Yoshino, T., et al., TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial.. Colorectal cancer in inflammatory bowe
Trang 2 2 2011 - 2013
2
5
6
7
10
11
14
14
14
14
15
17
17
18
19
23
34
1.5 KRAS 37
Trang 3 3 2011 - 2013
GENE KRAS 40
40
42
43
43
43
2.1.2 Hóa ch 43
44
2.2 45
45
46
46
48
2.2.5 -Dual Priming-Oligonucleotide) 49
52
56
56
6 56
Trang 4 4 2011 - 2013
KRAS 57
59
60
61
KRAS 62
64
67
68
69
Trang 5 5 2011 - 2013
Trung, khoa S
t n
l
Tôi sinh-Vi - -
Trang 7 7 2011 - 2013
DAN
APC: adenomatous polyposis coli
AKT: v-akt murine thymoma viral
CDK: cyclin dependent kinases
DPO: Dual priming oligo
DCC: deleted in colorectal carcinoma
DNA: Deoxyribonucleic acid
DNMT: DNA methyltransferase
DTCS: Dye terminating cycle sequencing
ddNTP: dideoxynucleotide triphosphate
EGFR: Epidermal growth factor receptor
EMEA:European Medicines AgenecyESMO: European society for medical oncology
ERBB: erbv- -b1 avian erythroblastic leukemia viral oncogene homolog EDTA: Ethylene diamine tetraacetic acid ERK: extracellular-signal regulated kinase FDA: Food and drug administration FAP: Familial Adenomatous Polyp FRZ: Frizzled
GSK-e-3 GRB: growth factor receptor-bound protein
GEFs: Guanine nucleotide exchange factors
GAPs: GTPase-activating proteins GTP: Guanosine- -triphosphate 5'GDP: Guanosine diphosphate HNPCC: Hereditary non-polyposis colorectal cancer
Trang 8 8 2011 - 2013
HER: human epidermal growth factor
receptor
HAT: Histon acetyltransferase
HDAC: Histon deacetylase
HRM: High Resolution Melting
IBD: Inflammatory bowel disease
IGF1R: insulin-like growth-factor-1
receptors
IRS-1: insulin receptor substrate 1
JUN: jun proto-oncogene
KRAS: Ki V- -ras2 Kirsten rat sarcoma 2
viral oncogene homolog
LRP: lipoprotein receptor-related protein
MEK: mitogene-activated protein kinase
MAPK: mitogene activated protein kinase
MMR: Mismatch repair enzymes
MSH: mutS homolog
MeCP2: methyl CpG binding protein 2
MBD: methyl-CpG binding domain
protein
MLH1: mutL homolog 1
HLH1: hemophagocytic lymphohistiocytosis 1 mt: mutant
NST
OD: Optical density p53: protein p53 p21: protein p21 PI3K: Phosphoinositide 3-kinase PDGFR: platelet-derived growth-factor receptor
PIP2: phosphatidylinositol-4, bisphosphate
5-PIP3: trisphosphate
phosphatidylinositol-3,4,5-PDK: phosphoinositide-dependent kinase PTEN: Phosphatase and tensin
homologue PIK3CA Phosphatidylinositol-4,5-: bisphosphate 3-kinase
PBS: Phosphate buffer saline PCR: Polymerase chain reaction pH: Hydrogene power
Trang 9 9 2011 - 2013
MSI: Microsatellite instability
SOS: son of sevenless
SHC: Src homology 2
SDS: Sodium dodecyl sulfate
TE: Tris-EDTA
TGF- transforming growth factor beta
TGFB:transforming growth factor beta
mTOR: mammalian target of rapamycin
RNA: Ribonucleic acid
RTK: receptor tyrosine kinase
SFRPs: Secreted Frizzled-related proteins TGFBR: transforming growth factor beta receptor
TP53: tumor protein p53 UICC: Union for International Cancer Control
UC: Ulerative colitis
WNT: Wingless-type wt: Wild type
µg Microgram
Microliter
Trang 11 11 2011 - 2013
14
15
17
23
- 25
-34 [10] 27
29
32
37
- dòng kháng EGFR [6] 38
Hình 49
-G38A 58 .
-G38A Error! Bookmark not defined -G35 61
KRAS-G34 62
Trang 12
ESMO Cetuximab Panitumumab
Trang 13
gene
20-3 T
Trang 18 guyên nhân gây
Escherichia coli , Helicobacter paratuberculosis, Trong
Trang 19gene , n gene
APC [1]
Trang 21Epigene
methyl hóa DNA
ethyl hóa DNA methyl (-CH3 (DNMT) [28, 29] gene cytosine trong các
-phosphate- methyl hóa cygene
geneCpG (CpG islands[21, 29, 30]
gene
gene
gene [30, 31]
Trang 22
enzyme H, do
gene
enzyme methyl hóa histon,
Trang 23
gene : APC TGF- TP53 , ,
Gene APC (adenomatous polyposis coli):
mã hóa protein APC tham
[24] )
[1]
y s -catenin ubiq - catenin
Trang 26 - gene SMAD2 SMAD3,
SMAD4 [28]gene SMAD2 và gene
microRNA-34 cromi RN
- cro
[1, 10] Protein p53 microRNA-34
s , 1.6
Trang 28 [21, 42]
gene KRAS, BRAF, PIK3CA [4, , 39, 43- ] 21 45
Oncogen KRAS (Kirsten rat sarcoma viral oncogene homolog): trên NST 1212.1, RAS
Trang 29
- KRAS
- ho
- RAS/ RAF/MEK/ERK phiên (2) RAS /PI3K/Rac
RAL, RalGDS,
Trang 30 30 2011 - 2013
(homodimerisation/EGFR-EGFR) (heterodimerisation/EGFR-HER2, EGFR-HER3, EGFR-HER4)
b b t ho t sau m t th i gian ng n [44] Khi gene KRAS
Trang 31KRAS
n
i trong gene
[49]
Gene PI K3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase):
, Gene PIK3CA thuc h gene protein heterodimeric, c u trúc phân t hoàn ch nh c a PIK3CA c k t h p t ti u hòa p85 và ti có ho t tính xúc tác p110 [2]
Trang 32 32 2011 - 2013
S ho ng cng tín hi u PIK3CA có th
u t ng ho c insulin liên k t v i vùng ngo
n ng nhRTKK3CA
de
Trang 33 33 2011 - 2013
tr c ti p v i PIK3CA kích ho ng [2, 21, 43, 48 53], PIK3CA c kích ho t s xúc tác ph n ng phosphoryl hóa chuy i phosphatidylinositol-4,5-bisphosphate (PIP2) thành phosphatidylinositol-3,4,5-trisphosphate (PIP3) PIP3 ti p t c kích ho t s ho ng c a phosphoinositide-dependent kinase (PDK) và serine-threonine kinase (AKT) AKT s xúc tác th c
hi n ph n ng phosphoryl hóa nhi u lo i protein trong t bào ch t và trong nhân mà
hong c a chúng s i ch
c ch quá trình apoptosis c a t ng tín hi u PIK3CA c u hòa
âm tính b i s ho ng c gene áp ch kh i u PTENa
Protein PTEN xúc tác quá trình chuy n PIP3 thành PIP2 nên làm gi m n PIP3 và c ch s ho ng cng tín hi u PIK3CA [2, 21]
Trang 35
Trang 36anti-
-866 (PIK3CA inhibitor) mTOR inhibitor) N
genegene [43, 57]
Trang 38 38 2011 - 2013
Nghiên c u d ch t h c cho th y có kho ng 40-45% b mang gene KRAS t bi n [12, 13]y, g n m t n a b nh nhân không có tác
d ng v i các thu u tr n có Các th nghi nh cetuximab và panitumumab ch t s có tác d ng kéo dài th i gian s ng và th th i gian s ng không b nh cho các b nh nhân gene KRAS (hình 1 ) i 10 [5, 11]
dòng kháng EGFR [6] B c kéo dài th i gian s ng thêm n u
b nh t bi u tr b ng TAS-102