Role of p53 in the ability of 1,2-diaminocyclohexane-diacetato-dichloro-Pt(IV) to circumvent cisplatin resistance.
Role of p53 in the ability of 1,2-diaminocyclohexane-diacetato-dichloro-Pt(IV) to circumvent cisplatin resistance.
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p53 在 1,2-二氨基环己烷-二乙酰基-二氯-Pt(IV) 规避顺铂耐药性的能力中的作用。
DOI：
10.1016/s0162-0134(99)00144-0
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发表时间：
1999
影响因子：
3.9
通讯作者：
Khokhar,AR
中科院分区：
文献类型：
--
作者：
Siddik,ZH;Hagopian,GS;Thai,G;Tomisaki,S;Toyomasu,T;Khokhar,AR
一些报告表明，顺铂耐药的机制是多因素的。然而，DNA损伤耐受似乎是更重要的机制。很明显，耐药性通常是一个主要的临床问题，已经采取了许多方法来规避这种临床障碍。一种方法是通过类似物开发，并且我们已经鉴定了1，2-二氨基环己烷-二乙酸二氯-铂（IV）作为在顺铂抗性中具有活性的类似物。对卵巢肿瘤细胞系的活性最大，其中潜伏的、不可诱导的野生型p53功能可以被类似物重新激活。p53的这种功能性激活也对应于对由类似物诱导的DNA损伤的耐受性的降低的阈值。有趣的是，具有突变或无效p53的细胞系对类似物具有交叉抗性。这些数据表明，顺铂耐药，由于DNA损伤耐受性的增加，可以通过p53功能的损失，并通过类似物的潜在的野生型p53的功能激活促进细胞死亡和规避这种耐药机制。
Several reports indicate that the mechanism of resistance to cisplatin is multifactorial. However, DNA damage tolerance appears to be the more significant mechanism. It is clear that resistance in general is a major clinical concern, and a number of approaches have been taken to circumvent this clinical impediment. One approach is through analog development, and we have identified 1,2-diaminocyclohexane-diacetatodichloro-platinum(IV) as an analog with activity in cisplatin resistance. The activity is greatest against ovarian tumor cell lines where the latent, non-inducible wild-type p53 function can be reactivated by the analog. This functional activation of p53 also corresponds to a reduced threshold for tolerance to DNA damage induced by the analog. Interestingly, cell lines with mutant or null p53 are cross-resistant to the analog. The data indicate that cisplatin resistance due to an increase in DNA damage tolerance can arise through a loss of p53 function, and that functional activation of latent wild-type p53 by the analog facilitates cell death and circumvents this resistance mechanism.