Diet and Cancer - CPNC

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Diet and Cancer - CPNC

Diet and Cancer

Steffen Loft


Causes of cancer as estimated by Doll and Peto

Infection

Food additives

Alcohol

Pollution

Geophysical factors

Medicines and medical procedures

Occupation

Industrial products

Unknown

Reproductive and sexual behaviour

Tobacco

Diet

0 10 20 30 40


Luft

Jord

Vand

Plante Dyr Menneske


Hvorledes undersøges kostsammensætningen

Befolkningsplan

•Forsyningsstatistikker

•Forbrugerundersøgelser

Individuelt

•Retrospektivt over 24 timer, uge eller måned

•Frekvensspørgeskema

•Prospektiv menuregistrering

•Prospektiv dobbeltportionering

Biomarkører

•Vitaminer o.a. i plasma

•Plantestoffer i urin

•Fedtsammensætning i fedtbiopsier


Epidemiologiske designs til undersøgelse af kost og kræftsammenhænge

Økologiske eller transkulturelle studier

•sammenligner geografiske regioner eller befolkninger med forskellig kost

•Forbedres med immigranter til højrisikoregionen

Case-control undersøgelser

•estimerer tidligere kostsammensætning ved interviews

•er oftest behæftet med en betydelig risiko for recall-bias

Kohortestudier

•registrerer kostsammensætning hos fx 50-100.000, som følges op fx 5-20 år

•Kan også baseres på biomarkører i nested case-control design

•confounding fra bl.a. livsstilsrelaterede risikofaktorer

Interventionsundersøgelser

•Vanskeligt pga. individuelle kostvalg og nødvendigt stort antal

•tilskud af mikronutrienter kan gennemføres optimalt (men kostbart)


Correlation between breast cancer

mortality rates and per capita consumption levels of fat

Age-adjusted death rate per 100,000

25

20

15

10

5

0

US

UK

DK

Thailand Mexico

Japan

0 20 40 60 80 100 120 140 160 180

Total dietary fat intake (g/day)


Kost og karcinogene effekter

• Carcinogener i fødevarer

- Aflatoxin – IARC gr. 1 (mutagen)

- Psoralener (bladselleri) – kræft i dyreforsøg (mutagen )

- Kaffesyre (æbler) – kræftfremkaldende i dyreforsøg (mekanisme )

- Dioxin o.l. (fisk/fede landbrugsprodukter) – IARC gr.1( promotor)

• Carcinogener/mutagener dannet ved tilberedning fødevarer

- Stegemutagener (heterocykliske aminer)

- PAH fra trækulsgrilling

- Nitrosaminer (fra nitrater)

- Akrylamid (ikke klassisk mutagen)

• Fødevarer/plantestoffer, der ændrer metabolisme

- Glucosinolater (indoler og isotiocyanater) fra fx kål

• Fødevarer med (andre) promotionseffekter

- mitogene effekter – fx alkohol

- fedt – tarmeffekt og overvægt (østrogen)


Carcinogenic effects of heterocyclic amine – cooked food mutagens

N

N

CYP1A2

UGT - (NAT) - (SULT)

NHOH

DNA

NAT

mutations

Colon and breast cancer


Mutagenetisk aktivitet af heterocykliske aminer – stegemutagener

I S. Typhimurium TA98 med aktivering med S9 mix

IQ

MeIQ

MeIQx

PhIP

Trp-P-1

Trp-P-2

Glu-P-1

Glu-P-2

AalfaC

MeAalfaC

Revertanter per

µg

433.000

661.000

145.000

1.800

39.000

104.200

49.000

1.900

300

200

Aflatoxin B1

Benzo[a]pyren

6.000

320


All factors and >60 years: RR 60

Colon cancer (breas

12

10

slow

fast

8

frequency

6

4

2

0

-3 -2 -1 0 1 2 3

Log NAT activity

Cooked food mutagens from meat, fish etc.

Liver CYP1A2

RR 2 for fast

Hydroxylamin (-glucorunide)

RR 2 for high

consumer

excretion

RR 2

colon

NAT1/2

mutagen


Aflatoxin dannes af Aspergillus flavus i fugt og varme – forårsager Levercancer

CYP3A4


Nested case-control studie af levercancer i forhold til

aflatoxin eksponering og hepatitis B bærer tilstand

baseret på kohorte-undersøgelse fra Kina

No aflatoxin in urine

Aflatoxin in urine

HBsAg

Cases

Controls

RR

Cases

Controls

RR

Negative

4

74

1.0

6

51

1.9

(0.5-7.5)

Positive

5

13

4.8

7

2

60.1

(1.2-19.7)

(6.4-561)


Nested case-control studie af lever cancer med p53 codon 249ser

mutation i forhold til aflatoxin eksponering og hepatitis B bærer

tilstand baseret på kohorte-undersøgelse fra Kina

Aflatoxin exposure

HBsAg carrier rate

Low

High

Total

Low/moderate

1.1%

17%

1.6%

High

4.7%

21%

18%

Total

1.8%

21%

9.8%

(6/337)

(50/237)

(56/574)

• p53 er vigtig tumorsupressorgen – check af DNA skade før

celledeling og signal til arrest eller apoptose ved større skade.

• Aflatoxin binder sig til baser i codon 249 in vitro

• Codon249ser mutationen følger geografisk aflatoxin


Kilder til Polyklorerede Bifenyler (PCB)

Cl

Cl

Siden 1929 brugt i.f.m.:

Cl

Cl

•Blødgørere i plast) (længe siden)

Cl

Cl

•Klæbe og konsistensmiddel

•Maling

•Elektrisk isolation

•Industrielle kemikalier

Produktion standset i 1977

Findes i 209 congener


DIOXINER OG FURANER

• Dannes som uønskede biprodukter fra:

– fremstilling af klorforbindelser, herunder 2,4-D

– Papirblegning

– Stålstøbning

– Afbrænding

– Motorkøretøjer

O

O

O

PCDD

PCDF

• Polychlorerede dibenzo-p-dioxiner (PCDD) : 75 congener

Polychlorerede dibenzo-furaner (PCDF) : 135 congener

• Mest toksiske:

2,3,7,8-tetraklordibenzo-p-dioxin (TCDD)

• Bioakkumuleres


Helbredseffekter af dioxiner

Viktor Jusjtjenko

Kloracne Dioxin forgiftning

Ses ved massiv eksponering

Kræft og og Reproduktionstoksicitet

Ses ved meget lave doser eksperimentelt (pg/kg)


Defekt vækst og cellecykluskontrol

CYP

GST

NAT2 etc.

Initiator

Procarcinogen

Carcinogen

Aktivering af proto-oncogen(er)

Inaktivering af tumor suppressor gen(er)

Normal celle Initieret

celle

initiering

Preneoplastisk

læsion

promotion

promotor

Malig

n

progression

tumor

Klinisk

kræft


1

2

3

4

X

X

X

X

1. Ganske få tumorer

2. Mange tumorer

3. Mange tumorer

4. Ingen tumorer

5

5. Ingen tumorer

tid

Resultater af et tumorforsøg med et dioxin - 2,3,7,8-TCDD på mus.

Tumorforekomst angives efter administration af dietylnitrosamin

(X) og TCDD ( ) på musehud i forskellig rækkefølge.


AhR -> hormoner, enzymer, - - -> toxicitet

Østrogen receptor cross talk

Fælles virkningsmekanisme

for dioxiner o.l. stoffer

Ligand

Hsp90

AhR

Arnt

t ex CYP1A1

XRE


Levertumorer hos rotter (%)

TCDD (ng/kg/dag)

100

90

80

70

60

50

40

30

20

10

0

0 1 10 100

Benigne

Maligne


Brysttumorer hos rotter (%)

TCDD (ng/kg/dag)

100

90

80

70

60

50

40

30

20

10

0

0 1 10 100

Benigna

Maligna


Indtag af dioxin og dioxinlignende PCB i Danmark

(2-4 pg/kg)

Æg 3%

Kød 9%

Fisk 58%

Mejeriprodukter

30 %


Risiko vurderings konceptet

Mekanisme – interaktioner - risikogrupper

Fare/risiko

identifikation

Epidemiologi

Eksperimentelt

% dyr med tumorer

Cancer:

tumorer

(mutagenicitet)

Dosisrespons

estimering:

Eksponerings

vurdering

TD 25

TD 50

Tolerable risk

Ekstrapolation til mennesker og/eller relevante doser

Risiko analyse Risiko håndtering


Toksikologiske dyreforsøg – hypotese:

1. 1. Uønskede virkninger som som forekommer hos hos mennesker vil vil også også

optræde hos hos forsøgsdyr (eller (eller i i reagensglasset)

(Kvalitativt)

2. 2. Dosis/koncentration, som som afslører toksisk virkning hos hos dyr dyr

muliggør farevurdering for for opståen af af samme effekt effekt hos hos

mennesker

(Kvantitativt)

Ekstrapolation fra dyreforsøg

Fra Fra høj høj til til lav lav dosis dosis

Fra Fra lille lille til til stort stort tal tal

Variation mellem arter arter (+stofskifteforskelle)

Variation i i sårbarhed hos hos mennesker


Ranking carcinogenic hazards from food based on rodent

studies. Human Exposure Rodent Potency index: % of TD 50

HERP (%) food carcinogen dose

140 (fumigation worker) EDB 150 mg (before 1977)

6.2 Comfrey-pepsin tbl. comfrey root 2.7 g

4.7 Wine (250 ml) ethanol 30 ml

0.3 Lettuce (1/8 head´) caffeic acid 66.3 mg

0.1 Apple (1 whole) caffeic acid 24.4 mg

0.1 Mushroom (15 g) hydrazines

0.1 Basil (1 g dried) estragole 3.8 mg

0.04 Orange juice d-limonene 5.5 mg

0.03 Peanut butter aflatoxin 64 ng

0.03 Carrot (1 whole) caffeic acid5.16 mg

0.006 Bacon (100 g pan fried) diethylnitrosamine 0.1 µg

0.0006 Well water (contam.) trichloroethylene 267 µg

0.0005 Hamburger (pan fried) PhIP 1.28 µg

0.00008 Hamburger (pan fried) MeIQx 111 ng

7 10 -9 Coffee (1 cup) MeIQ 0.064 ng


Attributable risk of carcinogens in food in DK

Aflatoxin – IARC gr. 1 (mutagen)

minimum exposure in DK

Cooked food mutagens (heated protein)

(Epidemiology support)

Acrylamide (heated carbohydrates)

(no epidemiology support yet)

Polyaromatic hydrocarbons (charcoal, smoke)

Dioxins, PCBs etc. (persistent pollutants)

With linear extrapolation from liver tumors in rats

(not supported by epidemiology)


Anticarcinogenese i dyreforsøg:

• kalorierestriktion

• antioksidanter (vit. C og E, ß-caroten)

• flavonoider og fenoler (antiox.+enzymmodifikation)

• indoler og isocyanater (enzymmodifikation)

• Cytokrom P450 hæmning eller begr. induktion

• GST induktion

• Cruciferae (korsblomstrerede: kål etc.)


World Cancer Research Fund 1997: Kost, Kræft og Forebyggelse

IARC monografier 2003 (frugtgrønt); 2004 (korsblomstrede grøntsager)


Frugt, grønt og kræft

• Mekanismer

• Dyreeksperimentelt resume

• Epidemiologi resume

• Intervention


Putative mechanism of carcinogenesis

Toxin

Metabolism

CYPs

MPO

Etc.

Reactive

metabolites

ROS/RNS

(oxidants)

inflammation

ROS/RNS (oxidants)

from inflammatory cells

activation

signalling

Metabolic defence – e.g. GSTs

oxidant defence

DNA damage

DNA repair

proliferation

Cell cycle control

apoptosis

mutagenesis

Chemoprevention

e.g. plant

cancer

Chemoprevention

e.g. plant


Resume af dyreeksperimentelle af frugt/grønt og kræft

Sikker virkning på kemisk induceret kræft i

•Colon

•Oesofagus

•Mamma

•(blære, mundhule )

Utilstrækkelig evidens for spontane tumorer

Mulige særlige effekter af bestemte, fx korsblomstrede

Mekanismer er mest sandsynligt knyttet til påvirkning

af enzymaktivitet


esume af epidemiologiske undersøgelser af sammenhæng

ellem indtag af frugt og grøntsager og kræftrisiko

ancer site Frugt Frugt Grøntsager Grøntsager

case-kontrol kohorte case-kontrol kohorte

avesæk 0.6 (0.3-1.1; 25) 0.8 (0.6-1.9; 9) 0.6 (0.3-1.7; 26) 0.9 (0.8-1.1; 8

olorektal 0.8 (0.3-1.7; 10) 0.9 (0.5-1.6; 12) 0.85 (0.6-2.3; 8) 1.0 (0.7-1.6; 7

unge 0.7 (0.3-1.2; 14) 0.8 (0.3-1.2; 14) 0.7 (0.2-1.5; 20) 0.9 (0.5-1.2; 1

lære 0.5 (0.5-1.0; 3) 0.7 (0.6-1.0; 4) 0.6 (0.6; 1) 0.8 (0.7-0.8; 2

ryst 1.0 (0.6-1.7; 16) 0.8 (0.6-1.1; 9) 0.7 (0.1-1.4; 21) 0.9 (0.9-1.0; 3

rostata 1.1 (0.4-1.5; 11) 1,1 (0.7-1.6; 10) 0.8 (0.3-1.4; 12) 0.9 (0.8-1.0; 6

ancreas 0.7 (0.1-0.9; 8) 0.9 (0.7-0.9; 3) 0.7 (0.4-1.0; 10) 0.8 (0.8-1.1; 3

ærdier er median RR (range af RR; antal studier). Signifikant effekt i metaanalys


Interventionsundersøgelser med ”simple antioksidanter”

he effect of vitamin E and beta carotene on the incidence of lung cancer and

ther cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer

revention Study Group.

Engl J Med. 1994 Apr 14;330(15):1029-35.

20 mg betacaroten, 50 mg vitamin E begge eller placebo 29122

Betacaroten: 18% [3% til 36%] øget risiko for lungecancer

Vitamin E: ingen effekt på lungecancer, men måske positiv effekt på prostata

isk factors for lung cancer and for intervention effects in CARET, the Betaarotene

and Retinol Efficacy Trial.

Natl Cancer Inst 1996 Nov 6;88(21):1550-9

30 mg betacaroten+25000 IE vitamin A til halvdelen af 18314

ygere/asbestudsatte

28% øget risiko for lungecancer; RR 1.36 [1.07-1.73] i præspecificeret analyse


G

T

T

A

T

A

C

A

C

C G

T

A

G

A

T

C

A

T

A

T

G

C

G

A

T

G

A

T

A

T

C

Types of oxidative DNA damage

NH 2

Fe 2+

Cu +

Strand breaks

DNA-protein crosslinks

O

N

N

dR

OH

5-OHdC

1

O 2

O

O

H 2 O 2

NOO -

Fe 3+

H 2 N

HN

N

H

N

NH

CHO

H 2 N

HN

N

H

N

N

O

FapyGua

dR

8-oxodG

dR

N

O

H 2 O 2

N

N

N

N

εdA

N

N

dR

N

N

N

M 1 dG

dR


25

40

20

30

15

20

10

10

Strand breaks in comet

Diet intervention

Vegetables

Placebo

5

0

0

Vitamins

-1 9 16 24 52

-5

FPG sites in comet

H2O2 induced sites in comet

Diet intervention

-1 9 16 24 52

Day

Day

EndoIII sites in comet

50

40

40

30

30

20

20

10

Diet intervention

10

Diet intervention

0

-1 9 16 24 52

0

-1 9 16 24 52


37 studies of multiple dose antioxidant and nutrient interventions

with oxidative DNA damage in WBC as end point were identified

ANOVA and Χ 2- tests were used to test predictors of the study showing

protective effects

• biomarker used (8-oxodG, strand breaks, ENDOIII sites, H 2

O 2

sensitivity)

• number of subjects

• smoking status

• types of antioxidant (single/multiple antioxidants/natural products)

• duration of the intervention trial and washout period

• power of study to detect a 50% difference

• strength of study design

The strength of the study designs were scored from 0 to 3

• Inclusion of a placebo group or period (1 point)

• Parallel intervention series of placebo and antioxidant (1 point)

• Samples taken after the termination of the intervention (1 point)

pdate of review in Møller & Loft, Am J Clin Nutr 76: 303-310, 2002; Boyle et al. Eur J Clin

utr 2000; Collins et al. Carcinogenesis 2003; Bub et al. J Nutr Biochem 2003; Møller et al.


37 studies of multiple dose antioxidant and nutrient interventions

showing protective or no effects on DNA damage in WBC

mean±SD;

median (interqu

protective effects

no effects

Study strength 1.0±0.9 (n=21) 1.9±0.6 (n=16) (p


Putative mechanism of carcinogenesis

Toxin

Metabolism

CYPs

MPO

Etc.

Reactive

metabolites

ROS/RNS

(oxidants)

inflammation

ROS/RNS (oxidants)

from inflammatory cells

activation

signalling

Metabolic defence – e.g. GSTs

oxidant defence

DNA damage

DNA repair

proliferation

Cell cycle control

apoptosis

mutagenesis

etabolic defence – e.g. GSTs Metabolic defence – e.g. GSTs

Chemoprevention

e.g. plant

cancer

Chemoprevention

e.g. plant


.Here we further investigate the association between DNA adduct levels and consumption of major

food groups and foods, and the estimated dietary intake of nutrients, taking into account the

possible modifying effect of metabolic polymorphisms, in a larger sample of 634 healthy adults

enrolled in a prospective study in Italy.

DNA adducts and five polymorphic metabolic genotypes (GSTM1, GSTT1, NAT2, CYP1A1 and

MTHFR) were determined in peripheral leukocytes by using 32 P-postlabeling technique and PCR

methods. DNA bulky adducts (mean: 7.82 ± 0.40/10 9 nt) were detected in 482/634 samples

(76.0%). Overall, DNA adduct levels were significantly and inversely associated with the intake of

raw leafy vegetables (P = 0.02), non-citrus fruits (P = 0.04), potassium (P = 0.01) and ß-carotene

(P = 0.05).

No association was evident with the five genotypes.

Overall, statistically significant interactions in predicting DNA adduct levels were observed

between the GSTM1-null genotype and consumption of leafy vegetables (P = 0.01), white meat (P

= 0.04), and intake of vitamin C (P = 0.04), vitamin E (P = 0.05) and ß-carotene (P = 0.02). Our

results suggest that the role of a diet rich in antioxidants in preventing or reducing DNA adduct

formation is restricted to subjects lacking the detoxifying activity of GSTM1 isoenzyme.


Antioxidant intervention and chromosomal aberration and chromatid b

Dusinská et al. Mutagenesis 18: 371-6, 2003

Intervention with vitamin E 100mg/day β-carotene 6mg/day, selenium 50µg/day

significant effects in rural control smokers (no effect in myorcardial infarct sur

chromosomal aberration

chromatid breaks


Cruciferous vegetables, mainly Brassica have cancer

preventive effects in observational epidemiology and

animal carcinogenesis studies. (Verhoeven et al 1996; 1997)

1'

O

S HO

R C

0 2'

NOSO 2 O, K

Semisystematic names of glucosinolates

R-groups

amino acid derived

3'

5' 6'

4'

OH

OH

OH

H 2 O

myrosinase

Brassica glucosinolates are activated by myrosinase

cleavage of the glucosidic bond.

Indolyle-derivatives induce Ah-receptor enzymes

S-side chain, e.g. sulphoraphane induce a series of ARE

related enzymes (quinone reductase and GSTs) but are

also eliminated by GSH conjugation

Possible gene-environment interactions have been

studied in relation to GSTs and lung, colon and breast

cancer

R

C

S H

N

O

SO 2 O K

Rapeseed glucosinolates

+ D-glucose

H 2 SO 2 O

Glucosinolate degradation pro

R N C S


Regulation of defense enzymes by diet –

genetic variation

glucosinolates

Præmutagens, e.g. tobacco smoke

xcretion

GST

GSH

enzymes

CYP’s,

Etc.

ITC

enzymes

CYP’s

NAT, o.a.

GST

QR

Mutagens - toxins

excretion

GST, QR

activation

Cancer


Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms,

and lung-cancer risk: a prospective study of men in Shanghai, China

London et al. Lancet 2000.


Regulation of defense enzymes by diet –

genetic variation

glucosinolates

Præmutagens, e.g. tobacco smoke

xcretion

GST

GSH

enzymes

CYP’s,

Etc.

ITC

enzymes

CYP’s

NAT, o.a.

GST

QR

Mutagens - toxins

excretion

GST, QR

activation

Cancer


No effect of fibre on colorectal

cancer in

The Nurses’ Health Study

Fibre Q2 Q3 Q4 Q5

Total 0.90 0.96 0.93

(0.71-1.13) 0.75-1.21) (0.72-1.19)

Cereal 0.90

(0.71-1.13)

Fruit 0.94

(0.74-1.18)

Vege 0.98

(0.78-1.23)

0.95

(0.75-1.19)

1.03

(0.82-1.29)

0.98

(0.78-1.25)

0.99

0.79-1.24)

0.88

(0.69-1.12)

1.13

(0.89-1.43)

0.95

(0.73-1.25)

1.0

(0.79-1.27)

0.86

(0.67-1.10)

1.35

(1.05-1.72)

Fuchs et al NEJM 1999; 340:169-76


Incidence of colorectal

cancer in 519 978 individuals

aged 25–70 years taking part

in the EPIC study from ten

European countries was

inversely associated with

dietary fibre in foods

Relative risk for the highest

versus lowest quintile of fibre

from food intake was 0·58

(0·41–0·85).

No food source of fibre was

significantly more protective

than others, and non-food

supplement sources of fibre

were not investigated.


1. I Kong Joakim af Judas tredje Regeringsaar drog Kong Nebukadnezar af Babel til

Jerusalem og belejrede det.

3 Kongen bød derpaa sin Overhofmester Asjpenaz at tage nogle Israeliter, dels af

kongelig Slægt, dels af adelig Byrd

6 Iblandt dem var Judæerne Daniel, Hananja, Misjael og Azarja

8. Men Daniel satte sig for, at han ikke vilde gøre sig uren med Kongens Mad eller

den Vin Kongen drak; derfor bad han Overhofmesteren om at blive fri for at gøre sig

uren dermed.

9. Og Gud lod Daniel finde Yndest og Velvilje hos Overhofmesteren;

10 men Overhofmesteren sagde til ham: "Jeg frygter for, at min Herre Kongen, som

har tildelt eder Mad og Drikke, skal finde, at I ser ringere ud end de andre unge

Mænd paa eders Alder, og at I saaledes skal bringe Skyld over mit Hoved hos

Kongen.”

11. Saa sagde Daniel til den Opsynsmand, som Overhofmesteren havde sat over

Daniel, Hananja, Misjael og Azarja:

12. "Prøv engang dine Trælle i ti Dage og lad os faa Grøntsager at spise og Vand at

drikke!

13. Sammenlign saa vort Udseende med de unge Mænds, som spiser Kongens

Mad; saa kan du gøre med dine Trælle, efter hvad du ser.”

14. Han føjede dem da heri og prøvede det med dem i ti Dage.

15. Og da de ti Dage var omme, saa de bedre ud og var ved bedre Huld end alle de

unge Mænd, som spiste Kongens Mad.16 Saa lod Opsynsmanden deres Mad og

Vinen, de skulde drikke, bringe bort og gav dem Grøntsager i Stedet.

Daniels bog 1, Gl. Testamente, Bibelen

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