【佳學(xué)基因檢測】Ras 抑制劑法呢基硫代水楊酸作為 1 型神經(jīng)纖維瘤病的潛在療法

基因檢測—實(shí)操性

數(shù)據(jù)分析博士醫(yī)師年度雙基練習(xí)《腫瘤治療效果與基因檢測結(jié)果的相關(guān)性》《Clin Cancer Res》在. 2006 Sep 15;12(18):5533-42.發(fā)表了一篇題目為《Ras 抑制劑法呢基硫代水楊酸作為 1 型神經(jīng)纖維瘤病的潛在療法》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Batya Barkan , Sigal Starinsky, Eitan Friedman, Reuven Stein, Yoel Kloog等完成。促進(jìn)了一種神經(jīng)科腫瘤的靶向藥物基因檢測的更為清晰的了解，進(jìn)一步增強(qiáng)了醫(yī)師與患者對腫瘤靶向藥物進(jìn)行選擇的臨床科學(xué)依據(jù)。

如何提高腫瘤基因檢測機(jī)構(gòu)的排名臨床研究內(nèi)容關(guān)鍵詞：

法尼基硫代水楊酸,神經(jīng)科,靶向藥物,RAS抑制劑,周圍神經(jīng)鞘瘤,神經(jīng)纖維瘤病

腫瘤靶向治療基因檢測臨床應(yīng)用結(jié)果

神經(jīng)科腫瘤靶向藥物治療的研究目的：法尼基硫代水楊酸 (FTS) 是一種 Ras 抑制劑，可將所有活性 Ras 異構(gòu)體從膜上去除。神經(jīng)科基因檢測項(xiàng)止組評估了 FTS 逆轉(zhuǎn)惡性周圍神經(jīng)鞘瘤 (MPNST) 的 1 型神經(jīng)纖維瘤病 (NF1) 相關(guān)腫瘤細(xì)胞系轉(zhuǎn)化表型的能力。實(shí)驗(yàn)設(shè)計(jì)：采用基因檢測對 NF1 突變進(jìn)行基因分型，分析等位基因損失，并分析神經(jīng)纖維蛋白表達(dá)水平在 MPNST 細(xì)胞系 ST88-14、S265P21 和 90-8 中測定。評估了 FTS 對 GTP 結(jié)合 Ras (Ras-GTP) 及其主要下游靶標(biāo)的影響，以及對小鼠細(xì)胞形態(tài)、貼壁依賴性和貼壁依賴性生長以及腫瘤生長的影響。 神經(jīng)科靶向藥物選擇研究結(jié)果：MPNST 細(xì)胞系是雙等位基因、NF1 失活和神經(jīng)纖維蛋白缺乏。佳學(xué)基因的基因解碼技術(shù)應(yīng)用研究表明，在所有 NF1 缺陷型 MPNST 細(xì)胞系（NF1 細(xì)胞）中，法尼基硫代水楊酸處理縮短了相對較長的 Ras 激活和向細(xì)胞外信號調(diào)節(jié)激酶、Akt 和 RalA 發(fā)出信號的持續(xù)時(shí)間，而在非 NF1（通常表達(dá)神經(jīng)纖維蛋白）中觀察到的持續(xù)時(shí)間MPNST 細(xì)胞系。 法尼基硫代水楊酸的這些影響導(dǎo)致 Ras-GTP 及其激活目標(biāo)的穩(wěn)態(tài)水平降低。 NF1 細(xì)胞的貼壁依賴性和非貼壁依賴性生長均受到法尼基硫代水楊酸的劑量依賴性抑制，并且該抑制與 Ras-GTP 水平呈正相關(guān)。 NF1 細(xì)胞被發(fā)現(xiàn)具有強(qiáng)肌動(dòng)蛋白應(yīng)力纖維，這種表型也被法尼基硫代水楊酸校正?？诜峄虼畻钏峥梢种坡闶竽Ｐ椭?NF1 腫瘤的生長。神經(jīng)科靶向藥物臨床前研究結(jié)論： NF1 細(xì)胞的法尼基硫代水楊酸治療使 Ras-GTP 水平正?；?，導(dǎo)致轉(zhuǎn)化表型的逆轉(zhuǎn)和腫瘤生長的抑制。因此法尼基硫代水楊酸可被視為治療 NF1 的潛在藥物。

腫瘤發(fā)生與反復(fù)轉(zhuǎn)移國際數(shù)據(jù)庫描述：

Purpose: Farnesylthiosalicylic acid (FTS) is a Ras inhibitor that dislodges all active Ras isoforms from the membrane. We assessed the ability of FTS to reverse the transformed phenotype of neurofibromatosis type 1 (NF1)-associated tumor cell lines of malignant peripheral nerve sheath tumor (MPNST).Experimental design: nf1 mutations were genotyped, allelic losses were analyzed, and neurofibromin expression levels were determined in MPNST cell lines ST88-14, S265P21, and 90-8. The effects of FTS on GTP-bound Ras (Ras-GTP) and its prominent downstream targets, as well as on cell morphology, anchorage-dependent and anchorage-independent growth, and tumor growth in mice, were assessed.Results: The MPNST cell lines were biallelic, NF1 inactive, and neurofibromin deficient. We show that FTS treatment shortened the relatively long duration of Ras activation and signaling to extracellular signal-regulated kinase, Akt, and RalA in all NF1-deficient MPNST cell lines (NF1 cells) to that observed in a non-NF1, normally expressing neurofibromin MPNST cell line. These effects of FTS led to lower steady-state levels of Ras-GTP and its activated targets. Both anchorage-dependent and anchorage-independent growth of NF1 cells were dose dependently inhibited by FTS, and the inhibition correlated positively with Ras-GTP levels. NF1 cells were found to possess strong actin stress fibers, and this phenotype was also corrected by FTS. NF1 tumor growth in a nude mouse model was inhibited by oral FTS.Conclusions: FTS treatment of NF1 cells normalized Ras-GTP levels, resulting in reversal of the transformed phenotype and inhibition of tumor growth. FTS may therefore be considered as a potential drug for the treatment of NF1.