Biedler J L, Spengler B A
Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Cancer Metastasis Rev. 1994 Jun;13(2):191-207. doi: 10.1007/BF00689636.
Spontaneously transformed Chinese hamster lung cells with high levels of resistance (approximately 100-fold to 70,000-fold) to actinomycin D, daunorubicin, or vincristine exhibit morphology and growth patterns characteristic of normal cells in vitro and reduced tumorigenicity in vivo. These reverse transformed, multidrug-resistant cells amplify and highly overexpress one or more genes encoding P-glycoprotein. Similarly, hydrocarbon-induced mouse sarcoma cells selected with actinomycin D, vincristine, or ethidium bromide developed high levels of resistance associated with reduced drug accumulation and suppression of malignancy. To determine whether human tumor cells would undergo similar changes and whether reverse transformation reflected an altered state of differentiation, nine multidrug-resistant sublines were selected with four agents from human neuroblastoma cells with well defined pathways of differentiation. Those five with resistance levels above about 125-fold showed a reduced tumor frequency as compared to control cells. All resistant sublines showed altered differentiation. The changes in transformation phenotype appear to be intrinsic and not the result of altered immunogenicity. Two additional consequences of high level multidrug resistance have been observed: change in ganglioside composition in the Chinese hamster cells, manifested as a block in higher ganglioside biosynthesis and/or a relative increase in GM3, and increase in epidermal growth factor receptor in all three cell systems. A tentative hypothesis links ganglioside and growth factor receptor changes to the change in transformation phenotype. The basis of the reverse transformation phenomenon is not known, but the major alterations in expression of P-glycoprotein, gangliosides, and the epidermal growth factor receptor implicate, in some way, the plasma membrane.
对放线菌素D、柔红霉素或长春新碱具有高水平抗性（约100倍至70000倍）的自发转化的中国仓鼠肺细胞在体外表现出正常细胞的形态和生长模式，并且在体内致瘤性降低。这些反向转化的多药耐药细胞扩增并高度过表达一个或多个编码P-糖蛋白的基因。同样，用放线菌素D、长春新碱或溴化乙锭筛选的碳氢化合物诱导的小鼠肉瘤细胞产生了高水平的抗性，这与药物积累减少和恶性程度抑制有关。为了确定人类肿瘤细胞是否会发生类似变化以及反向转化是否反映了分化状态的改变，从具有明确分化途径的人神经母细胞瘤细胞中用四种药物筛选了九个多药耐药亚系。与对照细胞相比，那些抗性水平高于约125倍的亚系显示出肿瘤发生频率降低。所有抗性亚系均表现出分化改变。转化表型的变化似乎是内在的，而不是免疫原性改变的结果。已经观察到高水平多药耐药的另外两个后果：中国仓鼠细胞中神经节苷脂组成的变化，表现为高级神经节苷脂生物合成受阻和/或GM3相对增加，以及在所有三种细胞系统中表皮生长因子受体增加。一个初步假说是将神经节苷脂和生长因子受体的变化与转化表型的变化联系起来。反向转化现象的基础尚不清楚，但P-糖蛋白、神经节苷脂和表皮生长因子受体表达的主要改变在某种程度上涉及质膜。
