MECHANISMS OF MULTIDRUG RESISTANCE IN CANCER-TREATMENT
MECHANISMS OF MULTIDRUG RESISTANCE IN CANCER-TREATMENT
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DOI：
10.3109/02841869209088904
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发表时间：
1992-01-01
期刊：
影响因子：
3.1
通讯作者：
HOCHHAUSER, D
中科院分区：
文献类型：
--
作者：
HARRIS, AL;HOCHHAUSER, D
晚期乳腺癌对一系列细胞毒性药物有反应，但总是产生耐药性。了解耐药机制可能会提供新的治疗选择。有几种主要的耐药机制。1)多药耐药表型。这是由于膜泵可以挤出广泛的抗癌药物-P-糖蛋白。它被一系列临床使用的钙通道阻滞剂如硝苯地平和维拉帕米抑制。其他几种180 KD、170 KD、300 KD和85 KD的膜蛋白也已报道，并与MDR相关。2)糖基转移和解毒机制。这是一个多基因酶家族，将谷胱甘肽结合到化学反应基团上。有三大类酶--酸性、碱性和中性。它们与多柔比星、美法仑、顺铂、苯丁酸氮芥和其他烷化剂的耐药性有关。其他保护系统包括金属硫蛋白和硒依赖性谷胱甘肽过氧化物酶。HSP 27赋予阿霉素抗性。3)拓扑异构酶II。DNA拓扑异构酶参与DNA代谢的多个方面，特别是遗传重组、DNA转录、染色体分离。它们是阿霉素、米托蒽醌、VP 16的靶点。低水平的表达与抗性相关。然而，它是雌激素诱导的，这可能具有治疗价值。已经报道了一种新的拓扑异构酶IIb，其更耐药。4)DNA修复许多基因参与了药物和辐射对DNA损伤的修复。缺陷的DNA修复可能使乳腺癌易感，并导致不良辐射反应。已证明修复增强是顺铂耐药的机制。有几个基因可被DNA损伤诱导，并可赋予抗性，例如A45。5)药物激活。丝裂霉素C以及环磷酰胺和VP 16需要活化才能发挥作用。低水平的细胞色素p450还原酶与MMC抗性相关。
Advanced breast cancer responds to a range of cytotoxic agents, but resistance always develops. Understanding the mechanisms of resistance may provide new therapeutic options. There are several major groups of resistance mechanisms. 1) The multidrug resistant phenotype. This is due to a membrane pump that can extrude a wide range of anticancer drugs - the P-glycoprotein. It is inhibited by a range of clinically used calcium channel blockers such as nifedipine and verapamil. Several other membrane proteins of 180 KD, 170 KD, 300 KD and 85 KD have been reported and are associated with MDR. 2) Glutathione transferances and detoxification mechanisms. These are a multigene family of enzymes that conjugate glutathione to chemically reactive groups. There are 3 major groups of enzymes-acidic, basic and neutral. They have been implicated in resistance to doxorubicin, melphalan cisplatinum chlorambucil and other alkylating agents. Other protecting systems include metallothionein and selenium dependent glutathione peroxidase. HSP27 confers doxorubicin resistance. 3) Topoisomerase II. DNA topoisomerases are involved in several aspects of DNA metabolism in particular genetic recombination, DNA transcription, chromosome segregation. They are a target for doxorubicin, mitoxantrone, VP16. Low levels of expression are associated with resistance. However, it is oestrogen inducible and this may be of therapeutic value. A novel topo IIb which is more drug resistant has been reported. 4) DNA repair. A score or more of genes are involved in the repair of DNA damage by drugs and radiation. Defective DNA repair may predispose to cancer of the breast and be responsible for adverse radiation reactions. Enhanced repair has been shown to be a mechanism of cisplatinum resistance. Several genes are inducible by DNA damage and may confer resistance e.g. A45. 5) Drug activation. Mitomycin C as well as cyclophosphamide and VP16 require activation for their effects. Low levels of cytochrome p450 reductase are associated with MMC resistance.