【佳學(xué)基因檢測(cè)】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(cè)—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(cè)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(cè)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(cè)的更為清晰的了解，進(jìn)一步增強(qiáng)了醫(yī)師與患者對(duì)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(cè)機(jī)構(gòu)的排名臨床研究?jī)?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?chē)窠?jīng)鞘瘤,神經(jīng)纖維瘤病

腫瘤靶向治療基因檢測(cè)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(cè)項(xiàng)止組評(píng)估了 FTS 逆轉(zhuǎn)惡性周?chē)窠?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(cè)對(duì) 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(cè)定。評(píng)估了 FTS 對(duì) GTP 結(jié)合 Ras (Ras-GTP) 及其主要下游靶標(biāo)的影響，以及對(duì)小鼠細(xì)胞形態(tài)、貼壁依賴(lài)性和貼壁依賴(lài)性生長(zhǎng)以及腫瘤生長(zhǎng)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(duì)較長(zhǎng)的 Ras 激活和向細(xì)胞外信號(hào)調(diào)節(jié)激酶、Akt 和 RalA 發(fā)出信號(hào)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(lài)性和非貼壁依賴(lài)性生長(zhǎng)均受到法尼基硫代水楊酸的劑量依賴(lài)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(zhǎng)。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?；瑢?dǎo)致轉(zhuǎn)化表型的逆轉(zhuǎn)和腫瘤生長(zhǎng)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(guó)際數(shù)據(jù)庫(kù)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.