3'-Deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin conquers multidrug resistance by rapid influx following higher frequency of formation of DNA single- and double-strand breaks.
The mechanism of action of 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2) was examined in a human leukemia cell line (K562) and its Adriamycin (ADM)-resistant subline (K562/ADM). ADM and MX2 showed an equivalent antitumor effect against K562. K562/ADM was highly resistant to ADM. In cellular pharmacokinetic studies, MX2 showed faster and greater influx than did ADM in both K562 and K562/ADM. The efflux of ADM was rapid in K562/ADM but not in K562. On the other hand, the efflux of MX2 was rapid in both cell lines. The formation of DNA single-strand breaks and double-strand breaks by ADM was significantly lower in K562/ADM than K562. On the other hand, formation of those breaks by MX2 was not decreased. Although some of the DNA breaks induced by MX2 were resealed, there was no difference in the degree of resealing in K562 and K562/ADM cells. On the other hand, most of the small number of DNA breaks in K562/ADM induced by ADM were resealed. The topoisomerase II activity in K562 and K562/ADM was not significantly different. It is concluded that MX2 conquers multidrug resistance by rapid influx following a higher frequency of formation of DNA single- and double-strand breaks in K562/ADM cells.
Horichi
N
N
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Tapiero
H
H
Sugimoto
Y
Y
Bungo
M
M
Nishiyama
M
M
Fourcade
A
A
Lampidis
T J
TJ
Kasahara
K
K
Sasaki
Y
Y
Takahashi
T
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001692:Biological Transport; D002360:Carubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000187:drug effects; D003630:Daunorubicin / Q000031:analogs & derivatives*; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; C053537:morpholinoanthracycline MX2; D004317:Doxorubicin; D002360:Carubicin; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin