Bates S E, Shieh C Y, Tsokos M
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Am J Pathol. 1991 Aug;139(2):305-15.
Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro, and a similar role has been hypothesized in vivo in human malignancy. Because expression of mdr-1 is increased in neuroblastoma cell lines by differentiating agents, the authors hypothesized a similar correlation with differentiation in vivo in neuroblastomas. In 12 tumors from 11 patients, total RNA analysis demonstrated no correlation with differentiation, but a correlation could be detected in the cell-based methods of analysis. The very primitive 'stroma'-poor, poorly differentiated neuroblastomas had low levels of mdr-1/P-glycoprotein. The intermediate grades had higher levels of expression and although heterogeneity of differentiation appeared within these tumors, both primitive and more differentiated cells expressed the gene at comparable levels within the tumor. One very well-differentiated neuroblastoma, a ganglioneuroma, had no detectable expression in the neurofibrillary material, but demonstrated expression in adjacent large ganglionic cells. Thus mdr-1/P-glycoprotein expression increased with increasing differentiation among tumors, and was present in ganglionic cells in the most well-differentiated tumor. The three tumors with the highest levels of expression were obtained from patients who received preoperative chemotherapy.
编码药物外排泵P-糖蛋白的mdr-1基因表达增加是体外获得性耐药的一个公认介质，并且在人类恶性肿瘤的体内情况中也推测有类似作用。由于分化剂可使神经母细胞瘤细胞系中的mdr-1表达增加，作者推测在神经母细胞瘤的体内分化情况中也存在类似关联。在来自11名患者的12个肿瘤中，总RNA分析显示与分化无相关性，但在基于细胞的分析方法中可检测到相关性。非常原始的“基质”少、低分化神经母细胞瘤的mdr-1/P-糖蛋白水平较低。中间分级的肿瘤表达水平较高，尽管这些肿瘤内出现了分化异质性，但原始细胞和分化程度更高的细胞在肿瘤内表达该基因的水平相当。一个高度分化的神经母细胞瘤，即神经节神经瘤，在神经纤维物质中未检测到表达，但在相邻的大神经节细胞中显示有表达。因此，mdr-1/P-糖蛋白表达随肿瘤分化程度增加而增加，并且在分化程度最高的肿瘤的神经节细胞中存在。表达水平最高的三个肿瘤来自接受术前化疗的患者。
