J. Dong et al., DIFFERENCE BETWEEN THE RESISTANCE MECHANISMS OF ACLACINOMYCIN-RESISTANT AND ADRIAMYCIN-RESISTANT P388 CELL-LINES, Oncology research, 7(5), 1995, pp. 245-252
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.