CC LOI THUC MI Y HA HN CHO VIC CHA TR CC T BO UNG TH V DI CN

Cc tnh cht c o ca cc t bo ung th v di cn cho php s t i mi cao v tim nng bin i khc nhau (bao gm mc biu hin cao ca cc yu t khng apoptosis, s vn chuyn thuc, v sa cha DNA v cc enzyme gii c) c th c kt hp vi tnh khng ca chng i vi cc liu php lm sng cha tr ung th hin ti v ti pht bnh. Vic loi b cc t bo ung th v di cn bng LPPT gp phn vo s tng trng ca chng, khng iu tr, do , l mi quan tm iu tr lu di.Nhng liu php mi ny s gp phn ci thin hiu qu vic iu tr ung th, di cn,ti pht v gy t vong. GII THIU Tin b ln i vi vic xc nh cc mc tiu iu tr mi trong cc t bo ung th trong nhng nm gn y dn n vic khm ph v pht trin ca cc loi thuc chng ung th mi. Nhng loi thuc chng ung th ha hn s ci thin hiu qu phng php iu tr lm sng bng cch phu thut ct b, liu php khng ni tit t, x tr v / hoc ha tr liu. c bit, s pht trin ca cc t bo b ung th xm ln sang cc t bo bnh thng hoc di cn thng lin quan vi tnh khng vi cc phng php iu tr thng thng hin nay, ti pht bnh, v ci cht ca bnh nhn ung th trong mt thi gian ngn. Do , phn t ch ca cc sn phm gy ung th khc nhau trong cc t bo ung th c lin quan n s tin trin ung th s cp v di cn sang cc m v cc c quan khc c th to thnh nhiu phng php tip cn y ha hn cho iu tr hn so vi n tr liu cho vic pht trin cc phng php iu tr kt hp mi chng li bnh ung th tch cc v ti pht. Quan trng hn, cc bng chng thc nghim cho thy s tch ly cc bin i gen v / hoc biu m trong cc m ni cha cc t bo gc trng thnh hoc cc th h con chu ca chng c th dn n bin i thnh c tnh t cc t bo ung th gc, cn c gi l ' t bo khi nguyn' hoc 'cc t bo ung th khi xng'. Da vo cc t bo ung th gc ny ngi ta c th bit r hn v cht sinh ung th, nu lng bch cu hoc cc t bo ung th khi xng khi u cao c th cung cp cc chc nng quan trng cho s pht trin cc t bo ung th s cp bng cch to ra vi s lng ln ca cc t bo khi u bit ha. h tr cho gi thuyt ny, ngi ta chng minh rng vic cm ng bin i gen hoc biu m trong cc t bo gc trng thnh hoc con chu ca chng c th dn n s bin i c tnh, s pht trin bnh bch cu hoc khi u trong c th ng vt. Nhng kt cu di truyn bao gm cc t bin c bit ca gen c ch khi u (p53, p16 INK4A , retinoblastoma hoc phosphatase, v s mt on trn nhim sc th s 10, hoc PTEN), kch hot cc t bin trong cc sn phm gy ung th nh RAS, sp xp li nhim sc th to ra cc protein dung hp gy ung th , hoc cho php cc tn hiu dn truyn khc nhau hot ng nh hedgehog, th th yu t sinh trng biu b (EGFR), HER2, Wnt / -catenin, v Notch. c bit, s tch ly cc on ngn telomere v cc t

bin, duy tr ng lc oxy ha, vim mn tnh, v x ha xy ra trong qu trnh lo ha c th dn n mt s bt n nh di truyn v bin i c tnh ca cc t bo cha trng thnh.

Hnh 1 xut m hnh ca giai oan u ung th , pht trin, di cn v iu tr tnh khng qua trung gian cc t bo ung th v di cn ban u. M hnh ny cho thy s bin i ca t bo gc trng thnh thnh cc t bo gc ung th c tnh, cng nh gip chng ta bit c th no l t bo gc ung th khi xng, m c l chng c tng cng thng qua di truyn trong cc t bo trng thnh ny v lm thay i v tr ca chng , bao gm cc t bo m m c hot ha. Vic phn chia i xng hoc khng i xng ca cc t bo gc ung th (CSCS) thnh transit-amplifying (TA) cng c xem

nh l t bo trung gianc th to ra s lng ln cc t bo ung th khc nhau. .Hn na, s di tr ca cc t bo ung th ban u, c th c gy ra bi con ng kch hot cc tn hiu gy ung th khc nhau trong sut qu trnh chuyn i gia biu m-trung m (EMT). S xm ln ca cc t bo ung th khi xng trong ni m c th dn n vic chng tr nn ph bin phm vi ngoi m v n cc m hay c quan xa hn. Bn cnh , kh nng di tr ca cc t bo di cn khi xng c th b mt thng qua qu trnh chuyn i biu m-trung m (MET) ti cc vng khi u s cp. Hin tng tim n ca cc t bo di cn v s kch hot chng gn lin vi s hnh thnh khi u th cp di cc iu kin c bit ti cc vng xa hn cng c minh ha. Phng php iu tr ung th mi, trong s dng phn t ch ca t bo ung th v di cn khi xng chng li s tin trin ung th v di cn cc m v cc c quan xa, cng c ch ra. Quan trng hn, cc tiu qun th ca cc t bo ung th cha trng thnh vi c tnh ging nh t bo gc c phn lp t cc m c tnh s khai ca bnh nhn ung th v thnh lp dng t bo ung th. Cc loi ung th c cha mt qun th ca cc t bo ung th khi nguyn, trong c ung th bch cu, u lympho, sarcomas, u c tnh, u no, v mt lot cc bnh ung th biu m bao gm c u, da v c, tuyn gip, ung th phi, c t cung, thn, gan, thc qun , tiu ha, i trng, bng quang, tuyn ty, tuyn tin lit, v, v ung th bung trng. Cc t bo ung th khi nguyn cho thy mt s t bo gc ging nh cc maker bao gm telomerase, aldehyde dehydrogenase (ALDH), CD133, CD44, CXC chemokine receptor 4 (CXCR4), KIT, cht vn chuyn ATP-binding cassette (ABC), v cc nhn t phin m nh Oct-3/4, Nanog, v SOX2. Cc t bo bch cu hoc cc t bo gc UT c th gia tng (in vitro v in vivo) dn n lm gia tng tng khi lng ca cc t bo ung th khc bit mang c im hnh thi phc tp v kiu hnh khng ng nht ca cc khi u nguyn thy ca bnh nhn (Hnh 1). Ngoi ra, s di cn ca cc t bo gc ung th trong sut qu trnh EMT vi nhng thay i trong m m cng c th dn n s xm ln ca chng t khi u ban u, ph bin thng qua tun hon ngoi vi ( Hnh 1 ). Kt qu l, cc khi u v cc t bo ung th di cn c pht hin ti cc vng trong cc khi u ban u, cng nh c phn lp t mu ngoi vi. Bn cnh , cc t bo ung th cha trng thnh vi cc c tnh ging t bo gc, cn c gi l cc t bo di cn khi xng, c pht hin v phn lp t cc mu khi u th cp t cc bnh nhn ung th v cc dng t bo ung th di cn. Mc d cc t bo ung th v di cn ni chung i din cho cc qun th t bo khi u nhng quan trng l cn lu rng: s lng, kiu hnh v cc chc nng ca chng c th khc nhau trong qu trnh tin trin ung th, sau khi iu tr, v sau khi bnh ti pht. Hn na, s lng cc t bo ung th khi nguyn vi cc c tnh ging t bo gc c th ph thuc vo cc phng php c s dng phn lp chng (in vitro v in vivo). c bit, mt t l ln hn ca cc t bo ung th khi nguyn c th c pht hin trong tng khi lng t bo ung th sau khi cm ng bi chng trnh EMT, cng nh sau khi iu tr ung th khi u, c th dn n mt loi b ng thi hng lot vi s lng ln cc t bo ung th c c tnh ging vi t bo gc c kh nng khng vi cc phng php iu

tr ung th thng thng. Ngoi ra, cc t bo di cn ban u c pht hin trong cc t bo ung th di cn c th tri qua qu trnh MET v i hi cc c im kiu hnh v chc nng c bit ti vi mi ca chng ph bin cc v tr di cn nht nh. Do , cc t bo di cn ban u c th cho thy cc kiu hnh v chc nng khc nhau v phn ng khc nhau vi cc phng php iu tr hin nay. Trong qu trnh iu tr, ngi ta cng chng minh rng kh nng khng li ca cc t bo ung th v di cn ban u i vi cc liu php lm sng hin nay c th gip chng c th ti khi u s cp hoc th cp khi bt u iu tr, v theo , gy ra ti pht bnh ung th. Do , cc phn t ch ca nhng t bo ung th v di cn cha trng thnh cng phi c xem xt khc phc tnh khng iu tr. V vn ny, chng ti tm tt cc nghin cu gn y xc nh cc phn t ch mi trong cc t bo ung th v di cn ban u. Cc thng tin c cung cp s gip chng ta trong vic a ra mt chin lc iu tr mi cho vic loi b khi lng t bo khi u, bao gm cc t bo ung th v di cn khi xng, v ci thin cc liu php lm sng hin ti chng li ung th di cn, ti pht, v gy cht. Kiu hnh ni ti v kiu hnh thu c ca cc t bo ung th v di cn ban u lin quan n kh nng chng li cc phng php iu tr ung th hin nay Nhiu th nghim chng minh c rng cc t bo ung th v di cn c th khng vi mt s loi thuc ha tr liu hoc x tr vo lc bt u iu tr v c c mt kiu hnh nng cao kh nng khng thuc (MDR) vi s pht trin ca bnh ung th hoc sau khi iu tr ban u. Mt s thuc tnh ni ti ca cc t bo ung th v di cn ph bin vi nhng bn sao ca chng, cc t bo gc trng thnh c tr trong m c th ng gp cho tnh khng ca chng vi cch phng php iu tr lm sng, v ti pht bnh hin nay. c bit, cc t bo ung th v di cn cha trng thnh, cng nh nh cc t bo gc trng thnh, c th tn ti nhng ni c hot ng trao i cht yu. Do , chng c th phn ha chm v mang tnh khng cao hn cc th h sau ca chng chng li cc tia bc x hoc cc loi thuc gy c cho t bo. Thng qua trng thi hot ng ca cc t bo ung th v di cn c th gii thch cho hin tng ng lu di lin quan vi s c tr ca chng ti cc khi ung th s cp m khng c du hiu lm sng hoc m bnh hc ca di cn r rng. Tuy nhin, nhng thay i trong vi trng ca cc t bo ung th v di cn khi xng dn n vic kch hot li con ng tn hiu mitogenic c th gy ra s gia tng ca chng v ti pht trin khi u v ti pht bnh (Hnh 1). Ngoi ra, mc biu hin cao ca cc cht vn chuyn thuc, sa cha DNA, v cc enzym gii c trong cc t bo ung th v di cn c l l ng tin cy mt phn, cho kh nng chng li bc x ion ha v cc loi thuc ha tr liu nht nh. C th hn, cc cht vn chuyn ABC ng mng plasmic hoc endolysosomal c th bo v cc t bo ung th cha trng thnh khi cc tc ng gy c t bo gy ra bi cc loi thuc ha tr liu v theo cch ny, gp phn vo kiu hnh MDR ca chng ( Hnh 2 ). Trong thc t, cc bm ABC ny c th ch ng loi b cc tc nhn gy c t bo ra khi t bo bng cch s dng nng lng thy phn ATP, v do lm gim tch ly thuc trong t bo

( Hnh 2 ). V vn ny, s biu hin cao ca bm ABC trong t bo ung th gc / t tin l c s ca phng php loi tr thuc nhum Hoechst (Hoechst dye), rt hu ch c lp mt phn nh t bo c xem nh l qun th ph (SP), biu th kh nng cao loi b thuc nhum Hoechst 33.342 t khi t bo ung th. Ngi ta quan st thy mt nhm nh cc t bo SP phn lp t cc khi u ca bnh nhn hoc cc dng t bo ung th khc nhau cho thy c cc c tnh ging nh t bo gc, bm ABC v cc yu t chng apoptosis hin din mc cao (in vivo) v kh nng khng cc loi thuc ha tr liu hoc liu php chiu x cao hn so vi cc t bo khng phi l SP. V d, cc t bo ung th gan HuH7 SP biu hin kh nng khng thuc cao (MDR1/ABCB1) m ha Pglycoprotein, protein khng ung th v (BCRP-1/ABCG2) v CEACAM6 biu th sc khng cao vi doxorubicin. Mt qun th t bo SP c pht hin trong cc t bo u nguyn bo thn kinh (neuroblastoma) t 15 trong s 23 bnh nhn (65%), trong c mc biu hin cao ca cc cht vn chuyn BCRP/ABCG2 v ABCA3. iu quan trng l cn lu rng, ging nh cc phng php lm giu v c lp cc tiu qun th nh ca cc t bo ung th gc khc - bao gm c t bo hot ha hunh quang, vic s dng cc khng th c bit chng li mt hoc mt s maker trn b mt t bo gc, v phn lp cytometric ca cc t bo da trn s hot ng ca enzim ALDH, da trn th nghim ca Aldehfluor phng php loi b thuc nhum Hoechst c th c nhng hn ch nht nh. Tht vy, cn phi lu rng s lng ca cc t bo ung th c pht hin trong qun th t bo SP so vi phn khng phi SP c th b nh hng ng k bi cc iu kin th nghim, bao gm c ngun gc ca cc m c tnh ca bnh nhn (khng c iu tr, iu tr, v cc bnh nhn ti pht), v iu kin nui cy c s dng. Hn na, c nhng bo co rng thuc nhum Hoechst c th gy c cho mt s loi t bo v cc qun th t bo SP c l khng pht hin c trong mt s t bo lnh tnh hoc c tnh.

Hnh 2 Con ng dn truyn tn hiu tim nng lin quan n hnh vi xm ln v khng thuc ca cc t bo ung th v di cn v cc phng php iu tr ung th mi bng cc yu t tn hiu khc bit. Cc hiu ng phn bo c tng cng thng qua s hot ha ca con ng tn hiu ni bo ring bit bng cc nhn t sinh trng khc nhau, (cytokine v chemokine) trong t bo ung th gc / t tin c minh ha. c bit, s iu chnh mc biu hin cao ca cc sn pm gene lin quan n s tng trng bn vng, s sng cn, xm ln, v di cn ca t bo ung th gc / t tin cng c ch ra. Hn na,vic gim tch ly thuc trong ni bo thng qua bm ABC v tng cng qu trnh chuyn ha thuc thng qua ALDH. Tc dng c ch gy ra bi cc tc nhn dc l, chng hn nh mt cht c ch hot ng ca receptor tyrosine kinase (RTK) (gefitinib, erlotinib hoc lapitinib), ng th th smoothened (SMO) ca hedgehog (cyclopamine or IPI-269609), NF-B, PI3K hoc yu t tn hiu mTOR, telomerase, bm ABC v DEAD (diethylaminobenzaldehyde) trong cc t bo ung th c ch ra. Ngoi ra, tc dng c ch gy ra bi mt khng th n dng (mAb) trc tip chng li phi t interleukin-4 (IL-4),th th CD44, RTK, phi t sonic hedgehog (SHH), phi t Wnt, yu t c ngun gc t t bo m m-1 (SDF-1), hoc mt cht i khng ca IL-4R v th th CXCR4 c ch nh. Vit tt: COX-2: cylooxygenase-2, MMPs: matrix metalloproteinase, VEGF: yu t tng trng ni m mch mu, uPA: urokinase plaminogen activator.

Ngoi ra, mc biu hin cao ca O6-methylguanine DNA methyltransferase trong cc t bo ung th v di cn c th bo v chng chng li cc tc dng gy c t bo gy ra bi cc tc nhn methylating v chloroethylating [carmustine, 1,3-bis (2-chloroethyl) -1 - nitrosourea, methyl methanesulfonate v temozolomide] bng cch sa cha nhm alkyl v tr -O6 ca guanine trong DNA. Hn na,cc t bo ung th gc / t tin c tm thy trong bnh bch cu, vng mc, phi, u v c, gan, ty, i trc trng, ung th v, v ung th tuyn tin lit cng cho thy mc biu hin cao ca ALDH. ALDHs l mt nhm cc enzym c vai tr quan trng trong qu trnh trao i cht v gii c t bo bng cch xc tc qu trnh oxy ha (kh) andehit thnh axit cacboxylic. Do , ALDHs c th gp phn vo vic gii c ca mt lot cc hp cht, bng cch chuyn v tr nhm akyl. V vn ny, c nhng bo co chc chn rng isoenzymes ALDH (bao gm c ALDH1 trong t bo cht),c mt trong mt s t bo gc v th h ca chng, c th ng mt vai tr rt quan trng trong sinh tng hp acid retinoic (RA) v quy nh v s phn ca t bo gc trong qu trnh bit ha. Sinh tng hp RA t vitamin A, cn c gi l retinol, bao gm hai bc oxy ha tun t l qu trnh oxy ha ca retinol thnh retinaldehyde, tip theo l chuyn i retinaldehyde thnh RA (xc tc bi NADP + ALDHs, bao gm ALDH1). Mc d ALDHs ng vai tr rt quan trng trong sinh tng hp RA mt s t bo gc nht nh ca ngi, bao gm cc t bo gc to mu v t bo gc thn kinh, mt vi nghin cu tm hiu mi quan h gia mc biu hin ALDHs v sinh tng hp RA trong cc t bo ung th vi kh nng khc thng, bao gm c t bo gc ung th trong sut qu trnh pht trin ca bnh. Cc kt qu t mt nghin cu gn y ch ra rng s c ch hot ng enzyme ALDH bng cch s dng mt tc nhn c ch c hiu l diethylaminobenzaldehyde trong cc dng t bo ung th v thc y hnh thnh khi u hnh cu. Ngc li, vic iu tr cc t bo ung th v vi cht ngoi sinh all-trans RA dn n s bit ha t bo v c ch kh nng hnh thnh khi u hnh cu. Nhng nghin cu ny cho thy rng s kch hot tn hiu RA, c th c gy ra thng qua isoenzymes ALDH trong cc t bo UT khi xng (bao gm c t bo ung th v khi xng), c th lm gim s lng qun th t bo cha trng thnh. Ngc li, s c ch ALDH1 trong qun th t bo tuyn ty MiaPaCa-2 bng cc siRNA lm gim kh nng xm ln ca chng. iu ny cho thy kh nng khc ca ALDHs, bao gm ALDH1 l thc y s di tr ca cc t bo ung th tuyn ty. Quan trng hn, cc khuyt im trong con ng tn hiu RA, chng hn nh methyl ha RA th th 2, v c ch phn hi ca ALDH gy ra nng RA cao trong ni bo c th xy ra trong mt s dng t bo ung th (bao gm c ung th t bo v) v cn tr kh nng bit ha ca RA. Hn na, ch c mt s isoenzymes ALDH c th xc tc cho s chuyn i ca vitamin A thnh RA, do , mc biu hin ca chng cc t bo UT gc c th l mt yu t quyt nh kim sot qu trnh sinh ung th. Trong tng lai, cn c nhiu hn na cc nghin cu v s lin quan gia mc biu hin ca cc isoenzyme ALDH khc nhau, sinh tng hp RA, v chc nng c th ca chng trong t bo ung th khi xng 7

so vi cc t bo bnh thng trong s pht trin ca cc loi bnh ung th khc nhau, cng nh ngha ca chng trong vic khng li cc liu php cha ung th hin ti v ti pht bnh. Cc c im kiu hnh khc c th ng gp cho s tn ti v khng iu tr ca nhng t bo cha trng thnh bao gm kch hot hot ng ca nhng con ng tn hiu a dng v mc biu hin cao ca chng v cc yu t chng apoptosis nh Bcl-2, survivin, NF-B v qu trnh EMT lin quan n phn t, bao gm c snail, slug, v twist. Nhng yu t tn hiu c th cc t bo cha trng thnh c li th sng st trong iu kin stress v tnh trng thiu oxy ph bin trong cc khi u s cp. Vi trin vng nh th, chng ti gii thiu LP cha bnh mi khc phc tnh khng iu tr v dit tr s lng t bo khi u (bao gm cc t bo ung th v di cn khi xng).

Liu php nhm trng ch phn t trong iu tr ung th, nhng t bo di cn khi xng v qu trnh bit ha ca chng
ch phn t ca nhng ch th sinh hc c trng v s loi b cc yu t dn truyn gin tip iu chnh cc s kin bin i din ra bnh UT v nhng tb di cn khi xng trong sut qu trnh din bin ca bnh. V c bit hn, trong qu trnh EMT v s di cn nhng v tr xa nhau a n mt chin lc cha tr mi y ha hn nhm ci tin cc liu php cha UT hin nay. Tht th v, vi d liu gn y ch ra rng tb gc nh nhng maker (gm c protein CD133 v CD44 ) c th hnh thnh c v s loi tb gc UT (biu hin c tnh) v do , c kh nng cha bnh UT bng cc PT. Chng hn, 1 KTD (mAb) anti- CD133 (khng CD133 ) khng li epitope 1 (AC133/W6B3C1) hoc epitope 2 (AC141) cm ng n tc dng gy c t nhng tb khi u FEMX-I (in vitro) v lm gim kh nng di cn ca chng (trong c th chut). (Epitope: nhn t quyt nh khng nguyn) Trong cng mt cch, vic dng cc phn t nh oligosaccharide hyaluronan c th cnh tranh hiu qu vi phi t hyaluronan t nhin khi gn kt vi th th CD44, cng lm c ch s hnh thnh nhng u thn kinh m ct sng sau khi cy ghp mt phn tb SP t dng tb u thn kinh m C6 ( chut). Hn na, vic x l nhng tb CD90+ vi tb gc v mt phn tb CD90 t dng tb gan MHCC-97L vi mt mAb anti- CD44 cm ng cho qu trnh apoptosis (s cht tb theo lp trnh) (in vitro), tri li, ch c phn tb CD90+t dng tb PLC l nhy cm vi cch x l ny. Quan trng hn, mAb anti-CD44 cng ngn chn s hnh thnh khi u cc b v ton c th bi phn nh tb CD90+ t dng tb MHCC-97L di da hoc cy vo trong gan ca chut. Mc d vic cha UT bng LPPT c tnh kh thi ln thng qua cc tb gc (biu hin cho nhng tb UT khi xng), nhng kh nng gy c ca nhng tc nhn ny trn cc m bnh thng- ni c tr ca nhng tb gc trng thnh/con cng cn c xem xt trc khi a vo cc th nghim lm sng. V vn ny, vic thay i mc tiu ca cc tc nhn dc l c th to ra cc LP cha bnh thay th ngn nga vic gy c tb trn ton h thng. Ngoi ra, trong s cc phn t ch thng c thay i trong cc tb UT v di cn khi xng, c cc yu t tng trng, yu t dn truyn tn hiu (cytokine v chemokine)

ng vai tr quan trng trong vic iu ha cc qt t ti to, bit ha v s di tr ca cc tb gc trng thnh/nh cc m bnh thng.

Cc yu t tng trng, con ng dn truyn tn hiu (cytokine and chemokine) trong LPPT
Mt vi nghin cu ch ra rng vic chuyn bin bnh UT sang c tnh v nhng tb di cn c lin quan n hot ng ca enzyme telomerase, cc yu t tng trng, cytokine v chemokine thng qua cc th th ca chng trong qt din bin ca bnh. Cc yu t ny bao gm: hedgehog, EGFR, HER2, Wnt/-catenin, Notch, yu t tng trng- (TGF-)/TGFR, interleukin (IL)-4/IL-4R, IL-6/IL-6R, IL-8/IL-8 receptor CXCR1, BMI-1, yu t tb gc/KIT, phc hp cht nn ngoi bo/integrin, v yu t c ngun gc t m m tb -1 (SDF-1)/CXCR4. c bit, cc telomerase ch ngn chn c cc con ng hnh thnh khi u bng cch s dng mAb, cc oligonucleotide i m, siRNA, hoc cc tc nhn c ch c hiu, dn n s c ch tng trng, cht tb theo lp trnh v lm gim s l ly lan cc tb UT (in vitro v vivo) V d, vic s dng chc c ch c hiu ca smoothened (SMO) co-recepter, cyclopamine hoc IPI-269609, cng nh cc yu t phin m siRNA GLI-1 ca hedgehog cascade, c xem l c kh nng lm gim mt lng ln tb UT khi xng v mm mng ca chng, ng thi c ch s tng trng ca khi u (in vitro v vivo). Hn na, vic x l cyclopamine ci thin c tc dng gy c t v s di cn nh cc loi thuc ha tr trn cc tb UT u thn kinh m, tin lit tuyn v tuyn ty. Tng t nh th, cht c ch c hiu ca EGFR tyrosine kinase l gefitinib v erlotinib gy ra tc dng chng tng sinh v gy c t bo trn cc t bo khi u khi xng EGFR + / CD133 + t 5 bnh nhn vi gliomablastomas (GBM tics). Trong c 2 TH vi Akt cao l khng nhy cm vi c 2 loi thuc, hoc ch nhy cm khi nng ca erlotinib cao. Nh vy, vic s dng kt hp cht c ch ca EGFR v Akt c th c hiu qu hn khi ch dng mt loi bnh nhn GBM. Trong mt th nghim khc, 40 ph n b UT v c iu tr kt hp gia erbB2 cng vi oral dual EGFR cng vi s dng ring cht c ch erbB2 tyrosine kinase laptinib trong 6 tun, cng vi LP ha tr chun v mAb trastuzumab anti-erbB2 cng lm thoi ha khi u 63% bnh nhn. Nhng d liu ny ch ra rng vic iu tr chc hn c hiu qu lm gim lng ln tb UT v khi xng CD44+/CD24low . Phn t ch ca IL-4 cha cytokine c th bo v cc tb gc UT biu b rut kt khi ci cht lp trnh bng cch s dng cht i khng (antagonist) IL-4R hoc khng th trung ha (neutralizing antibody) anti-IL-4 cng nhy cm vi cc tb khi u khi xng v tc dng chng khi u nh cc loi thuc ha tr chun. Vic s dng cc tc nhn dc l c th can thip vo s ly lan, duy tr vic ht khi u v s di tr ca cc tb gc UT n b mt mng trong v pha trong cht nn. Ngay c ty xng (bone marrow) cng c kh nng iu tr UT. C th hn, vic kha cc h thng gradient chemoattractant nh SDF-1/CXCR4 c th dn n s trit b cc khi u, cc tb UT khi xng di tr v di cn, do , ngn nga c vic lan truyn s di cn, ht khi u v ti pht bnh.

Cng vi , vic x l cc tb UT tin lit tuyn CD133+/CXCR4+ t khi u ban u cng vi mAb anti-CXCR4 cng trit b qt di tr nh protein ngoi sinh SDF-1 (exogenous protein) (in vitro). Tng t, vic x l dng tb UT tuyn ty di cn ngi L3.6 pl cha qun th tb UT CD133 + / CXCR4 +cng vi mAb cng lm gim kh nng di cn ca chng (in vivo). Tm li, LPPT c thc hin nhm chng li s xm ln ca cc t bo ung th khi xng cng nh m ng cc gen trong qu trnh EMT v iu ny lin quan n s sng cn ca cc tb UT v khng iu tr.

Qu trnh EMT trong liu php nhm trng ch

Trong sut giai on u ca bnh ung th, t nhng tb ung th khi xng v mm mng ca chng, ngy cng c nhiu kiu hnh c tnh c biu hin. V c bit hn na, qu trnh EMT c th gip chng trong vic di c v lan truyn sang nhng v tr xa hn. Ni chung, chng trnh EMT thng ph v s tng tc gia tb v tb vi nhau, t chc li cc phc hp ngoi bo, v cc tb ung th c li th sng st cao hn. C th hn, qu trnh EMT c th dn n c ch cc phn t bm dnh nh Ecadherin, cng vi l tng cng biu hin cc gen trung m nh vimentin, -catenin, snail, slug, v twist. iu ny ng vai tr quan trng trong vic chng li cc liu php tr ung th v ti pht bnh. Mt vi nghin cu ch ra rng liu php cha bnh nhm trng ch v nhng yu t tn hiu khc gp phn vo s sng cn ca cc tb khi xng UT chng li cc tia bc x v kiu hnh MDR, ng thi hn ch s tng trng ca khi u v s di cn. Trong liu php nhm ch, cc phn t ch thng thay i trong qu trnh bnh din ra, l cc tc nhn thc hin tn hiu t bo ca chng trnh EMT (Cripto-1, tenacin C, snail, slug, v twist), PI3K/Akt/mTOR, NF-kB, bm ABC, ALDHs, Bcl-2 v surviving, cng nh cc yu t tn hiu bi b apoptotic nh ceramide v caspase. Chng hn nh, trong mt chin lc sng lc cao nhm xc nh cc tc nhn gy c t bo, ngi ta thy rng EMT lin kt cht ch vi cc phn t v pht hin ra mt hp cht salinomycin, y nh l mt c tnh chn lc cho tb ung th v khi xng. iu ny cho thy rng, salinomycin c th c ch c s ht cc hch di cn v s tng trng ca khi u v (in vivo); lm gim mt lng ln tb UT v CD44+/CD24low v tng s lng cc tb biu m UT v. Ngc li, mt loi thuc ha tr liu thng c dng trong iu tr UT v l paclitaxel ch c tc dng gy c t trn cc tb biu m UT v, cn cc tb CD44+/CD24low th li tng ln sau qt iu tr. Nhng d liu ny nhn mnh tm quan trng ca vic s dng cc loi thuc hoc s kt hp ca cc tc nhn gy c t bo nhm vo cc tb ung th gc c kh nng sinh khi u cao, pht trin phc tr liu hiu qu iu tr v chn on bnh nhn ung th cng nh ti pht bnh.

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Hn na, dofequidar fumarate mt phc hp quinoline c th c ch knh vn chuyn ABC, lm gim tc dng ca cc loi thuc ha tr liu v lm tng tnh nhy cm ca cc tb SP vi cc tb gc c tch ra t nhiu dng tb UT khc nhau. Do , dofequidar fumarate c th l mt tc nhn cha bnh tim nng cho vic o ngc kiu hnh MDR ca cc tb UT cha trng thnh. Ngoi ra, hot ng lin tc ca cc yu t dn truyn tn hiu PI3K/Akt/mTOR gy ra bi cc yu t tng trng v s bt hot gen ca khi u PTEN thng qu vic xa b hoc gy t bin gen l s kin thng xuyn bin i trong nhiu loi UT ngi. V vy, vic s dng cht c ch c hiu ca Akt (perifosine) v mTOR (rapamycin hoc HSP90)- nhng tc nhn dn truyn tn hiu ngc- cung cp cc chc nng rt quan trng cho s pht trin bn vng ca t bo, s sng cn, v di c, y cng l mi quan tm ln trong vic gim s pht trin khi u v s lan rng ca cc t bo UT di cn khi xng. Trong thc t, vic c ch hot ng enzyme Akt kinase bng perifosine lm gim mt lng ln ALDH1-biu hin cc tb UT v khi xng v s pht trin ca khi u s cp v th cp. Hn na, s c ch con ng PI3K/Akt cm ng cho qt xm ln ca cc khi u no bng cch cy trc tip tb GBM ca mt bnh nhn sang c th chut suy gim min dch. Tuy nhin, theo mt bo co khc, hp cht thin nhin t cy bng ci xanh (broccoli) l sulforaphane gy ra hiu ng apoptotic trn cc tb UT tuyn ty khi xng thng qua s c ch ca NF-B gy ra nh con ng chng apoptotic, kt qu l cc khi u dn hoi t. Thc t l, knh vn chuyn thuc ABC c th ng vai tr chnh trong kiu hnh MDR ca cc tb gc UT, ngi ta nghin cu mt vi tc nhn dc l c ch hot ng ca bm ny. Ngi ta theo di vic iu tr tb SP t dng tb UT biu b H357 ( ming) vi cht c ch knh vn chuyn ABC l verapamil. Mitoxantrone Mc d c nhng kt qu quan trng nhng vn cn c thm nhiu nghin cu hn na chng minh cho hiu qu ca cc loi thuc v nh c th tr tn gc cc tb UT

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Targeted delivery strategies (cc cch phn phi thuc)

Cc tc nhn tr liu c a vo trong tb UT v di cn khi xng bng cch tip hp thuc n cc khi u-khng th c hiu, c t ca thuc s c gi trong liposome hoc nhng cht mang khc nh ht nano, cc tb gc c chuyn genCc phng php ny c th tng cng tc dng ca thuc, nng cao tnh chn lc, v tip tc phn phi thuc vo trong cc khi u khc, do lm gim c tnh h thng. Hn na, cc phng php iu tr da trn adenovirus oncolytic cng c xem l c hiu qu loi b ung th v t bo di cn. Th v hn, mt vi nghin cu gn y ch ra rng cc phn t RNA mch n nh v khng m ha, c chiu di khong 20-23 Nu (microRNA hay miRNAs) c vai tr kim sot nghim ngt trong vic biu hin gen, v chng c th gp phn gii thch nguyn nhn gy UT. miRNA c th tc ng n vng 3khng m ha ca cc phn t RNA ch, v nh vy m ngn cn qu trnh dch m ca chng hay ng hn l lm suy thoi qu trnh phin m cc phn t ch. Do , miRNA c th kim sot s biu hin ca mt lot cc protein c th l mc tiu tim nng tr liu iu chnh cc sn phm gen a dng m chng gp phn vo hnh vi c tnh ca cc t bo ung th khi xng. S di chuyn ca miRNA-124 hoc miRNA-137 gy ra s khc bit ca cc t bo gc ca chut trng thnh c ngun gc t oligodendroglioma v t bo gc ca con ngi c ngun gc t GBM v km hm s tng trng ca cc t bo GBM. Quan trng hn, vic x l cc tb UT v CD44 + / CD24-/low/Lin- phn tch t mt bnh nhn UT v bng LP ha tr cng vi let-7-lentivirus xa b s ly lan ca chng cng nh kh nng hnh thnh khi u (mammosphere) (in vitro v vivo). Vic tng cng biu hin let-7 km theo l biu hin ca H-RAS gim i v bin i ca nhm AT-hook 2, cc phn t ch c th lm gim kh nng ti pht pht bnh v tng cng s bit ha ca cc tb u v. Bng cch ny, vic cm ng bit ha cc tb UT bng cc tc nhn nh RA hoc cc cht tng hp tng t, interferons (IFNs) hoc chc c ch enzyme histone deacetylase cng c th l mt cch iu tr mi y ha hn. V d nh, mt nghin cu bo co rng vic iu tr IFN- lm gim ng k cc phn t bo SP nhy cm vi verapamil (verapamil-sensitive SP cell) t cc dng t bo ung th bung trng (ovarian cancer). ng ch hn l cc LP iu tr ung th nn c kt hp vi cc tc nhn gy c t bo nhm vo cc t bo gc UT ngn nga ti pht bnh.

Vi mi trng ca cc phn t ch (Molecular targeting of the microenvironment of cancer- and metastasis-initiating cells
and their differentiated progenies) V vi mi trng (microenvironment) cha cc tb gc UT cng ng vai tr tch cc trong vic chuyn sang giai on c tnh t nhng khi u u tin v s di cn sang nhiu 12

v tr xa nhau nn phn t ch ca cc tb m m ch cng c kh nng hn ch s pht trin ca khi u v qt to mch (angiogenic process). Khi quan st qt iu tr khi u thn kinh m U87 chut vi mAb anti-VEGF, bevacizumab, lm gim r rt mt vi mch (microvasculature) v s tng trng khi u. Tc dng chng cht sinh UT (anti-carcinogenic) ny km theo gim mt lng mch lien kt vi cc tb khi u CD133+/nestin+ . Vic kt hp gia cht c ch chng UT, VEGFR2 antibody DC101 v tc nhn gy c tb (cyclophosphamide) l c kt qu hn so vi x l c lp trong vic lm gim s lng cc tb sinh khi u thn kinh m m C6. Tuy nhin, mt vi nghin cu ch ra rng s hi phc v hp nht cc tb cha trng thnh c ngun gc t BM v cc tb gc trung m, tb gc ni m c th lm tng cng pht trin neoplastic v qt neovascularization. ng h cho quan im ny, mt nghin cu tin hnh dng cc tb ni m c ngun gc t BM Ngoi nhng nh hng sinh UT gy ra bi con ng hedgehog cc tb UT th cc tn hiu hedgehog c th gp phn vo vic hnh thnh nn nhiu bnh UT biu b con ngi bao gm: UT tuyn ty, rut kt, tuyn tin lit, v v bung trng. c bit hn, vic kha cc tn hiu hedgehog bng cht c ch SMO IPI-926 gy tc dng chng to mch v ci thin tc dng chng khi u ca gemcitabine bng cch ph v desmoplastic stroma trn tb UT tuyn ty (in vivo). Hn na, theo mt nghin cu gn y ch ra rng vic c ch tn hiu hedgehog bng cyclopamine trong UT ty cng gy c ch qt sinh khi u.

Concluding remarks (Kt lun)

Nhng nghin cu gn y v cc loi thuc cha bnh UT bng LP ch phn t tc ng ln cc tb UT cha trng thnh ng vai tr rt quan trng trong qt iu tr ca bnh nhn UT. c bit hn, ci tin cc phng php tr bnh UT hin nay th vic kt hp gia cc tc nhn tr liu l rt quan trng nhm chng li s di cn v ti pht bnh sau qt iu tr. Tuy nhin, cn c thm nhiu cuc iu tra, nghin cu hn na tm ra chnh xc cc ch th sinh hc c bit, cc sn phm gen thay th trong cc tb UT v di cn khi xng; v nhng thay i xy ra trong qu trnh bnh khi pht v di cn ti vi mi trng ca chng. iu quan trng hn na l xc nh cc c im v kiu hnh v chc nng ca cc tb c ngun gc t nhiu loi UT khc nhau cng nh xa b cc c ch lin quan n biu hin c tnh ca chng. Ngoi ra, nn tin hnh phn tch, so snh biu hin gen ca cc tb UT khi xng v qt EMT chng li cc m bnh thng, cn lm sng t nhng s kin bin i phn t xy 13

ra trong cc cc t bo c tnh v hu qu bnh l ca chng. Hn na, vic thnh lp cc c ch phn t lin quan vi s di cn cn phi c xc nh trc; hin tng ng v s kch hot cc t bo di cn ti cc a im xa nhau sau mt thi gian di cng l mi quan tm ln. Nhng nghin cu ny s dn n vic tm ra cc loi thuc mi v cc chin lc iu tr khc phc tnh khng iu tr v ngn nga ti pht trin khi u, di cn, v ti pht bnh m khng c tc dng gy c t bo trn cc t bo bnh thng, bao gm c gc trng thnh c tr trong m. LPPT c th kt hp vi nhiu LP khc nhau gy ra tc dng tt hn cho vic iu tr v thm ch cha lnh cho nhng bnh nhn c chn on b ung th di cn, ti pht, v cht trc .

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