DIFFERENT MODES OF ANTHRACYCLINE INTERACTION WITH TOPOISOMERASE-II-SEPARATE STRUCTURES CRITICAL FOR DNA-CLEAVAGE, AND FOR OVERCOMING TOPOISOMERASE-II-RELATED DRUG-RESISTANCE

In contrast to the classic anthracyclines (doxorubicin and daunorubici n), aclarubicin (ACLA) does not stimulate topoisomerase II (topo II) m ediated DNA-cleavage. This distinction may be important with respect t o topo II-related drug resistance, and the aim of this study was to cl arify drug-structures responsible for this difference. Various ACLA an alogs were tested for: (a) interaction with purified topo II, (b) indu ction of DNA cleavage in cells, (c) cellular uptake and (d) cytotoxici ty. A remarkable distinction was seen between analogs containing the c hromophore aklavinone (AKV) (e.g. ACLA) which have a carboxymethyl gro up (COOCH3) at C-10 and drugs with a beta-rhodomycinone (RMN) chromoph ore with hydroxyl groups at C-10 and at C-11. Thus, RMN-containing ana logs, including the aglycone RMN itself, effectively stimulated topo I I-mediated DNA cleavage. In contrast, AKV-containing drugs inhibited D NA cleavage and antagonized cytotoxicity mediated by RMN-containing dr ugs. In OC-NYH/VM cells, exhibiting multidrug resistance due to an alt ered topo II phenotype (at-MDR), cross-resistance was only seen to the RMN-containing drugs whereas no cross-resistance was seen to the non- DNA cleaving AKV-containing compounds. Thus, our data show that one do main in the anthracycline is of particular importance for the interact ion with topo II, namely the positions C-10 and C-11 in the chromophor e, and further that at-MDR was circumvented by a COOCH3 substitution a t position C-10. These findings may provide guidance for the synthesis and development of new analogs with activity in at-MDR cells.