DlfeU TR| N H A M TRONG DfCH VA LfNG DyNG TRONG B^NH DA
(MOLECULAR TARGETED THERAPY AND SKIN DISEASES)
TS.BS. VSn The Trung*
1. Gidi thieu
Nhdng nam gan day, vdi sU phat trien nhU vu bio eiia elc nganh di truyen, te bao hpc va y sinh hpe phan td, su hieu biet v l cd che benh hoe duac chuyen bien mdt cIch nhly vpt. Vile phat hien ngay cang nhieu elc phin td liln quan den cd che sinh benh dan den su ra ddi nhilu loai thudc mdi va lam thay doi quan diem dieu trj. Dudng truyen thdng tin ciia te bao (ceil signaling pathways) II mang lUdi dan truyen phdc tap dilu khien cle hoat ddng ben trong vdi sU tuong tic td ben ngoai te bio. SU dip dng diing vdi cic tfn hieu td mdi trudng xung quanh chung la nen ting ciia su phit trien, tU dieu chinh, hoat ddng mien djch va cin bing npi mdi. Mdt khiem khuyet nio dd trong he thdng nay ed the gay ra cac benh ly nhu ung thU, rdi loan mien djeh, tieu dudng... (1)
Ngay nay, ed nhilu loai thudc ed khi nang nhim chfnh xlc elc phan td bat thudng trong he thdng mang truyen tin niy. Nhieu nghien cdu thUc nghiem va lam sing cho thay cac thudc niy cd hilu q u i cao, giup keo dai tudi thp va cli thien chat lUpng sdng cOa benh nhan.
Dieu trj nham triing dfch (Molecular targeted
* Bp mon Da Liiu-BHYD TPHCM.
6 2 I DA Lieu HOC S6 11 (Thing 07/2013)
therapy) II khli niem kha mdi va nhanh chong trd nen phd bien trong y hoc. Vdi kien thdc va k? thuat y hoc hien nay, viec dilu tri ngay eang theo hudng dUa tren tdng trudng hpp cu the (individual-based therapy) chd khdng Ip dyng phIc do cho hing loat ca nhu trade diy,
Trong khudn khd bii nay, chung tdi chi sd lupe qua cac kT thult sinh hpc liln quan sukham phi ele md hinh blnh sinh va mdt sd thuoc
"ngam elc dfch"trong md hlnh dd.
2. KT thuat DNA micro array
KT thult DNA micro array II mdt cdng cu hien dai giup tim ra "ly lich cua benh ly'. Ben canh sucai tien cle kT thult phan tfch sinh hoc kinh dien (PCR, Immunoblotting, Elisa, hoa mo mien djch...), sU ra ddi cua kT thult DNA micro array (gene chip) da lam thay ddi bd mat nghien cdu di truyln. DNA micro array phin tich va so sanh toin dien nhanh chdng v l mdc dp bieu hien gene gida t l bao benh va te bio lanh. Tif dd giiip phit hien mdi nhdng gene bat thudng va tim ra nhdng phin td mdi cd lien quan den benh hpc (hlnh 1). KT thult niy cung giup tim ra nhdng bien ddi gene cda vi sinh khang thuoc Td do ngudi ta t i l p tuc nghien cdu v l tim ra thudc mdL
Bp cDNA cCia nhdm chdng va nhdm tham
DI&»Dan
Principle of cDNA microarray assay for gene expression
(rftor ObMD ft UuM 2002)
Red - "up-regulation' Green = "dcwn-regulatlon"
Black = consUtutfve expression
Hinh 7. Md hinh phdn tich gene k h I o dupe so s i n h . M i y p h a n tich nhan dien mdc dp bieu hien gene qua c i c mau sac.
Chuong trinh may tfnh se phan tfch v l so s i n h sukhac biet gida hai n h d m . T d d d ngudi nghien cdu se p h i n tich va k h u t n i m d t sd gene ed lien quan benh ly.
Vdi kT t h u l t micro array, Xianghong Zhou va cpng suda m d t l co che hoat hda t l bao lympho T va te b i o tua (DC) t r o n g benh vay nen mdt cleh kha toan dien, t r o n g d d ed it nhat 1338 genes v l rat nhieu cac cytokines cd lien quan viec hinh thanh t d n t h u o n g vay n i n (2).
Dieu tri nham t r d n g dich trong chuyen khoa ung t h u
Mac diJ t r o n g khudn k h d c h u y i n de da lieu nhung su de e l p van de ung t h u la can thiet vi d i y chuyen khoa t i l n p h o n g t r o n g ITnh vUc nghien cdu d i l u tri n h a m t r i i n g dfch. Hon nda, ung t h u da cung la m d t t r o n g nhdng ung t h u phd bien. Theo quan d i e m kinh dien, ung thU dupe chan doan va p h i n d p t h e o T N M va dp biet
bang ky thudt DNA-Mieroarray.
hda te bao. Tuy nhien, rat trUdng hpp cd cung d i e t i n h m d hpe va l i m s i n g nhung dien t i l n , tien lupng va d i p dng dieu tri k h i c nhau. Ngudn gde eua te bao ung t h u I I do bien doi gene, te bao t d n g hop protein mdt c l e h bat t h u d n g ve cau tnic v l / h o l c ve sd lUpng. Cle bat t h u d n g eCia gene lam suy yeu kha nang tU sda chCfa cua t l bao. Do vay te b i o p h i t trien m p t each khdng kiem soat. Chdc n i n g cung nhU sU biet hda eiia c i c te bao nay thay ddi theo khuynh hUdng l c tfnh ( x i m lan, di c i n , mat ehdc nang chet theo chuong trinh,..).
M d t t r o n g n h d n g thuoe dieu trj ung t h u kinh dien I I 5-FU (Fluorouracil). Thudc nay can thiep vao qua t r i n h chuyen hda eiia te bao qua viee dc che nhien m e n nhUTS, OPRT, TP... t d d d l i m suy yeu te bao ung t h u . Tuy nhien, d m d t sd b e n h n h i n , t i c d u n g dieu tri cua thudc bj g i i m do t h u d c bi thoai hda nhanh chdng bdi men d i h y d r o p y r i m i d i n e dehydrogenase (DPD). Hoat tfnh eao cOa DPD g i i j p te bao ung
So 11 (Thang 07/2013) D A L i e U H O C I 6 3
thu sdng sdt v l khing lai 5-FU. De cli thien hieu qui dilu trj, ngudi ta d l sin xuit mdt so loai thudc la hon hop sin pham gida 5-FU va chat dc ehe men (vf du UFT, S-1.,). Trong mdt nghiin edu t i l n lim sang tai Nhit Bin, chiing tdi da thanh cdng vdi cdng trinh nghiin cdu S-1 trin ung thu mIng phdi (malignant pleural mesothelioma). Trong nghien cdu niy, lan d i u tiln cdng bd t l bio ung tha mIng phdi chda lupng DPD cao. Khi dc che DPD bing chat khing men (CDHP) cd trong thinh phin cua S-1,5-FU phit huy tic dung va mang den hieu qui dieu tn (giim khdi lUpng u, giim the tfch tran djch mIng phdi, tang thdi gian sdng cdn so vdi nhdm chdng) (hlnh 2). (3)
20 40 60 Days after inoculation Hinh 2. Dieu tri vdi S-1 Idm gia tdng tuoi thg
trung binh cua dpng vdt thUe nghiim
(Van The Tning va c s Cancer Chemother Pharmacol 2010)
Hinh 3. Muc tieu tiem ndng vd cde thude liin quan trong suket noi qua igi gida tebdo lympho BvdT trong chien lUdc dieu tri binh lupus dd hi thdng
B-lymphocyledepleIion(l)rilu\imab, (2) eprahjzumab. reduction of dsDNA titers, (3) LJP 394/abelimus; blockade of T-cell costimulation (4) CTLA4-lg (abatacei andbelatacept),<5)lDEC131 dndBG9588.
blockade of B-cell slimulation, (6) belimum.
Ngu6n Kidney Jnicmaiional 73. 261-268 (Febmaiy (1)2008)
®,
Trong eo che benh sinh phde tap, ed nhieu phin td sinh hpe, nhieu receptors bj loi. Ngoai ra, te bio benh cd khuynh hudng thfch nghi vdi dilu trj v l cd kha nang kfch hoat du'dng truyen thdng tin benh ly mdi de "tholt khdi" sU dieu tri (khing thudc). Thudc dc che nhieu tyrosin kinase receptor SU6668 va E7080 la nhiJng thudc dang dope nghiin cdu v l thd nghiim lam sing. Chiing tdi cd djp nghiin cdu qua thude niy va thay nhieu hda hen (4,5) 3. D i l u trj nham trung dfch trong benh da
3. / Benh lupus do he thdng (SLE) Mdt t h i p nien gan diy, vdi sU hieu bilt sSu hon v l benh sinh cua benh lupus d d he thong, chien lupe d i l u tri mdi dUpc phat trien. Cach tiep can d i l u tri ngay nay nham den cac phlntCf d i e hieu. Ben canh k h i nang san xuat tU khang t h i , t l bao lympho B la chia khda kfch hoat he thong mien djch, d i e b i l t thdng qua cac cytokines v l cac t l bao trinh dien khing nguyin (APCs). Mdt phan quan trpng khac nda la sUkfcti hoat lympho B tdy thupc te b i o lympho T. Cac thudc mdi ra ddi n h i m vao c l lympho B (B-cel|
targeted therapies) va lymphoT, chang han nM cac khang the don ddng k h i n g CD-20 va k h l ^ y l u t d kfch thich te bao lympho B (BlyS) la nhdng thudc rat dope quan t i m trong phuong phap dieu trj hien dai (hinh 3).
Dcn
>- =.//
' ' CD20 ^' ' CD??B - l y m p h o c y t e
TftCl 8AFF-R
BCUA RAFF
..-. — CO40L_."'
MHC II Ag TCR
B7I,2 (4)
cozaciij' J
T-lymphocyle
64 I D A L i e u H O C S6 11 (Thing 07/2013)
Diln Dan
P h i n t d CD-20 t r i n h dien tren te bao lympho B trong giai doan sdm eCia qua t r i n h p h i t trien lympho B. Rituximab tieu huy nhanh chdng te b i o lympho B CD20 (+). Sau khi dieu trj vdi rituximab, m p t sd b e n h nhan t i i eau true lai lympho B va di vao giai d o a n lui b l n h .
BlyS thudc gia dinh TNF (BAFF), ddng vai trd kfeh hoat va b i l t hda lympho B. Do do, BlyS dudng nhu la muc tieu tuyet vdi eho dieu tri SLE. Ndng dp eao BlyS dddc t i m thay trong m d t sd b l n h n h i n v l chudt bj lupus dd. Belimumab la khang the ddn ddng cd ngudn gdc t d ngUdl gan vao BlyS va dc che hoat tfnh eua nd. Gan day FDA da ehdng nhan Belimumab cho dieu tri SLE (6,7,8).
3.2 Dieu tri nham trung dfch trong benh vdy nen
Mac d u cdn xa nda m d i cd sU h i l u biet ro r i n g v l nguyen n h i n sinh b l n h hpc ciia vay n i n , nhUng m d h i n h benh hpc chuyen b i l n t d da chua t d n t h u o n g t h a n h mang vay nen duoc m d t l vdi sU t h a m gia cua rat nhieu yeu t d ( h i n h 4 ) .
Noi da chUa cd t d n t h u o n g tap t r u n g nhieu n h i l u te bao cd n g u o n gde t i i y xuong. Bach cau di chuyen lien tue gida da v l hach bach huyet cd chdc nang "canh ehdng" c l e t i e nhan gay benh. Cac chat t r u n g gian huy d d n g te bao Langerhans (LC), t l bao tua (DC) tai cho v l
Symptomless Honieosiaiic iratlick
C'vomc lesion
Hinh 4. Md hinh sinh binh hge eda benh vdy nen vdi sU tham gia cOa nhieu yeu to
S o i l (Thang 07/2013) D A L I ^ U H O C I 6 5
Diln Dan
te bio lympho T dupe minh hpa (khung hinh trai). Mgt dieu trj ly tUdng la khdng l i m xlo trpn qui trinh sinh ly niy. Sau mdt kfch thfch, tdn thuong vly n i n elp hlnh thinh, trong dd DC v l lympho T trd nin hoat hda vdi sU hinh thanh elc xi-nap miln djch. Cho d i n nay van chUa bilt duoc t i c nhin nio giy kfch hoat chuoi phin dng niy (khung hinh gida). Kfch thfch cd t h i td b i n ngoai (phan td blnh hpc gin vao Toll-like receptors) hole tfn hilu td bin trong (HIV, thudc lithium, thudc chen thu the be-ta). IVlpt khi te bao trinh diln khing nguyen (APC) va lympho T bj hoat hda, ehiing ly gili elc cytokine, chemokine v l ylu td ting trudng (GF) m l chiing s i kfeh hoat sUtIng sinh
va thay ddi tfnh biet hda cua t l bao tao sdng (keratinocyte) cung nhutang sinh vi mach. Mot vdng xoln benh ly ddgc thanh lap vdi sU hoat hda liln tuc t l bao DC va T trong sang thuong vly nen m i n (khung hinh phii), Mdt loat cac cytokine, chemmokine v l yeu td ting trudng cd the hpp ldc cung vdi cac te bao tai cho, te bao td tiiy xUong duy tri tdn thuong vay nen dupe liet k l trong bing (dudi phii).
Vdi sU hieu biet kiln thdc md hinh giy blnh, ljch sd dieu trj blnh vay nen dang dan thay doi.
Neu nhu cle thudc dieu trj trong qua khd la tinh cd v l khdng rd cd c h l thi ngay nay cd nhieu thudc nhim v i o cle m i t xfch quan trong trong day ehuyin sinh blnh hpc (hinh 5). (9,10,11)
•Arsenic
•Ammoniated mercury
• Cnj(te coai lar
• Anthralin ' Corticosteroids
•UV-B
• Met h aire xate
• fuwianc acid
• PUVA
•CsA
• Vii D analoguBE
• VIlAantdogues
• frThiogiianine
• HydroKyurea
Bioiogita - Weiacew (LFA3TIP)
• Erallzumab(CDiia) ' Etanefcapl (TNF-o)
• Infllxfmab (TNF-n) RA
• Adrtimumab (TNF-Q) RA I FDA approved
rorpsoiiaEis
4 Potential targets
• Toelltraffidcing
• T cell activation
• Cytokine lnhft)lofs
• Counterdfenslves
Past Serendtputy •
Future
— ^ Smart drugs Hinh 5. Ljeh sddieu tri vdy nen. Trong qud khd, dieu tri mang tinh eau may.
Dieu tri hien dgi dUa tren kien thdc benh sinh, nhdm vdo cdc phdn tddqc hieu.
Nghiin edu y hpc phin t d d l giiip phit hien va hoan thien din kien thdc ve benh hpc. Cd vd sd cac vi du 6e minh hpa cho y kien niy, chang han nhu Desmoglein duoc xem la dich ngam trong benh pemphigus de phan biet chan doan cle dang lam sang va dieu tri (12). Sp hieu biet thau dao v l blnh hpc d mdc dp phin td giup ngudi lam lam sang nam dupe khai quit benh
ly, ly gili dupc cac tru'dng hpp blnh ket hop, cijng nhu thay ddi quan diem dieu trj. Qua cac nghien cdu thd nghiem lam sang, thude dac hieu nham triing dich cho thay cd tic dung hieu qua cao. IVlac diJ vay, hien nay cae thuoc nay cdn kha mdi va dat t i l n . Dp an toan, hieu qui, kinh te can dupc kiem djnh hOn nda qua thdi gian. Tuy nhien, dieu tri nham triing dich 6 6 I DA Ll£U HOC S6 11 (Thang 07/2013)
.mm^^^
g i n n h u 11 k h u y n h h u d n g cOa y hpc hien dai.
Nd la d d n g eo t h d i t h u c ngudi lam y hpe, d i e biet la gidi n g h i i n c d u say m e hpc t a p va t i m tdi nhdng g i l i phap m d i m l trudc d i y chua he b i l t . Tai cac nudc t i l n t i l n , c i c b l c sT l i m sang thudng xuyen lam n g h i e n c d u t r o n g p h d n g thf nghiem. Hp vda gidi v l b l n h hpc t r o n g khoa lam s i n g vda gidi ve ki t h u l t xet n g h i i m , do v l y hp t i l n bp rat nhanh va rat d d n g b d . C i c nude mdi ndi n h u Trung Quoc, H i n Qudc t h i cac bac sT l i m sang cung d l bat tay l i m t h i nghiem t d hdn thap kl trudc. Dieu k h i l m k h u y l t tai ele nudc dang p h i t trien n h u nudc ta la da sd c l e b l c sT l i m sang t i c h rdi khdi p h d n g thf nghiem vi khdng cd kinh phf de trang bi va d I o tao nhan lUe cung n h u chua thay ddi quan d i l m v l y hpc thuc h l n h . Du c h i i n g ta cd vu khf (thudc) hien dai nhUng neu khdng cd p h u o n g t i l n t i m kiem ddi phuong (xet nghiem) thi m d t ian nda chiing ta van t i l p tue m d m a m n h u kieu dieu trj t r o n g q u i k h d va gay n h i l u l i n g phf.
4 . Ket l u a n
Vdi k i l n t h d c gidi han ve cd che benh sinh, bai viet ngan nay chl m o n g nhan manh tam quan t r p n g cCia khuynh hUdng nghien cdu cung n h u quan d i e m dieu tri mdi t r o n g hien tai v l t u o n g lai gan. Tai Viet Nam, k h l i n i l m ' d i e u trj n h i m t n i n g d f c h " d l b i t d i u quen thude trong gidi c h u y i n khoa ung thU. Mdt sd thudc dieu tri n h i m t r i i n g dfch d l b i t dau sd d u n g tren benh n h i n da l i l u n h u ustekinumab, secukinumab, infliximab. Hy v p n g r i n g , t r o n g tUOng lal khdng xa, c i c CO s d y t l dUpc chii t r p n g trang bi nhdng p h u o n g tien xet nghiem de chon Ipc dieu tri d i i n g chl d m h , cac benh n h i n Viet Nam dUpc t i l p can vdt p h u o n g p h i p dieu tri hien dai vdi chi phf chap nhan dupc. Va d i e b i l t 11 nhdng ngudi lam y t l l i m s i n g se d m t h i y bj quyen ru bdi nhdng phan t d sinh hpc rdi m i l t m i i t i m kiem eae eo ehe mdi d d n g g d p s l u hdn vao n i n khoa hpc Viet Nam cung n h u t h i gidi.
TAI L I | U T H A M K H A O
1. Charles Sawyers. Review article Targeted cancer therapy. Nature 2004
2. Xianghong Z h o u , James G. Krueger, M i n g - Chih J. Kao et al. Novel mechanisms o f T-cell and dendritic cell activation revealed by profiling o f psoriasisonthe63,100-elementoligonucleotide array. Physiol Genomics 1 3 : 6 9 - 7 8 , 2 0 0 3 ;
3. Van The Trung et dl. The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodefiaent mice. Cancer Chemo Pharmacol 2010
4. Trung The Van et al. T5U-68 suppresses the progression of malignant pleural mesothelioma cells in SCID mice by inhibiting angiogenesis.
International Conference: Molecular Targets and Cancer Therapeutics~Nov 15-19, 2009;
Boston, MA
5. Ikuta, Yano S, Trung Van The et al. E7080, a multi-tyrosine kinase inhibitor, suppresses the progression of malignant pleural mesothelioma with different proangiogenic cytokine production profiles. Clin Cancer Res. 2009
6. Yun Deng and Betty P Tsao. Genetic susceptibility to systemic lupus erythematosus in the genomic area. Nature Review Rheumatol 2011
7. Mariana Postal Lilian TL Costallat, Simone Appenzeller. Biological Therapy in Systemic Lupus Erythematosus. International Journal of
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Rheumatology.Volume2012, Review Article.
8. Fanny Monneaux, Sylviane Muller.
Molecular therapies for systemic lupus erythemasosus: clinical trials and future propects.
Article Research & Therapy. Vol 11 No 3 9. Michelle A. Lowes et al. Pathogenesis and therapy of psoriasis. Nature Review 2011
10. Brian J.Nickoloff and Frank O.Nestle.
Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opprtunities.
The Journal of Clinical Investigation. Volume 113 (2004).
11. Jame G Krueger. The immunologic basis for the treatment of psoriasis with the new biologic agents. J Am Acad Dermatol (2002). Volume 46, Number 1
12, Masayuki Amagai, and John R. Stanley.
Desmoglein as a Target in Skin Disease and Beyond. Journal if Investigative Dermatology (2012). Volume 132.
6 8 i DA u e u HOC S6 11 (Thang 07/2013)
