本文選題：P-糖蛋白 + 乳腺癌耐藥蛋白��； 參考：《山東大學(xué)》2016年博士論文

【摘要】：顱內(nèi)腫瘤大致分為原發(fā)性腫瘤和轉(zhuǎn)移瘤。膠質(zhì)瘤是最常見的原發(fā)性腦腫瘤。膠質(zhì)母細(xì)胞瘤(Glioblastoma, GBM)是發(fā)病率和惡性程度最高的膠質(zhì)瘤。標(biāo)準(zhǔn)化治療后,GBM患者的2年生存期僅有25%。其他系統(tǒng)的惡性腫瘤發(fā)生腦轉(zhuǎn)移的幾率也非常高,例如肺癌發(fā)生腦轉(zhuǎn)移5年累積概率為16%,乳腺癌為7%,結(jié)腸癌為5%,而黑色素瘤腦轉(zhuǎn)移率可高達(dá)40%以上。盡管人們對癌癥發(fā)生、發(fā)展的分子機(jī)制了解有了巨大的進(jìn)步,對治療惡性腫瘤的靶向藥物的研發(fā)也有了長足的發(fā)展,但是中樞神經(jīng)系統(tǒng)(Central nervous system, CNS)就像腫瘤細(xì)胞的避難所,治療顱內(nèi)疾病(如原發(fā)顱內(nèi)惡性腫瘤和轉(zhuǎn)移瘤)的藥物很難有效到達(dá)顱內(nèi)病灶,這個(gè)問題一直困擾著所有CNS癌癥研究者們。這一現(xiàn)象主要是由于血腦屏障(Blood-brain barrier, BBB)的存在而引起的。在正常狀態(tài)下,BBB起到保護(hù)腦組織免受內(nèi)源性和外源性有毒物質(zhì)損傷。但是另一方面,這一屏障又可以阻擋大部分傳統(tǒng)的或新型藥物從血液循環(huán)系統(tǒng)進(jìn)入腦實(shí)質(zhì)或者腦內(nèi)病灶。因此有很多實(shí)驗(yàn)在研究BBB形成的機(jī)制,以及如何規(guī)避BBB對治療藥物運(yùn)輸?shù)淖璧K作用。BBB主要是由血管內(nèi)皮細(xì)胞構(gòu)成。與身體其他部位的血管內(nèi)皮細(xì)胞相比,BBB內(nèi)皮細(xì)胞的胞膜缺少孔隙,胞飲作用活力低,緊密連接將它們緊緊的連接在一起。而且這些內(nèi)皮細(xì)胞又同時(shí)被周細(xì)胞、星形細(xì)胞等緊密包繞,形成了第二層致密的脂質(zhì)層。這些特性使得物質(zhì)很難穿過BBB。一些必需的營養(yǎng)物質(zhì)(如葡萄糖)進(jìn)入腦內(nèi)受一些攝取轉(zhuǎn)運(yùn)蛋白嚴(yán)格調(diào)控。其他物質(zhì)通過BBB只能依靠被動擴(kuò)散。被動擴(kuò)散能力取決于分子脂溶性,分子質(zhì)量,電離度,血漿蛋白結(jié)合力和組織結(jié)合力等。然而一些物質(zhì)即使具備良好的被動擴(kuò)散的分子特性,它們穿透BBB進(jìn)入腦實(shí)質(zhì)內(nèi)的能力仍遠(yuǎn)遠(yuǎn)低于預(yù)期。經(jīng)過多年努力,研究者發(fā)現(xiàn)BBB上存在一系列外排轉(zhuǎn)運(yùn)蛋白,它們可以進(jìn)一步限制治療藥物進(jìn)入腦內(nèi)。在所有表達(dá)于BBB上的外排轉(zhuǎn)運(yùn)蛋白中,有兩種主要負(fù)責(zé)將滲透入腦實(shí)質(zhì)內(nèi)的抗癌藥物轉(zhuǎn)運(yùn)回循環(huán)血液,它們就是P-糖蛋白(P-glycoprotein, P-gp或ABCB1)和乳腺癌耐藥蛋白(Breast cancer resistance protein, BCRP或ABCG2).因此,在研發(fā)有效抗癌藥物的同時(shí),如何提高藥物滲透入腦也是決定治療腦腫瘤成敗的關(guān)鍵因素。目前規(guī)避BBB最有效的方法有兩種,首先是研發(fā)或者篩選出可以直接規(guī)避BBB限制作用的藥物。簡單說就是尋找出既具有良好的被動擴(kuò)散能力,又同時(shí)與外排轉(zhuǎn)運(yùn)蛋白,主要是ABCB1和ABCG2,親和力較低的有效的抗癌靶向藥物。第二個(gè)方法是,聯(lián)合應(yīng)用ABCB1和ABCG2的特異性抑制劑和有效的抗癌藥物,從而抑制ABCB1和ABCG2外排作用,增加抗癌藥物滲透入腦到達(dá)病灶能力。本課題包含兩部分,第一部分我們研究了五種Zeste同源物2增強(qiáng)子(Enhancer of Zeste Homolog 2, EZH2)特異性抑制劑與ABCB1和ABCG2的親和力,以及它們滲透入腦的能力。第二部分我們研究了特異性抑制ABCB1和ABCG2是否能增強(qiáng)BRAF抑制劑-威羅菲尼(Vemurafenib)治療黑色素瘤腦轉(zhuǎn)移灶的療效。第一部分ABCB1和ABCG2限制多種EZH2抑制劑滲透入腦目前發(fā)現(xiàn)EZH2在GBM中表達(dá)上調(diào),過表達(dá)的EZH2通過抑制分化來維持腫瘤細(xì)胞的干細(xì)胞性,這一作用提示EZH2是膠質(zhì)瘤進(jìn)展所必須的。另外,EZH2可以結(jié)合并甲基化信號轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活因子3(Signal Transducer and Activator of Transcription3, STAT3),從而增強(qiáng)膠質(zhì)瘤腫瘤樣干細(xì)胞(Glioma stem-like cell,GSC)中STAT3的活性,最終促進(jìn)GSC自我更新及GBM惡化。而抑制EZH2功能,可以阻斷GSC自我更新及存活相關(guān)的多條信號通路,提示EZH2是一個(gè)非常有前途的GBM治療靶點(diǎn)�；谝陨涎芯勘尘�,我們探討了5種結(jié)構(gòu)非常相似的EZH2抑制劑(EPZ005687,EPZ-6438,UNC1999,GSK343和GSK126)與ABCB1和ABCG2的相互作用。我們先在體外利用Transwell實(shí)驗(yàn)對這些化合物進(jìn)行了篩選,然后利用野生型(Wild-type, WT), Abcbl和／或Abcg2基因敲除鼠進(jìn)行了體內(nèi)實(shí)驗(yàn),進(jìn)一步研究了EPZ005687,EPZ-6438和GSK126體內(nèi)藥代動力學(xué)及BBB透過能力等。本實(shí)驗(yàn)發(fā)現(xiàn),雖然GSK126非常低的膜穿透力導(dǎo)致體外實(shí)驗(yàn)難以檢測其與轉(zhuǎn)運(yùn)蛋白的親和力,但是結(jié)合體內(nèi)實(shí)驗(yàn)結(jié)果,我們發(fā)現(xiàn)所有的EZH2抑制劑均可以被ABCB1和ABCG2轉(zhuǎn)運(yùn)。在體內(nèi),ABCB1和ABCG2都限制了EPZ005687和GSK126的BBB穿透力,而EPZ-6438在腦內(nèi)的累積僅受ABCB1限制,并且ABCB1和ABCG2特異性抑制劑-依克利達(dá)可以完全抑制其針對EPZ-6438的外排作用。另外,在本實(shí)驗(yàn)所用的基因敲除小鼠體內(nèi)存在一個(gè)未探明的因素,它明顯延長了EPZ005687和EPZ-6438在敲除鼠血漿內(nèi)停留時(shí)間,而這種現(xiàn)象并沒有在GSK126相關(guān)的體內(nèi)實(shí)驗(yàn)中發(fā)生。在WT小鼠中,所有組織內(nèi)GSK126的組織-血漿比低于EPZ005687或EPZ-6438的組織-血漿比。此外,GSK126在WT小鼠的口服生物利用度僅為0.2%,在Abcbl;Abcg2基因敲除小鼠這一數(shù)值僅增加至14.4%。這些結(jié)果可能是由GSK126較差的膜滲透性導(dǎo)致的,因而本論文質(zhì)疑GSK126的臨床有效性。雖然本實(shí)驗(yàn)所檢測的EZH2抑制劑都是ABCB1和ABCG2的轉(zhuǎn)運(yùn)底物,這一特性限制了這些化合物進(jìn)入腦實(shí)質(zhì)的能力和潛在的腦膠質(zhì)瘤治療效果,但是我們認(rèn)為EPZ-6438是這一系列化合物中最適合用于治療腦膠質(zhì)瘤的EZH2抑制劑。第二部分抑制ABCBl和ABCG2可提高威羅菲尼治療黑色素瘤腦轉(zhuǎn)移瘤療效在過去幾十年里,黑色素瘤發(fā)病率逐年上升。Ⅳ級黑色素瘤患者發(fā)生腦轉(zhuǎn)移的概率在40%以上,這是導(dǎo)致黑色素瘤患者死亡的主要因素之一。威羅菲尼作為BRAF蛋白抑制劑,是目前治療黑色素瘤最有效的化療藥物之一。由于威羅菲尼是ABCB1和ABCG2的轉(zhuǎn)運(yùn)底物,因此威羅菲尼口服利用率和腦內(nèi)累積量明顯受到這兩個(gè)轉(zhuǎn)運(yùn)蛋白限制,從而降低了其療效,尤其是對黑色素瘤腦轉(zhuǎn)移灶的療效�；谝陨涎芯勘尘�,我們在應(yīng)用威羅菲尼治療黑色素瘤腦轉(zhuǎn)移小鼠模型的時(shí)候,同時(shí)應(yīng)用ABCB1和ABCG2特異性抑制劑-依克利達(dá),以觀察該聯(lián)合用藥方法能否增加威羅菲尼的療效。我們首先將黑色素瘤細(xì)胞注射入WT小鼠,Abcb1和Abcg2基因敲除鼠腦內(nèi),制成黑色素瘤腦轉(zhuǎn)移小鼠模型。然后給予不同劑量的威羅菲尼或聯(lián)合應(yīng)用依克利達(dá),研究其藥代動力學(xué)及療效。本研究發(fā)現(xiàn),口服威羅菲尼24小時(shí)后,盡管WT小鼠血漿內(nèi)濃度比Abcbla/1b;Abcg2-/-小鼠血漿濃度僅低了1.4倍,但腦內(nèi)濃度卻比基因敲除鼠低了700多倍。依克利達(dá)可以提高威羅菲尼的口服利用率和腦通透能力,但是WT小鼠腦內(nèi)濃度仍低于基因敲除鼠腦內(nèi)濃度20多倍。表明ABCB1和ABCG2顯著抑制威羅菲尼滲透入腦,依克利達(dá)雖然可以顯著提高威羅菲尼滲透入腦的能力,但是并不能完全逆轉(zhuǎn)ABCB1和ABCG2對其限制作用。利用沒有BBB限制的皮下腫瘤模型時(shí),我們發(fā)現(xiàn)10 mg/kg威羅菲尼對Abcbl a/1b;Abcg2-/-小鼠的療效與25mg/kg威羅菲尼對WT小鼠的療效幾乎是一致的。利用腦轉(zhuǎn)移模型我們發(fā)現(xiàn),ABCBl和ABCG2顯著抑制了威羅菲尼對腦轉(zhuǎn)移黑色素瘤的治療作用,而依克利達(dá)可以一定程度地提高威羅菲尼的療效。另外我們還發(fā)現(xiàn)一個(gè)有趣的現(xiàn)象：在開始用藥的時(shí)候,基因敲除鼠顱內(nèi)腫瘤對藥物反應(yīng)比較敏感,腫瘤體積不再增大。但是用藥一周或兩周之后,腫瘤不再對威羅菲尼有反應(yīng),腫瘤迅速增長。我們試圖去探討該腫瘤在如此短的時(shí)間內(nèi)獲得耐藥性的機(jī)制。但很不幸的是我們利用免疫組織化學(xué)、Western和PCR等多種方法檢測相關(guān)信號通路,均未明確找出該耐藥性的產(chǎn)生機(jī)制。本實(shí)驗(yàn)研究表明ABCBl和ABCG2明顯的限制了威羅菲尼對黑色素瘤腦轉(zhuǎn)移瘤的治療效果,聯(lián)合應(yīng)用其抑制劑依克利達(dá)可以增強(qiáng)其療效,但仍不足以完全逆轉(zhuǎn)該限制作用。
[Abstract]:Intracranial tumors are roughly divided into primary tumors and metastatic tumors. Glioma is the most common primary brain tumor. Glioblastoma (GBM) is the most malignant and malignant glioma. After standardized treatment, the 2 year survival of patients with GBM is also very high in the incidence of brain metastases in other malignant tumors of 25%.. For example, the cumulative probability of 5 years of brain metastases in lung cancer is 16%, breast cancer is 7%, colon cancer is 5%, and the rate of melanoma brain metastases can be as high as 40%. Although people have great progress in the molecular mechanism of cancer development, the development of the molecular mechanism of cancer therapy has also developed greatly, but the central nervous system (Cent Ral nervous system, CNS) as a refuge of tumor cells, drugs for the treatment of intracranial diseases such as primary intracranial malignant tumors and metastases are difficult to reach intracranial lesions. This problem has been troubled by all CNS cancer researchers. This phenomenon is mainly caused by the presence of the blood brain barrier (Blood-brain barrier, BBB). In normal condition, BBB protects brain tissue from endogenous and exogenous toxic substances, but on the other hand, this barrier can block most traditional or new drugs from the blood circulation system into the brain parenchyma or brain lesions. So there are many experiments in the study of the mechanism of BBB formation and how to circumvent the treatment of BBB. .BBB is mainly composed of vascular endothelial cells. Compared with the vascular endothelial cells in other parts of the body, the membrane of the BBB endothelial cells is short of pore, and the activity of the cell is low, closely connected to connect them together. And these endothelial cells are closely wrapped around the pericytes and astrocytes. It is a dense layer of second layers of lipid. These properties make it difficult for the substance to pass through some of the essential nutrients (such as glucose) into the brain, which are strictly regulated by some uptake transporters in the brain. Other substances can only rely on passive diffusion through BBB. The passive diffusion ability depends on molecular fat solubility, molecular mass, ionization, plasma protein binding. However, even if some substances have good molecular properties of passive diffusion, their ability to penetrate BBB into the brain is still far lower than expected. After years of effort, researchers found a series of extracellular transporters on BBB, which can limit the entry of therapeutic drugs into the brain. In the outer row transporters on BBB, two kinds of drugs are responsible for transshipment of anticancer drugs into the brain parenchyma, which are P- glycoproteins (P-glycoprotein, P-gp or ABCB1) and breast cancer resistant proteins (Breast cancer resistance protein, BCRP, or ABCG2). Therefore, how to improve the effective anticancer drugs Drug penetration into the brain is also a key factor in the success of the treatment of brain tumors. At present, there are two most effective methods to avoid BBB. The first is to develop or screen out drugs that can directly circumvent the BBB restriction. It is simply to find out the good passive diffusion ability, and the same time and the external transporter, mainly ABCB1 and ABCG2, An effective anti-cancer targeting drug with low affinity. The second method is to combine the specific inhibitors of ABCB1 and ABCG2 and effective anticancer drugs to inhibit the ABCB1 and ABCG2 efflux and increase the ability of anti-cancer drugs to infiltrate into the brain to reach the focus. This topic includes two parts. In the first part, we studied the increase of five Zeste homology 2. The affinity between the Enhancer of Zeste Homolog 2, EZH2 (EZH2) specific inhibitors and ABCB1 and ABCG2, and their ability to infiltrate into the brain. Second we studied the efficacy of specific inhibition of ABCB1 and ABCG2 on the enhancement of BRAF inhibitor - Viv Lo Feeney (Vemurafenib) in the treatment of melanoma brain metastases. A variety of EZH2 inhibitors are infiltrated into the brain and the expression of EZH2 is up-regulated in GBM, and the overexpressed EZH2 maintains the stem cell nature of the tumor cells by inhibiting differentiation, which suggests that EZH2 is necessary for the progression of glioma. In addition, EZH2 can bind and methylation signal transduction and transfer activator 3 (Signal Transducer and Activator o) F Transcription3, STAT3), thereby enhancing the activity of STAT3 in glioma tumor like stem cells (Glioma stem-like cell, GSC), and ultimately promoting GSC self renewal and GBM deterioration. Inhibition of EZH2 function can block multiple signaling pathways associated with GSC self renewal and survival. In the study background, we explored the interaction of 5 very similar EZH2 inhibitors (EPZ005687, EPZ-6438, UNC1999, GSK343 and GSK126) with ABCB1 and ABCG2. We screened these compounds using Transwell experiments in vitro, and then used the wild type (Wild-type, WT), Abcbl and / or gene knockout mice. In this experiment, the pharmacokinetics and BBB transmittance of EPZ005687, EPZ-6438 and GSK126 were further studied. It was found that although the very low membrane penetration of GSK126 was difficult to detect its affinity with the transporter in vitro, we found that all of the EZH2 inhibitors were able to be ABCB1 and ABC in combination with the results of the experiment in vivo. G2 transport. In vivo, both ABCB1 and ABCG2 restrict the BBB penetration of EPZ005687 and GSK126, and the accumulation of EPZ-6438 in the brain is limited only by ABCB1, and ABCB1 and ABCG2 specific inhibitors, kkli, can completely inhibit the EPZ-6438 exocytosis. In addition, there is an unexplored gene knockout mouse in this experiment. It obviously prolongs the time of EPZ005687 and EPZ-6438 in the knockout rat plasma, and this phenomenon does not occur in GSK126 related in vivo experiments. In WT mice, the tissue plasma ratio of GSK126 in all tissues is lower than that of EPZ005687 or EPZ-6438. In addition, the oral bioavailability of GSK126 in WT mice is only the only oral bioavailability. For 0.2%, in Abcbl, Abcg2 gene knockout mice, which only increased to 14.4%., may be caused by the poor membrane permeability of GSK126, so this paper questions the clinical effectiveness of GSK126. Although the EZH2 inhibitors detected in this experiment are the transport bases of ABCB1 and ABCG2, this property restricts the entry of these compounds into the brain. Substantial ability and potential therapeutic effects of glioma, but we think that EPZ-6438 is the most suitable EZH2 inhibitor for the treatment of glioma in this series of compounds. The second part inhibition of ABCBl and ABCG2 can improve the efficacy of willfield in the treatment of melanoma brain metastases. The incidence of melanoma has increased year by year in the past few decades. The incidence of brain metastases in patients with grade IV melanoma is more than 40%, which is one of the major factors leading to the death of melanoma patients. As a BRAF protein inhibitor, willfield is one of the most effective chemotherapeutic agents for melanoma. Because Viv Lo Feeney is a transport substrate for ABCB1 and ABCG2, the oral utilization of willfield The accumulation of the two transporters in the brain is obviously limited by these transporters, which reduces the efficacy, especially for the brain metastases of melanoma. Based on the above research background, we used the ABCB1 and ABCG2 specific inhibitors, Cicia, to observe the mouse model of melanoma brain metastases. We first injected melanoma cells into WT mice, Abcb1 and Abcg2 gene knockout mouse brains to make a mouse model of melanoma brain metastases. Then we gave different doses of willfield or combined use of kkli to study its pharmacokinetics and efficacy. After 24 hours of willfield, the plasma concentration of WT mice was 1.4 times lower than the plasma concentration of Abcbla/1b and Abcg2-/- mice, but the concentration in the brain was more than 700 times lower than that of the gene knockout mice. 0 times. It shows that ABCB1 and ABCG2 significantly inhibit the infiltration of willoni into the brain. Although cideridis can significantly improve the ability of willfield to infiltrate the brain, it does not completely reverse the restriction of ABCB1 and ABCG2. Using the subcutaneous tumor model without BBB restriction, we present 10 mg/kg willfield to Abcbl a/1b; Abcg2-/- mice. The effect was almost the same as the effect of 25mg/kg willfield on WT mice. Using the brain metastasis model, we found that ABCBl and ABCG2 significantly inhibited the therapeutic effect of willfield on brain metastases, and the effect of willfield could be improved to a certain extent. In the beginning of the drug, the intracranial tumor of the gene knockout rat is more sensitive to the drug reaction, and the volume of the tumor no longer increases. But after a week or two weeks, the tumor no longer responds to willoni and the tumor grows rapidly. We try to explore the mechanism of the tumor's resistance to such a short time. Unfortunately, we use it. A variety of methods such as immunohistochemistry, Western and PCR were used to detect the related signaling pathways, and the mechanism of the drug resistance was not clearly identified. This study showed that ABCBl and ABCG2 significantly restricted the effect of willfield's treatment on melanoma brain metastases. Completely reversing the limitation.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R739.4

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4 蔡振鑫;黑色素瘤:預(yù)測致死性特征的30年臨床經(jīng)驗(yàn)[J];國外醫(yī)學(xué).外科學(xué)分冊;2004年02期

5 Helsing P.,Loeb M. ,馮義國;小直徑黑色素瘤:挪威黑色素瘤隨訪項(xiàng)目[J];世界核心醫(yī)學(xué)期刊文摘(皮膚病學(xué)分冊);2005年04期

6 Murray C.S.;Stockton D.L.;Doherty V.R. ;黨倩麗;;增厚的黑色素瘤:長久面對的挑戰(zhàn)[J];世界核心醫(yī)學(xué)期刊文摘(皮膚病學(xué)分冊);2005年08期

7 High W.A. ,Quirey R.A. ,Guillén D.R ,R.S. Taylor,劉超;7例甲單元原位黑色素瘤的臨床表現(xiàn)、組織病理和臨床預(yù)后[J];世界核心醫(yī)學(xué)期刊文摘(皮膚病學(xué)分冊);2005年02期

8 Curtin J.A.;Fridlyand J.;Kageshita T. ;B.C. Bastian;黨倩麗;;黑色素瘤不同位置的基因改變[J];世界核心醫(yī)學(xué)期刊文摘(皮膚病學(xué)分冊);2006年02期

9 Blaise S.;Rumeau-Trividic M.;Le Brun V.;周少娜;;黑色素瘤伴亞急性原發(fā)性纖維蛋白溶解[J];世界核心醫(yī)學(xué)期刊文摘(皮膚病學(xué)分冊);2006年04期

10 Weatherhead S.C.;Lawrence C.M. ;潘敏;;黑色素瘤篩查診所:檢出更多的黑色素瘤還是使患者消除顧慮?[J];世界核心醫(yī)學(xué)期刊文摘(皮膚病學(xué)分冊);2006年Z1期

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1 王倫邋王晨;早期發(fā)現(xiàn)黑色素瘤可挽救生命[N];科技日報(bào);2007年

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3 健康時(shí)報(bào)特約記者 管九蘋;澳大利亞免費(fèi)普查黑色素瘤[N];健康時(shí)報(bào);2010年

4 實(shí)習(xí)生 易立;黑色素瘤,是否無藥可治？[N];科技日報(bào);2011年

5 記者 張e，

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