Characterization of a human bladder cancer cell line selected for resistance to mitomycin C.
Characterization of a human bladder cancer cell line selected for resistance to mitomycin C.
复制标题
选择对丝裂霉素 C 具有抗性的人膀胱癌细胞系的表征。
DOI：
10.1002/ijc.2910580512
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发表时间：
1994
影响因子：
6.4
通讯作者：
Singh,SV
中科院分区：
文献类型：
--
作者：
Xu,BH;Gupta,V;Singh,SV
本研究描述了人膀胱癌细胞系J82/MMC的特征，该细胞系对丝裂霉素C（MMC）的耐药性是亲本细胞的6倍。通过将J82/WT细胞反复连续暴露于增加浓度的MMC来分离J82/MMC亚系。J82/MMC细胞系显示（1）对紫杉醇、5-FU和拓扑异构酶II抑制剂的附带敏感性;和（2）对顺铂、美法仑和MMC类似物BMY 25282和BMY 25067的交叉耐药。与J82/WT相比，J82/MMC细胞中两种关键MMC活化酶NADPH细胞色素P450还原酶和DT-心肌黄酶的水平显著较低，表明J82/MMC细胞对MMC的敏感性较低可能是由于药物活化不足所致。进一步的支持表明：1）BMY 25282降低了2种细胞系之间的毒性差异; 2）与J82/MMC相比，DT-心肌黄酶抑制剂双香豆素对野生型细胞的作用更强。虽然谷胱甘肽（GSH）水平没有不同，在这些细胞中，一个小的，但显着增加谷胱甘肽转移酶（GST）的活性，注意到在J82/MMC细胞。GST抑制剂依他尼酸显著增强MMC对J82/MMC细胞的细胞毒性。与J82/WT相比，在J82/MMC细胞系中还观察到抗氧化酶过氧化氢酶水平小幅但显著增加，但未观察到GSH过氧化物酶。因此，不能排除J82/MMC细胞对MMC相对较低的敏感性可能是由于氧自由基产生减少所致。与J82/WT相比，MMC诱导的DNA链间交联在J82/MMC细胞系中显著较低。我们的研究结果表明，在J82/MMC细胞系MMC耐药可能是多因素的。
This study describes characteristics of a human bladder cancer cell line J82/MMC that is 6‐fold more resistant to mitomycin C (MMC) than the parental cells. The J82/MMC sub line was isolated by repeated continuous exposures of the J82/WT cells to increasing concentrations of MMC. The J82/MMC cell line showed (1) collateral sensitivity to taxol, 5‐FU and topoisomerase II inhibitors; and (2) cross‐resistance to cisplatin, melphalan and MMC analogues BMY 25282 and BMY 25067. Levels of two key MMC activation enzymes, NADPH cytochrome P450 reductase and DT‐diaphorase, were significantly lower in J82/MMC cells compared with J82/WT, suggesting that lower sensitivity of J82/MMC cells to MMC may result from deficient drug activation. Further support is indicated by: 1) reduction in the differential in toxicity between the 2 cell lines by BMY 25282; and 2) a higher effect of DT‐diaphorase inhibitor dicumarol on the wild‐type cells compared with J82/MMC. Although glutathione (GSH) levels did not differ in these cells, a small but significant increase in GSH transferase (GST) activity was noticed in J82/MMC cells. GST inhibitor ethacrynic acid significantly enhanced MMC cytotoxicity in the J82/MMC cell line. A small but significant increase in the level of anti‐oxidative enzyme catalase, but not GSH peroxidase, was also observed in J82/MMC cell line compared with J82/WT. Thus, the possibility that relatively lower sensitivity of J82/MMC cells to MMC may result from reduced oxygen radical generation cannot be ruled out. MMC‐induced DNA interstrand cross‐linking was markedly lower in the J82/MMC cell line compared with J82/WT. Our results suggest that the MMC resistance in the J82/MMC cell line may be multifactorial.