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

Aclacinomycin (ACR) is an anthracycline anticancer drug that shows marked 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 underlying 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 cells showed respectively 2.0- and 270-fold resistance. Both P388/ACR and P388/ADM cells expressed large amounts of P-glycoprotein, and the amount 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 cells. The accumulation of ACR, however, was moderately reduced in both the resistant cell lines. ACR accumulation in P388/ACR and P388/ADM cells was reduced to respectively 37 and 64% of the level in P388 cells. The amount and the activity of topoisomerase II were comparable in P388 and P388/ACR cells, but they were reduced in P388/ADM cells. Consequently, the formation of protein (topoisomerase II)-DNA cross-links induced by a topoisomerase II inhibitor was more prominent in the P388 and P388/ACR nuclei than in the P388/ADM nuclei, Notably, ACR could reduce the protein-DNA cross-links equally in the nuclei of P388, P388/ACR, and P388/ADM cells. These results indicate that the reduced topoisomerase II in P388/ADM cells is involved in the mechanism of resistance against topoisomerase II inhibitors, such as ADM and etoposide, but is not responsible for the resistance against ACR. Our present results indicate that the limited cross-resistance of P388/ADM cells against ACR could result from ACR that accumulates well in the resistant cells expressing P-glycoprotein and inhibits topoisomerase II functions irrespective of the cellular topoisomerase II level. The strong cross-resistance of P388/ACR cells against ADM could be due to the strong expression of P-glycoprotein.