2012年8月13日 訊 /生物谷BIOON/ --在一項新研究中，愛爾蘭都柏林圣三一學院(Trinity College Dublin)研究了耐藥性卵巢癌細胞,。這些研究發(fā)現最近發(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記物以便改善臨床治療,。
對包括卵巢癌在內的很多癌癥而言，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,，但是大多數卵巢癌病人最后對化療產生耐藥性。確定給病人服用哪種化療藥物是一種復雜的過程,。人們作出的大多數決策基于病人所患的癌癥類型和癌癥的進展程度,。當前，人們正轉向對每名病人進行個人化修飾的化療治療,。
這項研究研究了被稱作IGROVCDDP的耐藥性卵巢癌細胞,。IGROV-1細胞最初從是一名卵巢癌病人體內獲得的。在實驗室中,，IGROV-1細胞經過數輪化療治療來模擬癌癥病人在診斷中接受的治療,。IGROV-1細胞產生的子細胞就是IGROVCDDP細胞，這些細胞在組織培養(yǎng)中進行培養(yǎng),，并且被用來研究它們如何產生耐藥性,。
IGROVCDDP細胞對用于卵巢癌一線治療的兩種化療藥物---順鉑(cisplatin)和紫杉醇(paclitaxel)---產生耐藥性。通過研究這些IGROVCDDP細胞,，研究人員能夠鑒定出哪些基因和蛋白發(fā)生改變,，和在診所內可能作為化療耐藥性的分子標記物。IGROVCDDP細胞有很多化療耐藥性的分子標記物,，并且突出強調耐藥性癌細胞中能夠同時存在的多種機制,。IGROVCDDP細胞擁有水平增加的藥物外排泵(drug-efflux pump),，即P-糖蛋白(P-glycoprotein)。通過將紫杉醇泵出這種癌細胞之外,，這就導致對這種藥物產生耐藥性,。這項研究突出強調了P-糖蛋白能夠與多種對順鉑產生耐藥性的機制共同存在。對順鉑產生耐藥性部分上是由谷胱甘肽途徑和癌細胞降低對這種藥物的攝取所調節(jié)的,。這些發(fā)現是朝理解卵巢癌病人體內耐藥性分子標記物如何相互作用和重疊的目標上邁出了一步,。(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
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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.
