Cellular pharmacology of idarubicinol in multidrug-resistant LoVo cell lines.
Idarubicin (IDA) is a daunorubicin (DAU) analog that is being used to treat a variety of human malignancies. The major circulating metabolite of IDA is idarubicinol (IDOL). After administration of IDA to patients, the systemic exposure to IDOL is greater than IDA. We investigated the cytotoxic effect of IDOL in the LoVo human colon-carcinoma cell line and its derivative multidrug-resistant (MDR) sub-lines. In LoVo-sensitive cells, the extracellular IDOL concentration inhibiting cell growth by 50% (IC50) was about 2-fold higher than IDA IC50 but lower than DAU IC50. After continuous exposure of the LoVo parental cells to 20 nM IDOL, 5 drug-resistant clones were obtained. All these clones exhibited an MDR phenotype, indicating that IDOL is involved in multidrug resistance. The resistance index (RI) to IDOL was investigated in LoVo MDR sub-lines obtained by IDOL (LoVo-IDOL-1), IDA (LoVo-IDA-1) and DOX (LoVo-DOX-1) selection. In spite of the drug used for their selection, all the MDR sub-lines exhibited an RI to IDOL lower than DAU and only 2-fold higher than IDA. In LoVo-IDOL-1 cells the RI was 5, 11 and 32 for IDA, IDOL and DAU respectively. Differences in the RI were explained by the greater intracellular tolerance exhibited by MDR cells to DAU than to IDOL and IDA. In the LoVo-IDOL-1 sub-line, the intracellular drug concentration inhibiting cell growth by 50% (IC50int) was higher than in the sensitive cells by 11.4-, 4.7- and 2.8-fold for DAU, IDOL, and IDA respectively. Differences in the intracellular tolerance were explained by the different intracellular distribution of DAU compared with IDOL and IDA. While DAU had a higher nuclear location in LoVo-sensitive cells than in resistant cells, IDOL and IDA maintained the same distribution both in sensitive and in resistant cells. In conclusion, contrary to what has been observed for other derivative metabolites of anthracyclines, the metabolism of IDA to IDOL must not be considered an inactivation pathway. IDOL is a potent inhibitor of cell growth and retains good activity in MDR cells.
Toffoli
G
G
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
Corona
G
G
Simone
F
F
Gigante
M
M
De Angeli
S
S
Boiocchi
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D015255:Idarubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C054440:idarubicinol; D015255:Idarubicin; D003630:Daunorubicin