細(xì)胞周期檢查點(diǎn)與腫瘤治療

細(xì)周檢點(diǎn)腫治本綜述由解螺旋學(xué)員hello負(fù)整理（2017年12月細(xì)胞周期指細(xì)胞從上次分裂結(jié)束到下次分裂結(jié)束所經(jīng)歷的過程，包括分裂期期和分裂間期。根據(jù)DNA合的情況間期又分為GDNA合成前期Gap1期DNA合成期）和G期DNA合后期，Gap2胞周期蛋白cyclin）細(xì)胞周期蛋白依賴性激酶（cyclindependentCdk是細(xì)胞周期調(diào)控系統(tǒng)的核心。隨胞周期進(jìn)程周期性出現(xiàn)及消失，哺乳動(dòng)物的包括cyclinA-HCyclin在子結(jié)構(gòu)上均含有一段保守序列，稱為細(xì)胞周期蛋白框，介導(dǎo)yclin與Cdk結(jié)合Cdk按發(fā)的先后順序命名為Cdk1~8激酶活性需要在cyclin和酸化的雙重作用下激活激抑制CKI）負(fù)性調(diào)節(jié)Cdk活性CKI分CIP/KIPINK4大家族在胞周期進(jìn)程中Cdk結(jié)合特定的，相應(yīng)的蛋白質(zhì)磷化，促進(jìn)期向，G期向M期轉(zhuǎn)換。細(xì)胞周期檢測(cè)（checkpoint能監(jiān)控細(xì)胞周期的活動(dòng)證細(xì)胞染色體數(shù)目的完整性及細(xì)胞周期正常運(yùn)行括未復(fù)制DNA檢測(cè)點(diǎn)錘體組裝檢測(cè)點(diǎn)色分離檢測(cè)點(diǎn)和DNA損檢測(cè)點(diǎn)。未復(fù)制DNA檢點(diǎn)監(jiān)控DNA復(fù)，決定細(xì)胞是否進(jìn)入M期，證細(xì)胞分裂必須發(fā)生于DNA復(fù)制之后紡體組裝檢測(cè)點(diǎn)監(jiān)紡錘體組裝定細(xì)胞是否進(jìn)入后期防止紡錘體裝配錯(cuò)誤的中期細(xì)胞進(jìn)入后期色體分離檢測(cè)點(diǎn)監(jiān)控后期末子代染色體在細(xì)胞中的位置定胞是否進(jìn)入末期及發(fā)生胞質(zhì)分裂染體分離正常的后期細(xì)胞可以通過染色體分離檢測(cè)點(diǎn)進(jìn)入末期DNA損檢測(cè)點(diǎn)監(jiān)控DNA傷的修復(fù)，決定細(xì)胞周期是否繼續(xù)進(jìn)行，負(fù)責(zé)監(jiān)測(cè)細(xì)胞DNA損傷的修復(fù)DNA損后，細(xì)胞周期檢查點(diǎn)激酶checkpoint）以阻滯細(xì)胞周期復(fù)受損的DNA而持基因組的穩(wěn)定性括（checkpointkinase1）和Chk2（checkpointkinase2究表明，生長因子如表皮生長因子epidermalgrowthfactor,EGF小衍生生長因子（plateletderivedgrowthPDGF化長因transforminggrowthfactor,TGF剪因子SR蛋特異proteinspecifickinase,SRPK1microRNA均參與了對(duì)細(xì)胞周期的調(diào)控。細(xì)胞周期與組織再生、腫瘤發(fā)生關(guān)系密切腫細(xì)胞可分為三類細(xì)胞周期行為不同的細(xì)胞增殖型細(xì)胞暫增殖型細(xì)胞和不增殖型細(xì)胞根據(jù)瘤細(xì)胞所處的有絲分裂時(shí)相確定有效的治療方法為瘤治療提供理論依據(jù)

。DNA損傷測(cè)點(diǎn)激酶Chk1在腫發(fā)生發(fā)展中扮演的角色尚有爭議。最初是癌1

基因，后續(xù)研究發(fā)現(xiàn)Chk1是基因，在三陰乳腺癌、肝細(xì)胞癌和宮頸癌中Chk1高表達(dá)

。有研究表明降低Chk1的表達(dá)水平會(huì)促進(jìn)成瘤，另一方面從促進(jìn)DNA損修復(fù)的角度Chk1對(duì)腫瘤生長和存活是必需的兩Chk1抑制劑在臨床前和臨床研究中證實(shí)有應(yīng)用前景，MK-8776和LY2606368。MK-8776致DNA雙斷裂，細(xì)胞發(fā)生凋亡性細(xì)胞死亡9。MK-8776與吉西他濱羥基脲和阿糖胞苷協(xié)同作用體外可以誘導(dǎo)急性髓細(xì)胞白血病腺癌細(xì)胞凋亡

。于此，MK-8776聯(lián)吉西他濱用于晚期實(shí)體瘤的第一個(gè)I期床實(shí)驗(yàn)已經(jīng)啟動(dòng)。另外一個(gè)I期床實(shí)驗(yàn)旨在探討糖胞苷和MK-8776用于發(fā)和難治性白血病的序貫給藥。在腫瘤細(xì)胞中，LY2606368可活化CDC25A，使CDK2活性增加?；罨腃DC25A-CDK2促進(jìn)S期進(jìn)，導(dǎo)致DNA雙斷裂，色體凝集，最終導(dǎo)致細(xì)胞死亡12。肺癌小鼠移植瘤模型中LY2606368可減慢腫瘤生。第一個(gè)臨床實(shí)驗(yàn)證實(shí)了LY2606368的腫瘤活性，治療轉(zhuǎn)移性肛門鱗狀細(xì)胞癌的緩解率達(dá)到15%細(xì)胞周期調(diào)控基因?yàn)榘悬c(diǎn)有望成為腫瘤治療的重要手段

，時(shí)序性變剪接的機(jī)制研究將為腫瘤治療提供新的靶點(diǎn)。參考文獻(xiàn)1.OttoT,SicinskiP.Cellcycleproteinsaspromisingtargetsintherapy.Naturereviews2017;17(2):2.HydbringP,MalumbresM,SicinskiNon-canonicalfunctionsofcellcyclecyclinsandcyclin-dependentkinases.reviewsMolecularcell2016;17(5):280-92.3.BarnumKJ,O'ConnellMJ.Cellcycleregulationbycheckpoints.

Methodsinmolecularbiology(Clifton,2014;1170:29-40.4.TamuraK.Developmentofcell-cyclecheckpointtherapyforsolidtumors.Japanesejournalofclinical2015;45(12):1097-102.5.XuJ,LiY,WangF,etal.SuppressedmiR-424expressionviaupregulationoftargetgeneChk1contributestotheprogressionofcancer.Oncogene2013;32(8):976-87.6.VerlindenL,VandenBemptI,EelenG,etTheE2F-regulatedgeneishighlyexpressedintriple-negativeestrogen/progesteronereceptor/HER-2breastcarcinomas.research2007;67(14):6574-81.7.XieY,WeiRR,HuangGL,ZhangMY,YuanYF,WangHY.Checkpointkinase1is2

negativelyregulatedbymiR-497inhepatocellularcarcinoma.Medicaloncology(Northwood,London,2014;31(3):844.8.ManicG,SignoreM,SistiguA,etal.CHK1-targetedtherapytodepleteDNAreplication-stressed,p53-deficient,hyperdiploidcolorectalcancerstemcells.Gut2017.9.GuziTJ,K,DwyerMP,etal.TargetingthereplicationcheckpointusingSCH900776,apotentandfunctionallyselectiveCHK1inhibitoridentifiedhighcontentscreening.Molecularcancertherapeutics2011;10(4):10.MontanoR,ChungI,GarnerKM,ParryD,EastmanA.PreclinicaldevelopmentofthenovelChk1inhibitorSCH900776incombinationwithDNA-damagingagentsandantimetabolites.therapeutics2012;11(2):427-38.11.SchenkEL,KohBD,FlattenKS,etal.Effectsselectivecheckpointkinase1inhibitiononcytarabineacutemyelogenousleukemiacellsinClinicalcancerresearch:officialjournalofAmericanAssociationforResearch2012;18(19):5364-73.12.KingC,DiazHB,etal.LY2606368CausesReplicationCatastropheandAntitumorEffectsthroughCHK1-DependentMechanisms.Molecularcancer2015;14(9):2004-13.13.VijayaraghavanS,KarakasC,Doostanetal.CDK4/6andautophagyinhibitorssynergisticallyinducesenesce