Difference between the resistance mechanisms of aclacinomycin- 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
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J
Dong
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M
Naito
T
T
Tatsuta
H
H
Seimiya
O
O
Johdo
T
T
Tsuruo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D015250:Aclarubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007941:Leukemia P388; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; C011157:aclacinomycins; D014750:Vincristine; D005047:Etoposide; D015250:Aclarubicin; D004317:Doxorubicin; D014700:Verapamil; D004250:DNA Topoisomerases, Type II