Streeter D G, Johl J S, Gordon G R, Peters J H
Cancer Chemother Pharmacol. 1986;16(3):247-52. doi: 10.1007/BF00293986.
3'-Deamino-3'-(4-morpholinyl)adriamycin (MRA) and 3'-deamino-3'(3-cyano-4-morpholinyl)adriamycin (MRA-CN) were compared with adriamycin (ADR) in ADR-sensitive (P388/S) and -resistant (P388/ADR) murine leukemia cell lines with respect to cytotoxicity and cellular accumulation. MRA is only two- to threefold more cytotoxic to P388/S in culture than ADR, whereas MRA-CN is 500-fold more cytotoxic than ADR to this cell line. Yet both MRA and MRA-CN retain their potency against P388/ADR in spite of a 150-fold decrease in potency for ADR. The observed noncross-resistance of both MRA and MRA-CN in P388/ADR correlates with their increased cellular uptake and retention relative to ADR and the inability of P388/ADR to exclude these analogs as readily as it does ADR. The decreased uptake of MRA and MRA-CN in P388/ADR relative to P388/S (1.5 to 2.0-fold), the increased efflux, and the ability of verapamil to enhance cellular uptake of these analogs in P388/ADR, as it does with ADR, all indicate that the mechanism of ADR-resistance effects ADR and the morpholino analogs in a similar manner but to far different extents. The potent cytotoxicity of MRA-CN appears to be related to strong cellular interactions of the drug with macromolecules that are characterized by its nonextraction from cells by chloroform: methanol or 10 M urea and may therefore represent covalent binding.
在对阿霉素敏感（P388/S）和耐药（P388/ADR）的小鼠白血病细胞系中，就细胞毒性和细胞摄取方面，对3'-脱氨基-3'-(4-吗啉基)阿霉素（MRA）和3'-脱氨基-3'(3-氰基-4-吗啉基)阿霉素（MRA-CN）与阿霉素（ADR）进行了比较。MRA在培养物中对P388/S的细胞毒性仅比ADR高两到三倍，而MRA-CN对该细胞系的细胞毒性比ADR高500倍。然而，尽管ADR的效力下降了150倍，但MRA和MRA-CN对P388/ADR仍保持其效力。在P388/ADR中观察到的MRA和MRA-CN的非交叉耐药性与其相对于ADR增加的细胞摄取和滞留以及P388/ADR不能像对ADR那样轻易排除这些类似物有关。相对于P388/S，P388/ADR中MRA和MRA-CN的摄取减少（1.5至2.0倍）、流出增加以及维拉帕米能够像对ADR一样增强这些类似物在P388/ADR中的细胞摄取，所有这些都表明阿霉素耐药机制以类似方式影响ADR和吗啉类似物，但程度差异很大。MRA-CN的强效细胞毒性似乎与其与大分子的强烈细胞相互作用有关，其特征是不能被氯仿：甲醇或10 M尿素从细胞中提取，因此可能代表共价结合。
