Y HOC VI^T NAM THANG 4 - s6 2^014

TONG QUAN

CAC LIEU PHAP irC CHE TAO MACH TRONG KHOI U

Nguyen Van Ba*, Quan Hoang Lam*, Nguyen Van Nam* SU phat then cua ung thu* phu thupc rat

nhieu vao qua trinh tan tao mach. Thong qua tan tao mach, cac te bao u du'dc cung cap nhu cau oxy va dinh duSng, ngoai ra tao mach con la cd sd cua di cSn xa. Khi c6 tinh trang ttiieu oxy hoac thieu du0ng m6, cac te bao u nhan diTdc tin hieu nay (thi/dng trung gian thong qua yeu to gay thieu oxy to chii'c 1 - HIF-1), de pha bo can bang tao mgch, phat dpng qua trinh tao mach trong u. Co nhieu yeu to thuc day qua trinh t in tao mach trong u, hau het chung la cac cytokines. Cac yeu t tao mach nay du^c tiet ra tif te bao u va cac t bao dem quanh u, l

Y HOC VlfT NAM THANG 4 Sd 2/2014

endostatin cung cd tac dung u'c che sy" tang tru'dng va di cu* cua te tDao npi mo,

Thrombospondin-l (TSP-1) la mpt glycopoprotein ngoai bao kich thu'dc Idn do nhieu loai te bao tiet ra. TSP-1 u'c che tang sinh va di cu" cua te bao npi mo tang thong qua viec u'c che hoat dong cua matrix metalloproteinase-9 {W^?-9), sau do huy dpng VEGF tiY khoang ngoai bao va gay nen qua trinh chet theo chu'dng trinh thong qua thy cam the CD36. Ngoai ra, peptide tong hdp lap dang I cua TSP-1 cung u'c che qua trinh tan tao mach va lam cac te bao npi mo chet theo chu'dng trinh [9].

Ill.THUOClJ'CCHEMMP l^atrix metalioprotelnases (MMPs) la mpt hp

cac enzym proteinases \\QX\ quan den viec tao hinh chat nen ngoai bao, cd dac diem chung nhu' sau: - Phan huy du'dc mpt hay nhieu thanh phan cua chat nen ngoai bao. - ChiJa ion kem. -Tien enzym du'dc hoat hoa do sy" phan giai protein. - Bi u'c che hoat dpng bdi cac chat u'c che MMP trong mo.

Cho den nay da biet du'dc hdn 23 lo?i ^\A? is ngu'di, trong do mpt so loai MMP dong vai tro quan trong trong qua trinh tan tao mach va di can cua u. De tao thanh khoi di can, cac te bao u phai di cu" va xam Ian vao khoang ngoai bao. Dong thdi, cac te bao npi mo du'dc kich thich bdi cac yeu to kich thich tao mach, cQng di chuyen va xam Ian vao khoang gian bao va hinh thanh nen cac nhu mach tir cac mach mau hien c6 {pre-existing vessel). Khi cac te bao ung thu" va te bao npi mo xam Ian khoang ngoai bao, cac MMPs, bao gom ca MMP-2 va MMP-9 du'dc cac te bao u, te bao npi mo va te bao dem tiet ra de tieu huy cac thanh phan khoang ngoai bao. Cac MMPs thu'dng du'dc tiet ra dang khong hoat dpng, chung du'dc cac proteolytic phan tach ki'ch hoat. Vi vay, viec u'c che MMPs hoac MMP hoat dpng se ngan clian te bao u hoac te bao npi mo di cu" va xam Ian, ket qua la u'c che qua trinh tao mach trong u [6].

Mariastat va Batimastat la cac chat ire che tong hdp MMP, chung u'c che hoat dpng cua MMPs tren pham vi rpng khi gan vdi vj tri kem la trung tam hoat dpng ciia MMP, sau do ifc che phat trien cua khoi u va qua trinh tao mach trong u. The he thuoc ifc che MMP mdi nhat, 6no-4817 cd tac dyng ifc che chpn Ipc hoat dpng ciia MMP.

Ono^817 tac dung tren MMP-2 va MMP-9, nhu'ng khong LTC che MMP-1. Ngoai ra, dieu^tii pho! hdp giu^ Ono-4817 vdi mot thuoc chong ung thu" lam tang hieu qua dieu tri khoi u [11].

IV. CAC THU6C CHAN INTEGRIN Integrins la protein mang xoan kep c6 cau

tao gom 2 chuoi a va p, dong vai tro nhu' cac phan tir bam dinh. Cac integrin bao gom cac chu6i a va p khac nhau va bieu hien cac lien ket dac hieu. Vi du, Integrin av/SS gan dac hieu vdi trinh ty Arg-Gly-ASP (RGD) trong vitronectin; Integrin a501 gan vdi fibronectin. Trong qua trinh tan tao mach, cac integrins lam trung gian phan utig giffa te bao npi mo vdi khoang ngoai bao, kiem soat viec gan ket te bao npi mo. Dac biet, integrin avfSS va av(^5 lam tang kich thich tao mach tren cac te bao npi mo, dong vai tro quan trpng trong qua trinh tan tao mach tai khoi u. Ngoai ra, integrin avJSSzbn la mpt chat trung gian MMP. Vi vay, integrin avp3 dieu hoa qua trinh tang sinh, di cu' va xam Ian ciia te bao npi mo. Vitaxin (LM609) la mot khang the khang integrin avfi3, chiing ire che bFGF gay nen qua trinh tan tao mach va lam cho te bao npi mo chet theo chu'dng trinh.

V. CAC THU6C U'C CHE PHAN TCT OICH {MOLECULAR TARGETING)

Hien nay, ngu'di ta dang ap dyng mpt so loai thuoc mdi u'c che tao mach trong dieu tr| ung thu' vdi cd che phan tir dich. ZD1839 {Iressa) la mot thuoc dieu tri ung thu" mdi, chung dap irng khong canh tranh vdi cac thu cam the yeu to phat trien bieu bi {epidermal growth factor-Bo?), ifc che phosphorylation thu cam the nay va ch^n cac tin hieu di kem. Khac vdi cac te bao binti thu'dng, cac te bao u tang tru'dng phy thupc mpt phan vao dap uTig EGF. Iressa du'dc xem nhu' mpt thuoc dieu trj ung thu' dac hieu. Hdn nC?a, ngu'di ta da xac dinh rang Iressa ire che tan tao mach bang each ire che san pham ciia mpt yeu to Icich thich tao mach de ngan chan tin lii^u EGF, (tin hieu nay tao ra cac yeu to kich thich tao mach VEGF va bFGF) [7].

VI. TAC DMNG KHANG ll^Q MACH CLIA LASER VA Ll|U PHAP QUANG D$NG (PDT)

Hieu qua dieu trj khoi u va cac mo b^nh ly khac ciia PDT la do sy phoi hdp giO^ chat nhay quang, nhu" porphyrin, chlorin, ho3c

Y HOC Vl&r NAM THANG 4 - SO 2C014

phOialoc^nine, vachum sang laser chieu vao u. Chiim sang laserco tac dung Idch thich chat nhay quang, chuyen chung ve trang thai hoat dpng. Cac chat nhay quang Ian lu'dt phan uTng vdi cac phan tu' oxy, cliuyen chung tu" trang thai binh thu'dng len trang thai oxy singlet, cd kha nang tieu diet khoi u. Cac hda tri lieu ung thu" thu'dng kem theo cac tac dung phu nang ne nhu' suy ti iy. Trong khi do PDT la lieu phap dieu trj khong gay tac dung phu nay, bdi cac chat nhay quang chi gay doc te bao khi tiep xuc vdi nguon sang laser d mpt bu'de song nhat djnh. Cac chat nhay quang ti'ch luy chpn Ipc trong to chirc ran phy thupc rat nhieu vao phirc hdp vdi cac dai thyc bao ky nUdc va LDL trong mau. Thyc te cac LDL du'dc ket hdp chpn Ipc trong te bao u thong qua cac thy cam the LDL tang bieu hien [4] .

Dy^ tren y tu'dng nay, nhieu nghien CU\J trUde day da chiTng to rang PDT dieu trj vdi myc tieu hp mach tan tao cd hieu qua ifc che phat trien u manh hdn nhieu so vdi PDT nham muc tiu rieng khoi u. Ngoai ra, cac phan tir mang dien tich du'dng (catlonic)\hxr\ tang tu'dng tac cua c ic chat nhay quang gan trong cac liposome vdi ccic t bao npi mo cua h^ mach tan tao. Cac phan tir mang dien tich du'dng (cationic) du'dc gSn chSt vdi cac phan t y mang dien tich am (anionic) trong huyet tu'dng do tu'dng tac tlnh dl$n. Theo cd che nay, ngu'di ta phat trien cac BPD-MA (thuoc nhay quang the he hai nhom Benzoporphyrin, ten thu'dng mai la Visudyne) gSn vdi polycatlon liposomes (BPD-MA PCLs). PCL la mpt chat keo polycation gSn liposome cd tich di?n duOng tren be mat. Trong thyc te, BPD-MA PCLs lam tSng hieu lye gay dpc te^bao ciia PDT ca tren In vitro va u'c che phat trien khoi u thong qua vipc pha huy h$ mach tai khoi u tren mo hinh chupt mang u. Ngay nay cang cd nhieu bSng chyng cho ttiay hieu lut iic che khoi u ciia PDT thong qua BPD-MA PCLs phu thupc vao tac dyng t6n thu'dng thanh mach bSng each gay chet theo chudng trinh cac te bao npi mo [10]. Cac ket qua nghien cu*u tren day cho thay PDT gay t^c dyng pha hiiy chpn Ipc cac mach mau tan t^o tai khdi u, do do nang cao hieu lyc dieu tri khoi u ma khong gay cac tac dyng phy dang ke nao.

T A I l l ? U THAM K H A O 1. Balnbridge J.W., Jia H., Dagherzadeh A.,

Selwood D., All R.R., Zachary X. (2003), "A peptide encoded by exon 6 of VEGF (EG3306) inhibits VEGF-induced angiogenesis in vitro and

Ischaemic retinal neovasculansation in vivo". Biochem Biophys Res Q}mmun, 302, pp. 793-799.

2. Bergers G. and Benjamin LE. (2003), 'Tumorigenesis and the Angiogenic Switch". Article for Nature Reviews Cancer, 3, pp. 401-410.

i . Claesson-Welsh L , Welsh M., I to N., Anand-Apte B., Soker S., Zetter B.R., O'Reilly M., Folkman J. (1998), "Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrtn-binding motif RGD". Proc. Natl. Acad. Sa. USA, 95, pp. 5579-5583.

4. Dougherty T. J., Gomer C. J., Henderson B. W., Jori G., Kessel D., Korbelik M., Moan J., Peng Q. (1998), "Photodynamic therapy". Can