Anthracyclines and their C-13 alcohol metabolites: growth inhibition and DNA damage following incubation with human tumor cells in culture.
Anthracyclines are important antitumor agents used in the treatment of solid tumors, lymphomas, and acute lymphoblastic as well as myelocytic leukemias. The clinical utility of agents such as doxorubicin and daunorubicin and their well-characterized cardiotoxicity have prompted many efforts to develop analogs that retain the desired spectrum of activity but are less cardiotoxic. One such analog is idarubicin (4-demethoxydaunorubicin), which is currently under study in the treatment of adult and pediatric leukemias. The major circulating metabolite of idarubicin is the alcohol product of ketoreductase biotransformation, idarubicinol. Following the administration of idarubicin to adult or pediatric patients, systemic exposure to idarubicinol is greater than that to idarubicin. Moreover, we have also documented the presence of idarubicinol in the cerebrospinal fluid of pediatric patients who have received idarubicin. Idarubicinol has been reported to have greater cytotoxic activity than other anthracycline alcohol metabolites, which are regarded as much less active products of metabolism. We therefore evaluated the growth-inhibitory and DNA-damaging activities of idarubicin, daunorubicin, doxorubicin, epirubicin, and their alcohol metabolites against three relevant (CCRF-CEM lymphoblastic leukemia, K562 myelogenous leukemia, and U87-MG glioblastoma) human tumor cell lines. We found that whereas idarubicin was 2-5 times more potent than the other three anthracycline analogs against these tumor cell lines, idarubicinol was 16-122 times more active than the other alcohol metabolites against the same three cell lines. In addition, idarubicinol and the parent drug idarubicin were equipotent, unlike the other anthracycline alcohol metabolites, which were much less cytotoxic than the corresponding parent drugs. We also assessed the ability of the four parent drugs and their alcohol metabolites to induce DNA single-strand breaks. Idarubicin was more potent than the other three anthracycline analogs and idarubicinol was much more effective than the other alcohol metabolites in inducing DNA damage. These studies in human leukemia and human glioblastoma cell lines support the hypothesis that idarubicinol plays an important role in the antitumor activity of idarubicin and that the activities of idarubicin and idarubicinol are related to their ability to damage DNA.
Kuffel
M J
MJ
Department of Oncology, Mayo Clinic, Rochester, MN 55905.
Reid
J M
JM
Ames
M M
MM
D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D003630:Daunorubicin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D015251:Epirubicin / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D015255:Idarubicin / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D015251:Epirubicin; D004317:Doxorubicin; C054440:idarubicinol; D015255:Idarubicin; D003630:Daunorubicin