Toffoli G, Corona G, Simone F, Gigante M, De Angeli S, Boiocchi M
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
Int J Cancer. 1996 Jul 3;67(1):129-37. doi: 10.1002/(SICI)1097-0215(19960703)67:1<129::AID-IJC21>3.0.CO;2-8.
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.
伊达比星（IDA）是柔红霉素（DAU）的类似物，正用于治疗多种人类恶性肿瘤。IDA的主要循环代谢产物是伊达比星醇（IDOL）。给患者使用IDA后，全身对IDOL的暴露量大于IDA。我们研究了IDOL对LoVo人结肠癌细胞系及其衍生的多药耐药（MDR）亚系的细胞毒性作用。在LoVo敏感细胞中，抑制细胞生长50%的细胞外IDOL浓度（IC50）比IDA的IC50高约2倍，但低于DAU的IC50。将LoVo亲代细胞持续暴露于20 nM IDOL后，获得了5个耐药克隆。所有这些克隆均表现出MDR表型，表明IDOL与多药耐药有关。在通过IDOL（LoVo-IDOL-1）、IDA（LoVo-IDA-1）和多柔比星（DOX）（LoVo-DOX-1）筛选获得的LoVo MDR亚系中研究了对IDOL的耐药指数（RI）。尽管用于筛选的药物不同，但所有MDR亚系对IDOL的RI均低于DAU，仅比IDA高2倍。在LoVo-IDOL-1细胞中，对IDA、IDOL和DAU的RI分别为5、11和32。RI的差异是由于MDR细胞对DAU的细胞内耐受性大于对IDOL和IDA的耐受性。在LoVo-IDOL-1亚系中，抑制细胞生长50%的细胞内药物浓度（IC50int）分别比敏感细胞中的DAU、IDOL和IDA高11.4倍、4.7倍和2.8倍。细胞内耐受性的差异是由于DAU与IDOL和IDA的细胞内分布不同。虽然DAU在LoVo敏感细胞中的核定位高于耐药细胞，但IDOL和IDA在敏感细胞和耐药细胞中的分布相同。总之，与蒽环类药物的其他衍生代谢产物不同，IDA代谢为IDOL的过程不能被视为失活途径。IDOL是一种有效的细胞生长抑制剂，在MDR细胞中仍保持良好的活性。
