Bashir I, Sikora K, Abel P, Foster C S
Department of Clinical Oncology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Int J Cancer. 1994 Jun 1;57(5):719-26. doi: 10.1002/ijc.2910570519.
We describe the selection of 3 new multidrug-resistant cell lines derived from tumor cells of different metastatic phenotypes within the Dunning R3327 model of rat prostatic carcinoma. Cell lines of weak (AT2) and strong (AT3 and MAT-LyLu) metastatic behavior were cultured in vitro and challenged with doxorubicin at progressively increasing concentrations. Chemosensitivity was determined colorimetrically by release of precipitated formazan pigment (MTT assay). Expression of the multidrug-resistance glycoprotein (P-170) was monitored immunocytochemically and by Western blotting using monoclonal antibody C219. The behavior of the parental and resultant drug-resistant cells was assessed by their growth in syngeneic rats. Doxorubicin challenge of the initially drug-sensitive parental prostatic carcinoma cell lines resulted in the rapid development of multidrug resistance together with simultaneous expression of P-glycoprotein. While lung and lymph-node metastases developed in host animals inoculated with parental AT3 and MAT-LyLu cells, no metastases developed in the multidrug-resistant progeny of these cell lines. This study has shown that Dunning rat prostate-carcinoma cell lines, previously sensitive to different cytotoxic agents, rapidly become multidrug-resistant and express P-glycoprotein following exposure to doxorubicin. Furthermore, development of multidrug resistance is associated with a less aggressive tumor phenotype and loss of metastatic potential. Nevertheless, it is unlikely that the non-metastatic phenotype of Dunning rat prostatic carcinoma cells is solely associated with expression of P-glycoprotein. These new multidrug-resistant cell lines exhibiting an altered behavioral phenotype will provide a valuable model with which to analyze the relationship between expression of P-glycoprotein and the metastatic phenotype of prostatic carcinoma cells.
我们描述了从大鼠前列腺癌邓宁R3327模型中不同转移表型的肿瘤细胞衍生出的3种新的多药耐药细胞系的筛选过程。将具有弱转移行为（AT2）和强转移行为（AT3和MAT-LyLu）的细胞系进行体外培养，并用浓度逐渐增加的阿霉素进行攻击。通过沉淀的甲臜色素释放（MTT法）比色测定化学敏感性。使用单克隆抗体C219通过免疫细胞化学和蛋白质印迹法监测多药耐药糖蛋白（P-170）的表达。通过亲代细胞和产生的耐药细胞在同基因大鼠中的生长情况评估其行为。对最初对药物敏感的亲代前列腺癌细胞系进行阿霉素攻击，导致多药耐药性迅速发展，同时P-糖蛋白表达。在用亲代AT3和MAT-LyLu细胞接种的宿主动物中出现了肺和淋巴结转移，而这些细胞系的多药耐药后代未出现转移。本研究表明，邓宁大鼠前列腺癌细胞系以前对不同细胞毒性药物敏感，在接触阿霉素后迅速产生多药耐药性并表达P-糖蛋白。此外，多药耐药性的发展与侵袭性较低的肿瘤表型和转移潜能的丧失有关。然而，邓宁大鼠前列腺癌细胞的非转移表型不太可能仅与P-糖蛋白的表达有关。这些表现出行为表型改变的新的多药耐药细胞系将为分析P-糖蛋白表达与前列腺癌细胞转移表型之间的关系提供一个有价值的模型。
