Larsen A K, Jacquemin-Sablon A
Laboratoire de Pharmacologie Moléculaire, UA 147 CNRS, Villejuif, France.
Cancer Res. 1989 Dec 15;49(24 Pt 1):7115-9.
We have previously shown that Chinese hamster lung cells resistant to 9-hydroxyellipticine, DC-3F/9-OH-E, display multiple phenotypical alterations including cross-resistance to a variety of drugs as well as loss of tumorigenicity. We now analyze a DC-3F/9-OH-E subline that has been maintained for a prolonged period of time in drug-free medium in order to clarify the relationships between the various phenotypic traits. The absence of selection resulted in a partial recovery of the ability to form colonies in soft agar as well as of the tumorigenicity in nude mice. In contrast, no change was observed with respect to population-doubling time. Our results also show that the resistance to 9-hydroxyellipticine, which is associated with an altered topoisomerase II activity, is stable in the absence of drug for more than 1 year. In contrast, the cross-resistance to doxorubicin is partially reversible and the cross-resistance to vincristine is totally reversible in the absence of selection. The cross-resistance to vincristine and doxorubicin is accompanied by a decreased drug uptake. Northern blot analysis shows that the multidrug resistance-associated Mr 170,000-180,000 glycoprotein is overexpressed in the DC-3F/9-OH-E cells and that the overexpression is lost in the absence of selection. We conclude that (a) the DC-3F/9-OH-E cells exhibit multiple mechanisms of resistance which can be dissociated, (b) the tumorigenicity and the altered topoisomerase activity are independent biochemical events whereas the oncogenic potential appears to follow the expression of the multidrug resistance, and (c) the multidrug resistance phenotype may be induced by a drug which is not itself recognized by the multidrug resistance mechanism such as 9-hydroxyellipticine.
我们先前已经表明，对9-羟基玫瑰树碱具有抗性的中国仓鼠肺细胞DC-3F/9-OH-E表现出多种表型改变，包括对多种药物的交叉抗性以及致瘤性的丧失。我们现在分析一个DC-3F/9-OH-E亚系，该亚系已在无药物培养基中长时间培养，以阐明各种表型特征之间的关系。缺乏选择导致在软琼脂中形成集落的能力以及在裸鼠中的致瘤性部分恢复。相比之下，群体倍增时间没有变化。我们的结果还表明，与拓扑异构酶II活性改变相关的对9-羟基玫瑰树碱的抗性在无药物的情况下稳定超过1年。相比之下，对阿霉素的交叉抗性部分可逆，对长春新碱的交叉抗性在无选择的情况下完全可逆。对长春新碱和阿霉素的交叉抗性伴随着药物摄取的减少。Northern印迹分析表明，多药耐药相关的170,000-180,000 Mr糖蛋白在DC-3F/9-OH-E细胞中过表达，并且在无选择的情况下这种过表达消失。我们得出结论：(a) DC-3F/9-OH-E细胞表现出多种可分离的抗性机制；(b) 致瘤性和拓扑异构酶活性改变是独立的生化事件，而致癌潜力似乎遵循多药耐药的表达；(c) 多药耐药表型可能由一种本身不被多药耐药机制识别的药物诱导，如9-羟基玫瑰树碱。
