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Inflammatory Bowel Disease, Colon
Cancer and Chemoprevention
[염증성 장염에 의해 발생하는 대장암의 화학적 암예방]
부산대학교 약학대학
김 남 득 교수
1
Contents • IBD overview
• Inflammatory Bowel Disease
• Ulcerative colitis vs. Crohn’s disease
• Diagnosis
• Treatment
• Colon cancer
• IBD mice model
• Chemoprevention of IBD-related colon cancer
• Summary
2
Inflammatory Bowel Disease (IBD) • Def.: a group of inflammatory conditions of the
colon and small intestine. • The major types of IBD are Crohn's disease (CD) and
ulcerative colitis (UC). • Accounting for far fewer cases are other forms of
IBD, which are not always classified as typical IBD: • Collagenous colitis • Lymphocytic colitis • Ischaemic colitis • Diversion colitis • Behçet's disease • Indeterminate colitis
Micrograph showing inflammation of the large bowel in a case of inflammatory bowel disease. Colonic biopsy. H&E stain.
3
Inflammatory Bowel
Disease - What Is It? • Inflammatory bowel disease (IBD)
results from the inappropriate and
ongoing activation of the mucosal
immune system, and this is driven by
the presence of normal luminal flora.
• Can be thought of as an autoimmune disease
• This unusual response is due to defects in:
1. the barrier function of the intestinal epithelium
2. the mucosal immune system
4
• Onset of IBD typically occurs in the second
and third decades of life.
The majority of patients experience relapse or
will progress to chronic disease.
• Two main forms of IBD are Crohn’s Disease and Ulcerative
Colitis (UC).
Susceptibility to IBD is inherited and genetic factors are
more important in Crohn's Disease than in Ulcerative Colitis.
Inflammatory Bowel
Disease - What Is It?
5
IBD: A comparison of incidence rates
Incidence Year
Crohn’s disease (patients/105/year)
Ulcerative colitis (patients/105/year)
North America 1993 6.9 8.3
2004 14.6 14.3
North Europe 1993 7.0 11.8
South Europe 1993 3.9 8.7
UK 1994 8.3 13.9
India 2000 NA 6.0
New Zealand 2004 7.6 16.5
South Korea 2005 1.34 3.08
Japan 1991 0.51 1.9
Hong Kong 2001 1.0 1.2
*Incidence rates (cases/100,000/year) *Ahuja and Tandon, J. Digestive Diseases 2010; 11; 134-147.
6
IBD: A comparison of prevalence rates
Prevalence Year
Crohn’s disease (patients/105)
Ulcerative colitis (patients/105)
North America 2001 162 246
2004 201 238
North Europe 1987 54 161.2
South Europe 1992 40 121
UK 1996 214 122
India 2000 NA 44.3
New Zealand 2004 104 155.2
South Korea 2005 11.2 30.9
Japan 1998 13.5 -
1991 - 18.1
Hong Kong 2006 - 7.0
1994 1.3 -
*Prevalence rates (cases/100,000) *Ahuja and Tandon, J. Digestive Diseases 2010; 11; 134-147.
7
Impact of Race and Ethnicity
A
Whites had stronger family history of IBD and colorectal cancer.
African Americans with CD had higher incidence of arthritis.
Disease severity similar across all groups.
pANCA served as a sensitive maker for Mexican Americans as 100% with
UC were positive compared with 40% in whites
8
• Incidence of IBD in South Korea:
– Prevalence for UC in South Korea: quadrupled from
7.57/105 individuals in 1997 to 30.9/105 individuals in
2005
– Onset: 30% between 10 and 19 years of age
– Young children: <2%
– Peak age of onset: 20s & 30s, again in 60s (smaller
second peak)
– Adjusted prevalence rates of CD and UC per 100,000
individuals were 11.2 and 30.9, respectively
– The ratio of the incidence rates of UC to CD was
decreasing in Korea CD showed a trend of more
accelerated incidence rate compared to UC.
– Male predominance in the incidence of CD.
*Kim and Kim, Gut and Liver, 2010; 4(1) 1-14. 9
• Scope of disorder (United States)
– 700,000 physician visits per year
– 100,000 hospitalizations per year
– CD accounts for two thirds
• Long-term outlook
– Chronic, lifelong disease
– Acute flare-ups alternating with remission
– Complications and increased mortality
– Surgery for 50% to 80% of CD patients
Calkins BM. Digestive Diseases in the United States: Epidemiology and Impact. Bethesda, Md: National Institutes of Health; 1994.
10
• CD is a condition of
– Chronic inflammation potentially involving any
location of the GIT from mouth to anus.
– It is a lifelong disease arising from an interaction
between genetic and environmental factors
• UC is an inflammatory disorder that affects the
rectum and extends proximally to affect
variable extent of the colon.
Crohn’s Disease vs. Ulcerative Colitis
11
Crohn’s Disease vs. Ulcerative Colitis • Crohn’s and UC differ in the location and nature of the inflammation.
• Crohn's Disease: can affect any part of the GI tract
(most cases start in the terminal ileum)
• Ulcerative Colitis: restricted to the colon and rectum
12
Comparison of the distribution patterns of Crohn’s disease and ulcerative colitis, as well as the different conformations of the ulcers and wall thickenings.
13
Clinical features of CD
• Abdominal pain
• Diarrhea
• Fever
• Malabsorption
• Colonic bleeding
• Intestinal obstruction
• Fistulas
• Small bower cancer
• Colorectal cancer
18
Clinical features of UC • Mild colitis • Moderate colitis • Severe colitis • Extraintestinal manifestations: a. arthritis b. Uveitis c. Erythema nodosum d. Pyoderma gangrenosum e. Primary sclerosing
cholangitis • UC and colorectal cancer: colorectal epithelial dysplasia colorectal carcinoma
• CRC: UC > CD
19
ETIOLOGIC HYPOTHESES
• Persistent infection
– Mycobacteria
– Helicobacter sp.
– Listeria
– Toxigenic E. coli
• Defective mucosal integrity
– Altered mucus
– Increased permeability
– Cellular starvation
– Impaired restitution
• Dysbiosis (장내미생물교란)
– Protective bacteria
– Aggressive commensals
• Dysregulated immune
response
– Loss of tolerance
– Aggressive cellular activation
– Defective apoptosis
– Antineutrophil cytoplasmic
antibodies are found in 80%
of patients with UC
• Family history of IBD – More common for CD than for UC
– CD: chromosome 16 with NOD2/CARD15 locus
21
Pathogenesis of IBD
• 항염증: IL-10, TGFβ
• 염증유발: - Th1 cytokines (IL-12, IL-18, IFN-γ, TNFα, IL-2, IL-1β, TL1A)
- Th17 cytokines (IL-23, IL-17)
- Th2 cytokines (IL-4, IL-5, IL-13)
22
IBD: Systemic Complications
*Higher incidence in women.
Eye
inflammation*
Liver and bile duct inflammation
Skin lesions
Arthritis and joint pains
Kidney stones
Growth failure in children
Lower
bone density*
Subfertility*
Gallstones
Ovaries
Uterus
25
Diagnosis of IBD Diagnosis is generally done by:
an assessment of inflammatory markers in stool
a colonoscopy (to allow for a visual diagnosis)
a biopsy of pathological lesions
non-specific: can also use blood test (surrogate markers for
inflammation, e.g. ESR, nutritional deficiencies)
Diagnosis of non-specific IBD is only made once all other
possibilities have been ruled out, such as:
Infection
Ischemia
Physical damage
Allergies
Colon Cancer
NSAID enteropathy
(ESR, 적혈구침강속도)
27
Treatment of IBD
• Goals of therapy
– Induce and maintain remission.
– Ameliorate symptoms
– Improvements quality of life
– Adequate nutrition
– Prevent complication of both
the disease and medications
Adapted from: Hanauer et al, Am J Gastroenterol 2001; 96: 635 28
Drug therapy for Crohn’s disease - 2008
First line therapy
5-ASA (mesalamine)
balsalazide
budesonide
antibiotics
(metronidazole,
Cipro, rifaximin,
amoxicillin,
minocycline,
tetracycline)
Immunomodulators/
Second line therapy
corticosteroids
budesonide
azathioprine/6-MP
methotrexate
Biologic Therapy
infliximab
adalimumab
certolizumab pegol
natalizumab
Investigational
Immunomodulators
mycophenolate mofetil
leflunamide
FK 506
thioguanine
stem cell transplant
Biologics - in development
mesenchymal stem cells
abatacept
thalidomide
anti IL-12 (ABT-874)
Trichuris suis
probiotic therapy
visilizumab (anti-CD3)
Adacolumn (leukocytopharesis)
golimumab
fontalizumab
Nutritional therapy
elemental diet
TPN
29
UC-약물치료(질병관리본부) 메살라민(Mesalamine) : 경증에서 중증의 궤양성 대장염을 치료하고 궤양성 대장염의
증상을 완화시키기 위해 사용. 국소적인 메살라민(Mesalamine)으로 좌약형과 관장형이
있으며 좌약형은 직장에 염증이 있을 때만 사용할 수 있고, 관장형은 하행결장이 시작
되는 부분까지만 약물이 도달하므로 하행결장 이후에 있는 병변에만 사용할 수 있음(예:
아사콜(Asacol)).
발살라자이드(Balsalazide) : 메살라민과 유사한 약효를 가진 전구약물로, 증상을 완화
시키는데 좋은 효과를 보임. 보통 활성기에서 호전된 궤양성 대장염 환자의 유지
(maintainance)요법에 사용됨.
30
31
코르티코스테로이드 : 활성기 치료에 있어서는 메살라민보다 효과적임. 그러
나 유지요법으로 장기간 사용하는 것은, 치료효과보다 부작용이 더 많이 발
생할 수 있어서 권장되지 않음.
궤양성 대장염 환자의 약 50%는 아미노살리실레이트(Aminosalicylate)와 같
은 항염증제에 치료 효과를 보임. 활성기에는 코르티코스테로이드(예: 프레
드니손)가 중요한 치료제이나 이로 인해 체중 증가, 여드름과 같은 부작용이
생길 수 있으므로 주의해야 함. 심한 경우 병원에 입원해야 하고, 코르티코스
테로이드의 정맥 주입이 필요하다. 또한 과도한 출혈 시 수혈이 필요함
Summary of Standard Therapy Induction of
Remission
Maintenance of
Remission
Adverse Effects
Steroids Established 70-
90%
Ineffective Yes
5-ASA
(Mesalamine, 5-aminosalicylic
acid)
Minor effect Conflicting
evidence
Yes
Antibiotics No No
Immune
Suppresants
Established
55%
Established Yes
Methotrexate Established Not
demonstrated
Yes -
teratogenic
Biologicals Established Established Yes
32
The pipeline of IBD
Pre-clinical
Phase I Phase II Phase III Pre-reg. Launched
12
Biologicals
Small molecules
Natalizumab/
Elan/Biogen
STA5236/Syntha
Kappaproct/
Index/Serono
OCP 6535/
Otsuka
RDP58/
Genzyme/SangStat
Lecithin/
Dr. Stremmel
Cytokine/chemokine
Adhesion molecules
Transcription factors
Anti TNF
Mucosal barrier
Phosphodiesterase IV inhibi
tion
Cell homing Cytokine release
Onercept/Serono
MLN-2/Millenium
EGF/
Hitachi-Nippon
Fontolizumab/
PDL
Basilixmab/Novartis
ABT-874/J695/
Abbott-Wyeth
Visilizumab/
PDL
CNI1493/
Pharma Science
Early pipelines not empty but specific IBD i
nformation is lacking on the plethora of ant
i-inflammatory approaches. Most such com
pounds are patented for IBD which does no
t infer IBD development intent. Adalimumab/
Abbott
Sargamostim/
Schering-Berlex
CDP-870
Celltech-UCB
Alicaforsen/
Isis
Oprelvekin/
Wyeth
Infliximab/
Centocor/Schering- Pl
ough
ADDITIONAL OTHER INDICATIONS:
Oprelvekin thrombocytopenia post-chemo (launched)
CDP-870 rheumatoid arthritis (Ph III)
Adalimumab rheumatoid arthritis (launched)
Sargamostim neutropenias post-chemo (launched)
Natalizumab multiple sclerosis (pre-reg)
Infliximab rheumatoid arthritis (launched)
psoriasis/psoriatic arthritis (pre-reg/Ph III)
33
<성별 10대암 조발생률, 2009년> (2012년 2월 현재)(단위: 명/10만명)
위(80.2)
대장(60.6)
폐(56.4)
간(47.9)
전립선(29.6)
갑상선(20.8)
방광(10.3)
췌장(9.8)
담낭 및 기타 담도(9.6)
신장(9.4)
갑상선(108.2)
유방(54.1)
대장(40.0)
위(39.4)
폐(22.8)
간(16.2)
자궁경부(15.1)
담낭 및 기타 담도(9.8)
췌[장(8.0)
난소(7.2)
34
2010년 암종별 사망자수 : 남녀전체 한국의 사망원인(2010)
1. Cancer (25.6%) 2. 심혈관질환
폐암 15,623
간암 11,205
위암 10,032
대장암 7,701
췌장암 4,306
담낭 및 기타 담도암 3,502
유방암 1,868
백혈병 1,618
비호지킨 림프종 1,430
식도암 1,352
35
Stages of colon carcinogenesis ~50% of US population
have adenoma(s) by age 70 years
37
Schematic of the morphologic and molecular changes in the adenoma-carcinoma sequence. It is
postulated that loss of one normal copy of the tumor suppressor gatekeeper gene APC occurs early.
Indeed, individuals may be born with one mutant allele of APC, rendering them extremely likely to
develop colon cancer. This is the "first hit," according to Knudson's hypothesis. The loss of the
normal copy of the APC gene follows ("second hit"). Mutations of the oncogene K-RAS seem to
occur next. Additional mutations or losses of heterozygosity inactivate the tumor suppressor gene
p53 (on chromosome 17p) and SMAD2 and SMAD4 on chromosome 18q, leading finally to the
emergence of carcinoma, in which additional mutations occur. It is important to note that while there
seems to be a temporal sequence of changes, as shown, the accumulation of mutations, rather than
their occurrence in a specific order, is more important.
대장 – 결장과 직장의 선암 (선종-선암종 과정)
38
• As many as 4 million people (including one million Americans, 23,000 Australians, and 250,000 Canadians) worldwide suffer from a form IBD.
• The cost of lost productivity to U.S. businesses due to IBD is estimated to be as much as $.8 billion a year.
• The risk of colon cancer for people with IBD increases by 0.5% to 1% yearly approximately 8 to 10 years after diagnosis.
• Also people with IBD are five times more likely to develop colon cancer than the general public.
Inflammatory Bowel Diseases (IBD, e.g., Crohn’s Disease, Ulcerative Colitis)
40
Risk of CRC in IBD: Factors that Increase Risk
• Duration >8-10 years
• Extent of colitis:
• Extensive disease
• Backwash ileitis
• Family history of colon cancer
• Primary sclerosing cholangitis (1차성 강직성 담관염)
• Early age at onset of colitis
• Histologic activity
• Dysplasia at surveillance
45
Risk of CRC in IBD: Factors that Decrease Risk
• Prophylactic colectomy
• Surveillance colonoscopy
• Regular doctor visits
• Chemoprevention
• 5-ASA ?
• UDCA Yes (PSC patients)
• Folate ?
• Thiopurines No
46
47
Cell death
Activated Carcinogens
Procarcinogens
Detoxification & Secretion
Metabolic activation
Healthy Cell Damaged Cell (precancerous)
Cancer Cell
Repeated damage
Chemotherapy
C h e m o p r e v e n t i o n
Initiation Promotion Progression
(1-2 days) ( >10 years) ( >1 years )
Initiated Cell
48
Animal Models of Inflammatory Bowel Disease
Human IBD
IBD represents an important chronic
disease affecting the GI tract of man
and domesticated animal species.
The 2 IBD entities in humans are Crohn’s
disease (CD) and Ulcerative colitis
(UC).
Immune mediated - responds to
immunomodulatory drugs
The pathogenesis of IBD involves: 1. Failure of immune regulation
2. Genetic susceptibility.
3. Environmental triggers (microbial flora).
4. Disruption of the mucosal barrier.
Mouse models of IBD
DSS (Dextran sulphate) colitis: Oral administration of this
sulphated polysaccharide to mice induces a self limiting
colitis
TNBS (Trinitrobenzene sufonic acid) colitis: Colonic
inflammation is induced by intrarectal administration of
TNBS dissolved in 50% ethanol
Canine IBD
Small intestine: Lymphocytic-plasmacytic enteritis (LPE),
eosinophilic enteritis and eosinophilic gastro-enteritis
(EGE)
Large intestine; Lymphocytic-plasmacytic colitis,
eosinophilic colitis, histiocytic ulcerative colitis (HUC)
(mainly PAS-positive macrophages), and regional
granulomatous colitis (mainly PAS-negative macrophages)
Organ site Species Carcinogen Endpoint measured
Mammary Gland
Rat MNU adenocarcinoma
Rat DMBA adenoma, adenocarcinoma
Lung
Mice
B[a]P adenoma
NNK adenoma
Vinyl carbamate adenoma, adenocarcinoma
Colon
Rat AOM adenoma, adenocarcinoma
Mice AOM adenoma, adenocarcinoma
Mice DMH adenocarcinoma
Mice MAMAc adenocarcinoma
Mice
AOM + DSS (inflammation)
adenoma adenocarcinoma
Carcinogenesis Models:
49
New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents Wogonin,
Baicalein and Baicalin. Cancer Treatment Reviews 35 (2009) 57–68
기원
Scutellaria baicalenesis (속썩은풀)
생약명 : 황금 (黃芩)
Scutellariae Radix
속썩은풀의 주피를 벗긴 뿌리가 약용으로 사용됨
성미
청열조습 (淸熱燥濕): 열을 내리고 땀조절
사화해독 (瀉火解毒): 항염증
Effect of baicalein on AOM/DSS-
induced colon cancer model in mice
52
김동환 박사과정
Baicalein induced cell growth inhibition
(*p<0.05, **p<0.01, ***p<0.001 vs. untreated control)
*** ***
***
* ***
***
25 C 50 100 (μM)
p53
p73
MDM2
β-actin
Wild type
Baicalein (24 h)
p21
p53
p73
p53 null type
Baicalein (24 h)
25 C 50 100 (μM)
MDM2
p21
β-actin
Baicalein induced cell growth inhibition
Con 25 50 100
Annexin V
PI
p53+/+
p53-/-
14.02% 1.81%
83.11% 1.06%
18.09% 1.44%
79.97% 0.5%
18.47% 1.67%
78.88% 0.98%
19.42% 1.79%
77.77% 1.02%
9.80% 1.37%
87.91% 0.92%
4.59% 9.45%
82.87% 3.09%
8.18% 10.5%
74.79% 6.53%
15.7% 9.12%
72.93% 2.25%
Baicalein induced cell growth inhibition
Baicalein induced apoptosis through the
extrinsic pathway
25 C 50 100 (μM)
Wild type
Baicalein (24 h)
PARP
Cleavage
β-actin
25 C 50 100 (μM)
p53 null type
Baicalein (24 h)
PARP
Cleavage
β-actin
Death Receptor Pathway
Mitochondrial Pathway
Apoptotic Insults
Mitochondria
Cytochrome c
Apaf1
Pro-caspases 9
Active Caspase 9
Caspase 8 Activation
Caspase 3, 6, 7
Death Substrates
Cell Death
TNF, TL1A
TNF-R1, DR3, DR6
TRADD
FADD
Pro-caspase 8
FasL, TRAIL
Fas, DR4, DR5
FADD
Pro-caspase 8
tBID
Apoptosis: Death Receptor Pathway (Extrinsic Pathway) and
Mitochondrial Pathway (Intrinsic Pathway)
25 C 50 100 (μM)
pro-caspase-3
β-actin
p53 null type
Baicalein (24 h)
pro-caspase-8
pro-caspase-9
25 C 50 100 (μM)
pro-caspase-3
Wild type
Baicalein (24 h)
pro-caspase-8
pro-caspase-9
β-actin
DR5
TRAIL
DR5
TRAIL
Baicalein induced apoptosis through the
extrinsic pathway
25 C 50 100 (μM)
PPAR γ
Wild type
Baicalein (24 h)
p50 (NE)
p65 (NE)
iNOS
β-actin
PPAR γ
p53 null type
Baicalein (24 h)
25 C 50 100 (μM)
β-actin
iNOS
Baicalein suppressed the activation of NF-kB
through PPARγ activation
Summary • The chronic IBDs, Crohn’s disease and ulcerative colitis have seen notable
successes culminating in the discovery of 99 published susceptibility
loci/genes (71 Crohn’s disease; 47 ulcerative colitis) to date.
Approximately one-third of loci described confer susceptibility to both
Crohn’s disease and ulcerative colitis.
• There is substantial overlap in susceptibility loci/genes between IBD and
other diseases. Presently approximately 51 IBD loci show overlap between
up to 23 different diseases.
• Need long term management with primary goal to induce then maintain
remission and prevent complications of both the disease and drugs.
• Chemoprevention uses specific natural or synthetic compounds in an attempt
to prevent, halt or reverse the process of carcinogenesis, and is an
attractive way to fight CRC development.
• Further studies are required to explore the chemopreventive effects of
diosgenin, baicalein, astaxanthin, ginseng on colon carcinogenesis in
human clinical studies.
64