DETERMINANTS OF DRUG RESPONSE IN A CISPLATIN-RESISTANT HUMAN LUNG-CANCER CELL-LINE
DETERMINANTS OF DRUG RESPONSE IN A CISPLATIN-RESISTANT HUMAN LUNG-CANCER CELL-LINE
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DOI：
10.1111/j.1349-7006.1990.tb02602.x
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发表时间：
1990-05-01
期刊：
影响因子：
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通讯作者：
SAIJO, N
中科院分区：
文献类型：
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作者：
FUJIWARA, Y;SUGIMOTO, Y;SAIJO, N
为了阐明顺铂耐药的机制，我们对从野生型（PC-9）中选择的人非小细胞肺癌细胞系（PC-9/CDDP）进行了表征，以获得对顺铂的耐药性。 PC-9/CDDP对顺铂表现出28倍的耐药性，与其他化疗药物有交叉耐药性，包括苯丁酸氮芥（×6.3）、美法仑（×3.7）和3-[（4-氨基-2-甲基-5-嘧啶基）]甲基-1-（2-氯乙基）-1-亚硝基脲（ACNU）（×）。 3.9）。野生型或耐药细胞中均不表达 mdr-1 mRNA。谷胱甘肽 S-转移酶 (GST).pi 的 mRNA 和蛋白质水平。两条线相似。 GST-.mu。同工酶等量存在，并且硒依赖性和非依赖性谷胱甘肽过氧化物酶和谷胱甘肽还原酶的活性没有变化。耐药细胞中人金属硫蛋白IIA的mRNA水平和细胞内总金属硫蛋白水平降低。在耐药细胞中发现细胞内谷胱甘肽 (GSH) 水平显着升高（20.0 与 63.5 nmol/mg 蛋白质），并且用丁硫氨酸亚磺酰亚胺控制这些水平会产生对顺铂或苯丁酸氮芥的部分敏感性。尽管该细胞系的金属硫蛋白水平降低，但增加的 GSH 可能也在决定 PC-9/CDDP 的氯化镉抗性中发挥了作用。 PC-9/CDDP 中铂的细胞内水平降低也导致了顺铂耐药表型。因此，在耐药细胞中至少选择了两种不同的机制，这些机制赋予表型并允许对其他亲电药物具有一定程度的交叉耐药性。
To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non-small cell lung cancer cell line (PC-9/CDDP) selected from the wild type (PC-9) for acquired resistance to cisplatin. PC-9/CDDP demonstrated 28-fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (.times. 6.3), melphalan (.times. 3.7) and 3-[(4-amino-2-methyl-5-pyrimidinyl)]methyl-1-(2-chloroethyl)-1-nitrosourea (ACNU) (.times. 3.9). There was no expression of mdr-1 mRNA in either wild-type or resistant cells. The mRNA and protein levels of glutathione S-transferase (GST) .pi. were similar in the two lines. A GST-.mu. isozyme was present in equal amounts and the activities of selenium-dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs. 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC-9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC-9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.