2012年8月13日 訊 /生物谷BIOON/ --在一項(xiàng)新研究中,，愛(ài)爾蘭都柏林圣三一學(xué)院(Trinity College Dublin)研究了耐藥性卵巢癌細(xì)胞,。這些研究發(fā)現(xiàn)最近發(fā)表在PLoS ONE期刊上，將有助于人們理解耐藥性卵巢癌中的分子標(biāo)記物以便改善臨床治療,。
對(duì)包括卵巢癌在內(nèi)的很多癌癥而言,，化療仍然是唯一的治療選擇。盡管化療能夠獲得成功的療效，但是大多數(shù)卵巢癌病人最后對(duì)化療產(chǎn)生耐藥性,。確定給病人服用哪種化療藥物是一種復(fù)雜的過(guò)程,。人們作出的大多數(shù)決策基于病人所患的癌癥類(lèi)型和癌癥的進(jìn)展程度。當(dāng)前,，人們正轉(zhuǎn)向?qū)γ棵∪诉M(jìn)行個(gè)人化修飾的化療治療。
這項(xiàng)研究研究了被稱(chēng)作IGROVCDDP的耐藥性卵巢癌細(xì)胞,。IGROV-1細(xì)胞最初從是一名卵巢癌病人體內(nèi)獲得的,。在實(shí)驗(yàn)室中，IGROV-1細(xì)胞經(jīng)過(guò)數(shù)輪化療治療來(lái)模擬癌癥病人在診斷中接受的治療,。IGROV-1細(xì)胞產(chǎn)生的子細(xì)胞就是IGROVCDDP細(xì)胞,，這些細(xì)胞在組織培養(yǎng)中進(jìn)行培養(yǎng)，并且被用來(lái)研究它們?nèi)绾萎a(chǎn)生耐藥性,。
IGROVCDDP細(xì)胞對(duì)用于卵巢癌一線治療的兩種化療藥物---順鉑(cisplatin)和紫杉醇(paclitaxel)---產(chǎn)生耐藥性,。通過(guò)研究這些IGROVCDDP細(xì)胞，研究人員能夠鑒定出哪些基因和蛋白發(fā)生改變,，和在診所內(nèi)可能作為化療耐藥性的分子標(biāo)記物,。IGROVCDDP細(xì)胞有很多化療耐藥性的分子標(biāo)記物，并且突出強(qiáng)調(diào)耐藥性癌細(xì)胞中能夠同時(shí)存在的多種機(jī)制,。IGROVCDDP細(xì)胞擁有水平增加的藥物外排泵(drug-efflux pump),，即P-糖蛋白(P-glycoprotein)。通過(guò)將紫杉醇泵出這種癌細(xì)胞之外,，這就導(dǎo)致對(duì)這種藥物產(chǎn)生耐藥性,。這項(xiàng)研究突出強(qiáng)調(diào)了P-糖蛋白能夠與多種對(duì)順鉑產(chǎn)生耐藥性的機(jī)制共同存在。對(duì)順鉑產(chǎn)生耐藥性部分上是由谷胱甘肽途徑和癌細(xì)胞降低對(duì)這種藥物的攝取所調(diào)節(jié)的,。這些發(fā)現(xiàn)是朝理解卵巢癌病人體內(nèi)耐藥性分子標(biāo)記物如何相互作用和重疊的目標(biāo)上邁出了一步,。(生物谷：Bioon.com)
本文編譯自Researchers investigate drug resistant ovarian cancer to improve clinical treatment
doi: 10.1371/journal.pone.0040717
PMC:
PMID:
Resistance to Paclitaxel in a Cisplatin-Resistant Ovarian Cancer Cell Line Is Mediated by P-Glycoprotein
Britta Stordal1,2*, Marion Hamon1, Victoria McEneaney2, Sandra Roche1, Jean-Pierre Gillet3, John J. O’Leary2, Michael Gottesman3, Martin Clynes
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
