Can cytotoxic activity of anthracyclines be related to DNA damage?
Accumulation, cytotoxicity, and DNA damages produced by doxorubicin (DOX), pirarubicin (THP-DOX), fluoro-doxorubicin (ME2303) or its isolated metabolite M1 have been investigated in human myelogenous leukemia cells, sensitive (K562) and resistant to DOX (K562/DOX). These compounds differed by lipophilicity and/or sugar moiety either with (DOX, THP-DOX) or without (ME2303, M1) amino group. In K562 cells, the cytotoxicity was correlated to DNA single-stranded breaks and the intracellular drug amount of DOX or M1. This was not true when the cells were treated with THP-DOX or ME2303. In addition, THP-DOX produced total DNA protein cross-linking. In K562 cells DNA damage was not repaired, while in K562/DOX repair of DNA damage produced by all drugs could be observed. Although in K562/DOX cells drug accumulation was much reduced, higher intracellular drug concentration was required to induce similar level of cytotoxicity and DNA damage. Thus, cytotoxicity produced by anthracycline is not always associated with DNA damage. Different level of resistance to DOX, THP-DOX, ME2303 or M1 is associated with reduced drug accumulation which varies with the structure.
Nishiyama
M
M
Laboratoire de Pharmacologie Cellulaire et Molèculaire, ICIG, Hôpital Paul Brousse, Villejuif, France.
Horichi
N
N
Mazouzi
Z
Z
Bungo
M
M
Saijo
N
N
Tapiero
H
H
D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D004317:Doxorubicin; C027260:pirarubicin