Elsevier

Biochemical Pharmacology

Volume 52, Issue 4, 23 August 1996, Pages 635-642
Biochemical Pharmacology

Research paper
Collateral sensitivity to the bisdioxopiperazine dexrazoxane (ICRF-187) in etoposide (VP-16)-resistant human leukemia K562 cells,☆☆

https://doi.org/10.1016/0006-2952(96)00338-3Get rights and content

Abstract

Etoposide (VP-16)-resistant K562 cells (K/VP.5) were 26-fold resistant to VP-16, due in part to a reduction in DNA topoisomerase II (topoisomerase II) protein levels. Compared with parental K562 cells, VP-16-resistant K/VP.5 cells were found to be 3.4-fold more sensitive to the effects of dexrazoxane (ICRF-187), a topoisomerase II inhibitor that does not stabilize topoisomerase II-DNA covalent complexes. In contrast, K/VP.5 cells were 4.0-fold cross-resistant to merbarone and showed no cross-resistance to fostriecin, two other topoisomerase II inhibitors that do not stabilize topoisomerase II-DNA covalent complexes. Preincubation with ICRF-187 resulted in greater inhibition of subsequent VP-16-induced topoisomerase II-DNA covalent com- plexes in K/VP.5 cells than in K562 cells. Conversely, preincubation with merbarone resulted in less inhibition of VP-16-induced topoisomerase II-DNA covalent complexes in K/VP.5 cells than in parental K562 cells. Preincubation with fostriecin had little effect on VP-16-induced topoisomerase II-DNA covalent complex formation in either cell line. The onset rates for ICRF-187 inhibition of VP-16-induced topoisomerase II-DNA complex formation were similar in sensitive and resistant cells. In addition, ICRF-187 had a comparable concentration-dependent inhibitory effect on the topoisomerase II catalytic activities of K562 and K/VP.5 cells. Together, our results indicate that collateral sensitivity to ICRF-187 in K/VP.5 cells is due to decreased topoisomerase II protein levels rather than to an alteration in topoisomerase II activity. Furthermore, results suggest that ICRF-187, merbarone, and fostriecin have different mechanisms of action that can be studied effectively in K/VP.5 and K562 cells. BIOCHEM PHARMACOL 52;4:635–642, 1996.

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    This work was supported, in part, by Grant DHP-125 from the American Cancer Society and Leukemia Society of America Translational Research Grant 6238-95.

    ☆☆

    This work was supported by N.LH. Grants NS 26511 and NS 30882. F. J. E. is a recipient of a United States Public Health Service Research Career Development Award (NS01396) from the National Institute of Neurological Disorders and Stroke.

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