DIFFERENCE BETWEEN THE RESISTANCE MECHANISMS OF ACLACINOMYCIN-RESISTANT AND ADRIAMYCIN-RESISTANT P388 CELL-LINES

Aclacinomycin (ACR) is an anthracycline anticancer drug that shows mar ked effects in Adriamycin (ADM)-resistant tumors. ADM, however, is not effective against ACR-resistant tumor cells. When tumor cells acquire resistance to ACR, though the resistance is not easily acquired, they show strong cross-resistance to ADM. To study the mechanism underlyin g these phenomena, we studied the resistance mechanism of ACR- and ADM -resistant P388 leukemia cells. The P388/ACR cells showed 4.9- and 100 -fold resistance to ACR and ADM, respectively, whereas the P388/ADM ce lls showed respectively 2.0- and 270-fold resistance. Both P388/ACR an d P388/ADM cells expressed large amounts of P-glycoprotein, and the am ount was 3-fold higher in the P388/ACR than in the P388/ADM cells. As a result, the accumulation of vincristine and ADM were greatly reduced in P388/ACR and P388/ADM cells, as compared with the parental P388 ce lls. The accumulation of ACR, however, was moderately reduced in both the resistant cell lines. ACR accumulation in P388/ACR and P388/ADM ce lls was reduced to respectively 37 and 64% of the level in P388 cells. The amount and the activity of topoisomerase II were comparable in P3 88 and P388/ACR cells, but they were reduced in P388/ADM cells. Conseq uently, the formation of protein (topoisomerase II)-DNA cross-links in duced by a topoisomerase II inhibitor was more prominent in the P388 a nd P388/ACR nuclei than in the P388/ADM nuclei, Notably, ACR could red uce the protein-DNA cross-links equally in the nuclei of P388, P388/AC R, and P388/ADM cells. These results indicate that the reduced topoiso merase II in P388/ADM cells is involved in the mechanism of resistance against topoisomerase II inhibitors, such as ADM and etoposide, but i s not responsible for the resistance against ACR. Our present results indicate that the limited cross-resistance of P388/ADM cells against A CR could result from ACR that accumulates well in the resistant cells expressing P-glycoprotein and inhibits topoisomerase II functions irre spective of the cellular topoisomerase II level. The strong cross-resi stance of P388/ACR cells against ADM could be due to the strong expres sion of P-glycoprotein.