Jiang X R, Macey M G, Kelsey S M, Collins P W, Gutteridge C N, Miki T, Adachi K, Yamabe S, Newland A C
Department of Haematology, London Hospital Medical College, Whitechapel, U.K.
J Chemother. 1993 Oct;5(5):334-43. doi: 10.1080/1120009x.1993.11741079.
The antitumor activities of four novel doxorubicin (DOX) analogues, YM1, YM3, YM4 and YM6 in relation to their structure and drug transport properties, have been investigated in U937 monocytic and CCRF-CEM lymphoid drug sensitive leukemia cell lines, as well as in CEM/VLB100, a drug resistant subline displaying high levels of P-glycoprotein. Treatment of all cell lines with YM1, 3, 4 and 6 produced a dose-dependent decrease in DNA, RNA and protein synthesis as measured by [3H]-thymidine, [3H]-uridine and [3H]-leucine uptake respectively. YM1 was more effective than YM3, YM4 or YM6 against the drug sensitive cells. The antitumor effects of all these DOX-analogues on macromolecule synthesis in U937 and CCRF-CEM cells were lower than that of DOX and epirubicin (EDR). A rapid accumulation of the novel anthracyclines was found in all cell lines compared with DOX or EDR. However, the maximal accumulation of the DOX-analogues was lower than that of EDR. There is a greater efflux from CCRF-CEM sensitive cells and less from CEM/VLB100 resistant cells of the DOX-derivatives when compared with EDR and DOX. Drug-induced cytotoxicity significantly correlated (P < 0.05) with drug retention levels in CCRF-CEM and U937 drug sensitive cells as indicated by an inverse correlation curve between anthracycline retention and drug-induced IC50 value. It was demonstrated that an increased level of drug retained within the sensitive cells would therefore produce a more cytotoxic effect of the drug. However, no such correlation was observed in CEM/VLB100 resistant cells. YM3 was shown to have an increased antitumor activity against CEM/VLB100 resistant cells compared with DOX with a lower resistance factor. These results showed that the antitumor effects of four novel DOX-analogues, like DOX or EDR, were associated with inhibition of DNA replication, transcription and translation. The finding that resistant leukemic cells are more susceptible to the cytotoxic effect of YM3 than DOX warrants further investigation to identify the intrinsic mechanism of resistance.
研究了四种新型阿霉素（DOX）类似物YM1、YM3、YM4和YM6相对于其结构和药物转运特性在U937单核细胞和CCRF-CEM淋巴样药物敏感白血病细胞系以及CEM/VLB100（一种显示高水平P-糖蛋白的耐药亚系）中的抗肿瘤活性。用YM1、3、4和6处理所有细胞系后，分别通过[3H]-胸苷、[3H]-尿苷和[3H]-亮氨酸摄取量测定，DNA、RNA和蛋白质合成呈剂量依赖性下降。YM1对药物敏感细胞的作用比YM3、YM4或YM6更有效。所有这些DOX类似物对U937和CCRF-CEM细胞中大分子合成的抗肿瘤作用均低于DOX和表柔比星（EDR）。与DOX或EDR相比，在所有细胞系中均发现新型蒽环类药物快速蓄积。然而，DOX类似物的最大蓄积量低于EDR。与EDR和DOX相比，DOX衍生物从CCRF-CEM敏感细胞中的外排更多，而从CEM/VLB100耐药细胞中的外排更少。如蒽环类药物蓄积与药物诱导的IC50值之间的负相关曲线所示，药物诱导的细胞毒性与CCRF-CEM和U937药物敏感细胞中的药物保留水平显著相关（P<0.05）。结果表明，敏感细胞内保留的药物水平升高会因此产生更强的药物细胞毒性作用。然而，在CEM/VLB100耐药细胞中未观察到这种相关性。与DOX相比，YM3对CEM/VLB100耐药细胞的抗肿瘤活性增强，耐药因子更低。这些结果表明，四种新型DOX类似物的抗肿瘤作用与DOX或EDR一样，与抑制DNA复制、转录和翻译有关。耐药白血病细胞对YM3的细胞毒性作用比DOX更敏感这一发现值得进一步研究以确定耐药的内在机制。
