Multiple mechanisms of resistance to cis-diamminedichloroplatinum(II) in murine leukemia L1210 cells.
Multiple mechanisms of resistance to cis-diamminedichloroplatinum(II) in murine leukemia L1210 cells.
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发表时间：
1987-04
期刊：
影响因子：
11.2
通讯作者：
V. Richon;N. Schulte;A. Eastman
中科院分区：
文献类型：
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作者：
V. Richon;N. Schulte;A. Eastman
作为顺铂(cis-DDP)耐药的实验模型，小鼠白血病L1210细胞暴露于顺式-顺铂(cis-DDP)浓度逐渐升高的环境中，产生了多种耐药细胞系。用敏感细胞和抗性细胞进行种内杂交，以确定顺式顺铂抗性是显性还是隐性性状。与亲本细胞相比，杂交细胞表现出一定程度的抗性。为了确定这是由于单一的共显性特征还是来自各种耐药机制的贡献，研究了细胞和杂交细胞在药物积累方面的变化，以及可能使药物失活的谷胱甘肽水平的变化。顺铂耐药细胞显示药物积聚减少50%，细胞内谷胱甘肽增加1.7倍。用丁硫氨酸亚磺胺降低这些细胞中的谷胱甘肽水平，并不会使它们对顺铂敏感。杂交细胞与顺式顺铂敏感细胞具有相同的谷胱甘肽积累量和水平。对耐1，2-二氨基环己烷铂(II)类似物的细胞进行了平行研究。这些细胞也表现出药物积累减少，但谷胱甘肽没有增加。因此，谷胱甘肽积累量的减少和谷胱甘肽的增加都可能介导抗性。这两种机制都代表了细胞杂交中表现出的隐性特征。这些机制只能解释这些细胞中的一小部分阻力。一种主要的、主要的机制发生在DNA被铂化之后，但这是否涉及DNA修复、复制后修复或其他一些尚不清楚的过程仍有待确定。
As an experimental model for resistance to cis-diamminedichloroplatinum(II) (cis-DDP), murine leukemia L1210 cells have been exposed to a stepwise increase in cis-DDP concentration to produce a variety of resistant cell lines. Intraspecies hybrids of the sensitive and resistant cells were made to determine whether cis-DDP resistance is a dominant or recessive trait. Hybrid cells displayed a partial degree of resistance as compared to the parental cells. To determine whether this was due to a single codominant trait or contribution from a variety of resistance mechanisms, the cells and hybrids were investigated for alterations in the accumulation of drug, as well as alterations in glutathione levels which might inactivate the drug. The cis-DDP-resistant cells demonstrated both a 50% reduction in accumulation of drug and a 1.7-fold increase in intracellular glutathione. Reducing the glutathione levels in these cells with buthionine sulfoximine did not sensitize them to cis-DDP. The hybrid cells had the same accumulation and the same levels of glutathione as the cis-DDP-sensitive cells. Parallel studies were performed with cells resistant to 1,2-diaminocyclohexaneplatinum(II) analogues. These cells also demonstrated reduced drug accumulation but no increase in glutathione. Therefore, both a decrease in accumulation and increase in glutathione may mediate resistance. Both mechanisms represent recessive traits as demonstrated in the cell hybrids. These mechanisms can only account for a small part of the resistance in these cells. A major, dominant mechanism occurs after the DNA has been platinated, but it remains to be determined whether this involves DNA repair, postreplication repair, or some other as yet unidentified process.