Roovers D J, van Vliet M, Bloem A C, Lokhorst H M
Department of Hematology, University Hospital Utrecht, The Netherlands.
Leuk Res. 1999 Jun;23(6):539-48. doi: 10.1016/s0145-2126(99)00041-7.
The clinical utility of anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) for treatment of multiple myeloma (MM) is limited by the occurrence of multidrug resistance (MDR). Highly lipophilic anthracyclines like idarubicin (IDA) might circumvent MDR and thereby enhance chemotherapeutic efficacy. To determine the efficacy of IDA in myeloma cells, the pharmacokinetics and cytotoxicity of IDA and its major metabolite idarubicinol (IDAol) were compared with those of DNR, DOX, and doxorubicinol (DOXol) in the cell line RPMI 8226-S and two MDR sublines (8226-R7 and 8226-Dox40) that overexpress the drug transporter P-glycoprotein (Pgp). Cytotoxicity assays using MTT (viability) or annexin V (apoptosis) showed a 10-50-fold higher potency of IDA compared with DNR or DOX in the MDR variant cell lines. The difference in cytotoxicity was lower in the sensitive parental cell line (3-fold). These results are explained by a better intracellular uptake of IDA compared to DNR in resistant 8226 cell lines. The Pgp-inhibitor verapamil affected IDA uptake only in the most resistant cell line 8226-Dox40. This indicates that IDA is less sensitive than DNR to transport-mediated MDR. IDAol was at least 32-fold more cytotoxic than DOXol, and more susceptible to Pgp transport than IDA. These studies demonstrate that the efficacy of IDA in MDR MM cell lines is superior to that of DOX or DNR, and that IDA may become an important drug in the treatment of MM, especially in refractory disease.
阿霉素（DOX）和柔红霉素（DNR）等蒽环类药物在治疗多发性骨髓瘤（MM）时，其临床效用受到多药耐药（MDR）的限制。像伊达比星（IDA）这样的高亲脂性蒽环类药物可能会规避多药耐药，从而提高化疗疗效。为了确定IDA在骨髓瘤细胞中的疗效，在RPMI 8226-S细胞系以及两个过表达药物转运蛋白P-糖蛋白（Pgp）的多药耐药亚系（8226-R7和8226-Dox40）中，将IDA及其主要代谢产物伊达比星醇（IDAol）的药代动力学和细胞毒性与DNR、DOX和多柔比星醇（DOXol）进行了比较。使用MTT（活力）或膜联蛋白V（凋亡）进行的细胞毒性试验表明，在多药耐药变异细胞系中，IDA的效力比DNR或DOX高10至50倍。在敏感的亲本细胞系中，细胞毒性差异较小（3倍）。这些结果可以解释为，与耐药的8226细胞系中的DNR相比，IDA的细胞内摄取更好。Pgp抑制剂维拉帕米仅在耐药性最强的细胞系8226-Dox40中影响IDA的摄取。这表明IDA比DNR对转运介导的多药耐药更不敏感。IDAol的细胞毒性至少比DOXol高32倍，并且比IDA更容易受到Pgp转运的影响。这些研究表明，IDA在多药耐药的MM细胞系中的疗效优于DOX或DNR，并且IDA可能成为治疗MM的重要药物，尤其是在难治性疾病中。
