Richon V M, Schulte N, Eastman A
Cancer Res. 1987 Apr 15;47(8):2056-61.
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.
作为对顺二氨二氯铂（II）（顺铂）耐药的实验模型，小鼠白血病L1210细胞已逐步暴露于浓度递增的顺铂中，以产生多种耐药细胞系。制备了敏感细胞和耐药细胞的种内杂交细胞，以确定顺铂耐药是显性还是隐性性状。与亲代细胞相比，杂交细胞表现出部分耐药程度。为了确定这是由于单一的共显性性状还是多种耐药机制的作用，对细胞和杂交细胞进行了研究，以观察药物积累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累减少50%，细胞内谷胱甘肽增加1.7倍。用丁硫氨酸亚砜胺降低这些细胞中的谷胱甘肽水平并不能使它们对顺铂敏感。杂交细胞的药物积累和谷胱甘肽水平与顺铂敏感细胞相同。对1,2-二氨基环己烷铂（II）类似物耐药的细胞进行了平行研究。这些细胞也显示药物积累减少，但谷胱甘肽没有增加。因此，药物积累减少和谷胱甘肽增加都可能介导耐药。如细胞杂交实验所示，这两种机制均代表隐性性状。这些机制只能解释这些细胞中耐药性的一小部分。一种主要的显性机制发生在DNA被铂化之后，但尚有待确定这是否涉及DNA修复、复制后修复或其他尚未确定的过程。
