Supino R, Mariani M, Prosperi E, Parmiani G
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Cancer Chemother Pharmacol. 1988;21(3):251-4. doi: 10.1007/BF00262780.
A B16 melanoma cell line in which resistance to doxorubicin (Dx) had been induced by in vitro exposure to the drug, was found not to be cross-resistant with 4'-deoxy-4'-iodo-doxorubicin (4'-I-Dx), a new Dx derivative. Dx was 200 times less active in resistant than in sensitive cells, whereas the iodo derivative compound had the same level of activity in both cell lines. Cytotoxicity of Dx was dependent on concentration and on length of treatment, whereas that of 4'-I-Dx was correlated only with drug concentration. In an effort to explain this different behavior, intracellular retention and distribution of the two drugs was examined. Uptake and efflux of 4'-I-Dx in sensitive and resistant cells were similar, and cellular retention of the drug was 5-25 times higher than that of Dx. In addition, intracellular distribution of the iodo-derivative compound was similar in both cell lines, whereas more nuclear Dx was found in sensitive than in resistant cells. These differences may explain not only the lack of cross-resistance, but also the different cytotoxic behavior, of 4'-I-Dx.
一种通过体外暴露于阿霉素（Dx）诱导出对阿霉素耐药的B16黑色素瘤细胞系，被发现对一种新的阿霉素衍生物4'-脱氧-4'-碘阿霉素（4'-I-Dx）不存在交叉耐药性。阿霉素在耐药细胞中的活性比在敏感细胞中低200倍，而碘衍生物化合物在两种细胞系中的活性水平相同。阿霉素的细胞毒性取决于浓度和处理时间，而4'-I-Dx的细胞毒性仅与药物浓度相关。为了解释这种不同的行为，研究了两种药物在细胞内的滞留和分布情况。4'-I-Dx在敏感细胞和耐药细胞中的摄取和流出相似，且该药物在细胞内的滞留比阿霉素高5至25倍。此外，碘衍生物化合物在两种细胞系中的细胞内分布相似，而在敏感细胞中发现的核内阿霉素比耐药细胞中的更多。这些差异不仅可以解释4'-I-Dx缺乏交叉耐药性的原因，还可以解释其不同的细胞毒性行为。
