated inhibition of topoisomerase II DNA decatenation activity compared with CHO cells (IC50 = 400 VS 45 mu M), but were only 1.4-fold (IC50 = 110 VS 83 mu M ) resistant to etoposide. DZR cells contained one-half the level of to poisomerase II protein compared with parental CHO cells. However, the specific activity for decatenation using nuclear extract topoisomerase II was unchanged. Etoposide (100 mu M) induced topoisomerase II-DNA c omplexes in DZR cells and isolated nuclei were similarly one-half the level found in CHO cells and in isolated nuclei. However, the ability of 500 mu M dexrazoxane to inhibit etoposide (100 mu M)-induced topois omerase II-DNA covalent complexes was reduced 4- to 6-fold in both DZR cells and nuclei compared with CHO cells and nuclei. In contrast, the re was no differential ability of aclarubicin or merbarone to inhibit etoposide-induced topoisomerase II-DNA complexes in CHO compared with DZR cells and isolated nuclei. It was concluded that the DZR cell Line acquired its resistance to dexrazoxane mainly through an alteration i n the topoisomerase II target. (C) 1997 Elsevier Science Inc.