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Fibrosarcoma Fibroma

Liposarcoma Lipoma

Chondrosarcoma Chondroma

Osteogenic sarcoma

Osteoma

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Synovial sarcoma

Mesothelioma

Invasive meningioma Meningioma

Leukemias

Lymphomas

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Rhabdomyosarcoma Rhabdomyoma

Squamous cell or epidermoid

carcinoma Squamous cell papilloma

Basal cell carcinoma )(

Adenocarcinoma Adenoma

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Cystadenocarcinoma Cystadenoma

Bronchogenic carcinoma Bronchial adenoma

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cell carcinoma (transitional) Transitional cell papilloma ) (

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TABLE 7-3 -- Occupational Cancers

Agents or Groups of

Agents

Human Cancer Site

for Which

Reasonable Evidence

Is Available Typical Use or Occurrence

papers, and floor tiles

Benzene Leukemia, Hodgkin

lymphoma

Principal component of light oil.

Although use as solvent is

discouraged, many applications exist

in printing and lithography, paint,

rubber, dry cleaning, adhesives and

coatings, and detergents. Formerly

widely used as solvent and fumigant

Beryllium and

beryllium compounds

Lung Missile fuel and space vehicles.

Hardener for lightweight metal

alloys, particularly in aerospace

applications and nuclear reactors

Cadmium and

cadmium compounds

Prostate Uses include yellow pigments and

phosphors. Found in solders. Used

in batteries and as alloy and in

mental platings and coatings

Chromium

compounds

Lung Component of metal alloys, paints,

pigments, and preservatives

Ethylene oxide Leukemia Ripening agent for fruits and nuts.

Used in rocket propellant and

chemical synthesis, in fumigants for

foodstuffs and textiles, and in

sterilants for hospital equipment

Nickel compounds Nose, lung Nickel plating. Component of

ferrous alloys, ceramics, and

batteries. Byproduct of stainless

steel arc welding

Radon and its decay

products

Lung From decay of minerals containing

uranium. Can be serious hazard in

quarries and underground mines

Vinyl chloride Angiosarcoma, liver Refrigerant. Monomer for vinyl

polymers. Adhesive for plastics.

Formerly inert aerosol propellant in

pressurized containers

Modified from Stellman JM, Stellman SD: Cancer and workplace. CA Cancer J Clin

46:70, 1996.

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TABLE 7-6 -- Inherited Predisposition to Cancer

Inherited Cancer Syndromes (Autosomal Dominant)

Gene Inherited Predisposition

RB Retinoblastoma

p53 Li-Fraumeni syndrome (various tumors)

p16INK4A Melanoma

APC Familial adenomatous polyposis/colon cancer

NF1, NF2 Neurofibromatosis 1 and 2

BRCA1, BRCA2 Breast and ovarian tumors

MEN1, RET Multiple endocrine neoplasia 1 and 2

MSH2, MLH1, MSH6 Hereditary nonpolyposis colon cancer

PATCH Nevoid basal cell carcinoma syndrome

Familial Cancers

Familial clustering of cases, but role of inherited predisposition not clear for each

individual

Breast cancer

Ovarian cancer

Pancreatic cancer

Inherited Autosomal Recessive Syndromes of Defective DNA Repair

Xeroderma pigmentosum

Ataxia-telangiectasia

Bloom syndrome

Fanconi anemia

, ulcerative colitis ,Helicobacter pylori gastritis ,

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A nilcyC, E nilcyC"), F2E,"-, srotcaF noitpircsnarT 72p - 12p: srotibihnI piK/piC -. " 1G -

( ?!). , FRA41p - A4KNI61p: srotibihnI FRA/A4KNI -( ?!) " , 2MDM " 35p -. 35p , AND-

. FRA41p "

4

, BR/1PD/F2E - BR. , BR " 03-7 " , esalytecaeD enotsiH "

, " esalytecaeD enotsiH - 4KDC-D nilcyC" BR . F2E). 2KDC-E nilcyC " BR( F2E

noitacilpeR AND - A snilcyC - E snilcyC .1G

292'

7-7

)sesaniK tnednepeD-nilcyC( KDC" BR , D nilcyC 4KDC

.1G . , S/1G -, 1G - E nilcyC 2KDC

.M/2G, S- A nilcyC .M/2G B nilcyC 1KDC

romuT - 12p. KDC-nilcyC " 72p ,12p :ylimaF piK/piC

. rotcaF htworG gnimrofsnarT srosserppuS htworG - 72p. 35p rosserppuS ,A4KNI61p :ylimaF FRA/4KNI

FRA41p. BR 4KDC-D nilcyC A4KNI61p

. 2MDM" 35p FRA41p tniopkcehC

, , rosserppuS romuT 35p " 12p.

35p. XAB - S/1G 35P . 2MDM

.M/2G detatuM aisatceignaleT aixatA )MTA(

- AND " M/2G S/1G 35p .

, esatahpsohP 52cdC 35p - . , , 1KDC-B nilcyC

. AND-, 2ACRB - 1ACRB

5

, 75p - 72p ,12p : piK/piC - 12p . sKDC snilcyC

35p . rosserpuS romuT , 35p

, ., FRA41p - a4KNI61p FRA2/a4KNI1 -

- D nilcyC a4KNI61P. srosserppuS romuT - , " BR 4KDC-D nilcyC 4KDC

" a4KNI61P. , , 1G ), FRA91p ( FRA41p a4KNI - ( ). -

a4KNI - (?) FRA41p. 35p ).secneuqes gnidoc-eneg ezilitu ot yaw "lacimonoce" na rof gnidivorp (

a4KNI61p , : FRA41p a4KNI61p .35p FRA41p -, 4KDC-D nilcyC

")stniopkcehC ("

' '. , . M/2G - S/1G -:

S/1G -' , , - ' S- AND-, AND-. AND-

-. AND . S/1G, . , - AND

, AND- , AND.

. AND- M/2G -

. . 2G - M/2G . "

. ), srosneS( AND ,

AND) . srecudsnarT langiS ( DAR .

. esaniK KHC - ) detatuM aisatceignaleT aixatA( MTA S/1G - . . 12p, 35p "

. 35p - M/2G .

, .

.

:

, .

. " .

1 .)?evitanretlA( 4 esaniK fo rotibihnI A4KNI

2 .emarF gnidaeR evitanretlA FRA

6

392' , snietorpocnO

. snietorpocnO, . srotcaF htworG -

, snietorpocnO - . , :

, . rotcaF htworG .1 noitcudsnarT langiS, .2

.) " sregnesseM dnoceS, ( .3

. noitcudsnarT langiS .AND .4 . , .5

- ,

langiS edacsaC - . . , srotcaF htworG - noitcudsnarT

.

snietorpocnO -,

. , " sesurivorteR gnimrofsnarT etucA "" ""

- . 9891- .

) secneuqeS gnimrofsnarT euqinU ( .-) cno-v (

- cno-v , . , , , " AND

, . AND- . ,

-v - " , . , cno-v amocraS naimiS -, SEF-v emocraS enileF - cno

, , SIS SEF -. SIS-v ".-v"-

. ANR , , .

. - .- AND larivorP - "

" , larivorP lanoitresnI -). cno cno-c (

, - -. , sisenegatuM .

, - - , , "

AND -. : - AND noitcefsnarT AND ? "

AND ). refsnarT eneG detaideM-AND(

, stsalborbiF) detcefsnarT(

AND : .

7

.

scno-v -. SAR-

. )K( netsriK - )H( yevraH -

- , . 02 - .

, srotpeceR ro sdnagiL rotcaF htworG - - "

). 13-7 ( srotcaF noitpircsnarT, noitcudsnarT langiS

" snietorpocnO

snietorpocnO). , , 8-7 ( .

) . scno-c (-,

-) 2? snietorpocnO -) , 1 : ?

srotcaF htworG -

"

devireD-teletalP( FGDP- niahC- -, SIS . samocrasoetsO - samotycortsA -), , rotcaF htworG

, FGDP- . , . ,

. ,

) noitcudsnarT langiS( SAR

gnimrofsnarT -FGT, " ,

rotcaF htworG lamredipE FGE - . rotcaF htworG -FGT. rotpeceR FGE - "

. srotpeceR FGE samotycortsA

8

492'

- . 13-7 . AND, ,

htworG tsalborbiF( sFGF, SIS- , FGFB , . , 2-TNI - 1-TSH), rotcaF

htworG etycotapeH. setyconaleM -, samonaleM -, sFGF - , samonicraC ralucilloF - TEM-c rotcaF

-nisebmob samonicrac gnul llec llamS . (?) . ekil

,

, " . , " .

. - ,

).3( esaniK enisoryT " esaniK - ,

enisoryT - , . noitcudsnarT langiS - noitalyrohpsohP

.. ,

eneG " , ,

, esaniK enisoryT, TER . stnemegnarraeR

9

- Gene Rearrangements .- RET Glial Cell

Line-Derived Neurotrophic Factor ,

. RET - ,Parafollicular C

, , - Parathyroid .

RET Familial Medullary

Thyroid Carcinoma MEN 2A - MEN 2B (24 .)- MEN 2A ,

RET , - Medullary Thyroid

Carcinoma - Parathyroid .- MEN 2B ,

RET - Tyrosine Kinase

-Thyroid - Adrenal ,- Parathyroid.

'295

7-8 - ,

Category Protooncogene

Mode of

Activation Associated Human Tumor

Growth Factors

PDGF- chain SIS Overexpression Astrocytome

Osteosarcoma

Fibroblast growth factors HST-1 Overexpression Stomach cancer

INT-2 Amplification Bladder cancer

Breast cancer

Melanoma

TGF TGF Overexpression Astrocytomas

Hepatocellular carcinomas

HGF HGF Overexpression Thyroid cancer

Growth Factor Receptors

EGF-receptor family ERB-B1

(ECFR)

Overexpression Squamous cell carcinomas of lung, gliomas

ERB-B2 Amplification Breast and ovarian cancers

CSF-1 receptor FMS Point mutation Leukemia

Receptor for neurotrophic

factors

RET Point mutation Multiple endocrine neoplasia 2A and B,

familial medullary thyroid carcinomas

PDGF receptor PDGF-R Overexpression Gliomas

Receptor for stem cell

(steel) factor

KIT Point mutation Gastrointestinal stromal tumors and other soft

tissue tumors

Proteins Involved in

Signal Transduction

GTP-binding K-RAS Point mutation Colon, lung, and pancreatic tumors

H-RAS Point mutation Bladder and kidney tumors

N-RAS Point mutation Melanomas, hematologic malignancies

Nonreceptor tyrosine

kinase

ABL Translocation Chronic myeloid leukemia

Acute lymphoblastic leukemia

RAS signal transduction BRAF Point mutation Melanomas

WNT signal transduction -catenin Point mutation Hepatoblastomas, hepatocellular carcinoma

01

, - 8-7

enegocnootorP yrogetaC

fo edoM

romuT namuH detaicossA noitavitcA

noisserpxerevO

yrotalugeR raelcuN

snietorP

amohpmyl ttikruB noitacolsnarT CYM-C srotavitca lanoitpircsnarT

gnul fo amonicrac llec llams ,amotsalborueN noitacifilpmA CYM-N

gnul fo amonicrac llec llamS noitacifilpmA CYM-L

srotalugeR elcyC-lleC

amohpmyl llec eltnaM noitacolsnarT D NILCYC snilcyC

srecnac laegahpose dna tsaerB noitacifilpmA

recnac tsaerB noisserpxerevO E NILCYC

ro noitacifilpmA 4KDC esanik tnedneped-nilcyC

noitatum tniop

amocras ,amonalem ,amotsalboilG

), 71( gnurpshcsriH TER

- TER- . , citamoS -, dioryhT - samonicraC yralludeM. eniL mreG

.B2 NEM -, TER- stnemegnarraeR

" . ), rotcaF gnitalumitS-ynoloC 1( 1-FSC -, SMF-c

cityconomoleyM cinorhC). saimekeuL dioleyM( FGDP-, )9;21(t saimekueL

. FGDP -, STE

cidaropS - . . , TEM-c, samonicraC dioryhT yrallipaP

" . TEM-c , , noitacifilpmA eneG - ,

.

692' BRE . rotpeceR FGE -

, samonicraC lleC suomauqS - %08-) RFGE( FGE -, 1B %001-08-), 82( samotsalboilG , samotycortsA - %05-

. samonicraC -, , - , FGE- ), ueN / 2 REH( 2B BRE,

, , samonicraconedA namuH - %52- , 2B BRE - .

. 2B BRE . yparehT detegraT , ,

enisoryT - yparehT detegraT , TIK-c - . , TIK-c esaniK

enisoryT), rotcaF leetS( rotcaF lleC metS - , .esaniK

11

snietorP gnicudsnarT langiS

- snietorpocnO - . , noitcudsnarT langiS

(, " ) .

- . noitcudsnarT langiS - , eninauG PTG SAR- noitcudsnarT langiS - nietorpocnO

.snietorP G, : etahpsohpirT

SAR -

SAR . SAR - %02-51- . -

SAR. SAR- . SAR - esaPTG -,

. SARN - SARK ,SARH 16 95, 21 citaercnaP - %09 , . ,

%05, SAR- samonicracoignalohC - samonicraconedA dioleyM - samonicraconedA gnuL - %03- ,

, SARK -. , ( ) saimekueL. SARN - , SARH -

, . SAR -

" . sisenegotiM - SAR , FGE - " , SAR,

, SAR. 1-FSC - FGDP, . noitcudsnarT langiS ,

, igloG - muluciteR cimsalpodnE - " , .

). " etahpsohpiD enisonauG( PDG SAR, ). 23-7( PTG- PDG " SAR , -

PAM -. 1-FAR" esaniK PAM -, , SAR. sisenegotiM " sesaniK

, SAR- noitcudsnarT langiS -, , " ( ).PDG- PTG, esaPTG

), PTG" PDG( egnahcxE editoelcuN) 1 : ( SAR-

SAR- PTG- SAR-, sisylordyH PTG) 2( - SAR- . PDG- ,

SAR- PTG " PDG . snietorP gnisaeleR-editoelcuN eninauG"

esaPTG -. , snietorP retpadA " . snietorP gnitavitcA esaPTG sPAG " SAR

, 0001 esaPTG - SAR- sPAG. , noitcudsnarT langiS - PDG - PTG

sPAG- . SAR"" -, PAG SAR. SAR-

, PTG . , "" esaPTG esaPTG -. gnilangiS cinegotiM

21

, esaPTG), 1-FN( nimorbiforueN - " "" ). seneG rosserppuS romuT - (

) sesaniK PAM/FAR/SAR( edacsaC gnilangiS SAR -, SAR-

, SAR -, FARB - . , - - . %08- samonaleM - %06-

, samonaleM sesaniK PAM/FAR/SAR .

SAR, srotcaF htworG noitcudsnarT langiS - ,

S - 1G - . , " snilcyC - SAR. sKDC - snilcyC"

. 1-PA esaniK PAM -

, SAR - . . SAR-itnA

esarefsnarT lysenraF , " SAR ), SAR- (

), sesaniK PAM dna FAR(, gnilangiS SAR - . syawhtaP SAR, rotpeceR FGE - SAR

792'

( SAR. , SAR 23-7

esaniK APM - FAR SAR. PTG SAR), PDG, PTG SAR- .

. lysenraF " (?) SAR - , .

31

, . , - , SAR- SAR-

. gnilangiS

sesaniK enisoryT - langiS sesaniK enisoryT, 3

, , LBA-c . noitcudsnarT .

, " esaniK enisoryT LBA , , saimekueL citsalbohpmyL etucA - aimekueL dioleyM -.

9 LBA-c - ( RCB -), 33-7( 22

enisoryT - LBA-c, ). , esaniK enisoryT, , LBA-RCB -. , esaniK

aimekueL dioleyM - , . LBA-RCB - , ""etalyseM binitamI

. .esaniK enisoryT

srotcaF noitpircsnarT srotalugeR lanoitpircsnarT noitcudsnarT langiS

).seneG rednopseR( . noitacilpeR AND - ,

. AND AND . sniamodoemoH -, " " reppiZ enicueL, xileH-pooL-xileH

AND . , ,

.

, NUJ SOF, BYM, CYM , CYM . ,

, , .

41

892'

suonegoleyM cinorhC - amohpmyL ttikruB - 33-7

.aimekueL

CYM - ylraE etaidemmI -, , CYM

- ( , seneG esnopseR, . CYM ANRm -). 3

, CYM- , CYM -.

. AND. XAM

51

, . , 2D nilcyC - esalyxobraceD enihtinrO, , , : CYM -

. esanietorP ,

)?erutluc ni( , , CYM CYM ( ). CYM

, . CYM "

, , CYM

. CYM- , CYM .

CYM). 33-7( B, amohpmyL ttikruB - CYM-L - CYM-N '... , ,

) , .43-7( samotsalborueN -

sesaniK tnednepeD-nilcyC dna snilcyC

, sKDC - snilcyC .

D nilcyC . , sKDC - snilcyC , D nilcyC - . 4KDC

lleC eltnaM( samohpmyL - , - , , " ( 1D nilcyC -), samohpmyL

). E nilcyC. samotsalboilG - samocraS - 4KDC - ()

, .

rosserppuS romuT : -

etatS ydaetS " ). (

rosserppuS romuT) . sisenegonicraC(" seneG rosserppuS romuT). , "9-7( seneG

, . ( )

. rosserppuS romuT, " , seneG rosserppuS romuT - ,

. 000,02- 1, amotsalboniteR

61

992'

, CYM-N -. samotsalborueN - CYM-N - :43-7

suoenegomoh ,detargetni yllamosomorhC - setuniM elbuoD lamosomorhC artxE -, p2 .31 9,4, semosotuA. ( , ...) noiger gniniats

, %04- , samotsalboniteR - %06

- . ". tiH-owT : " nosdunK ,

, ") tiH tsriF , ("") tiH dnoceS , ("

) stih, , (- ( ). . ,

sisenegocnO -" tiH-owT " amotsalboniteR

romuT " nosdnuK - , seneG rosserppuS

: amotsalboniteR

, BR - amotsalboniteR noiteleD. , 41q31 .41q31

) stiH owT ( BR- ). , 53-7( amotsalboniteR -

-. BR - ( , (?) stsalboniteR

). , 31 , 41q31. : stsalboniteR - " BR

. BR- aniteR

71

amocrasoetsO amotsalboniteR BR-( ) . ,

amonicraC lleC llamS , amonicraconedA , , BR - . ,

, BR sesaniK tnednepeD-D nilcyC, a4KNI .

BR , .

BR- ( ). . BR -

BR , , BR-, ). HOL(

, .

., BR - - amotsalbotapeH, smliW 11

raelC eneG rosserppuS romuT) uadniL leppiH noV( LHV -. amocrasymodbahR HOL . samonicraC laneR lleC

. seneG rosserppuS romuT

, seneG rosserppuS romuT . , ,

. AND-, , noitcudsnarT langiS -. 9-7 seneG rosserppuS romuT

, seneG rosserppuS romuT ).sisenegonicraC(

BR- , BR- . eneG rosserppuS romuT - BR -

( ) . nietorpohpsohP, BR- BR . ,

).63-7 ( S/1G -

030'

smsalpoeN namuH ni devlovnI seneG rosserppuS romuT detceleS -- 9-7 ELBAT

ralullecbuS

noitcnuF eneG noitacoL

sromuT

htiw detaicossA

snoitatuM citamoS

sromuT

htiw detaicossA

detirehnI

snoitatuM

-FGT ecafrus lleC rotpecer

fo samonicraC noitibihni htworG

noloc

nwonknU

fo amonicraC noisehda lleC nirehdac-E

hcamots

cirtsag lailimaF

recnac

fo tcepsa rennI

enarbmem amsalp

SAR fo noitibihnI 1-FN

langis

dna noitcudsnart

elcyc-llec 12p fo

sisotamorbiforueN samotsalborueN

dna 1 epyt

samocras

18

TABLE 7-9 -- Selected Tumor Suppressor Genes Involved in Human Neoplasms

Subcellular

Location Gene Function

Tumors

Associated with

Somatic Mutations

Tumors

Associated with

Inherited

Mutations

inhibitor

Cytoskeleton NF-2 Cytoskeletal

stability

Schwannomas and

meningiomas

Neurofibromatosis

type 2, acoustic

schwannomas and

meningiomas

Cytosol APC/-catenin

Inhibition of

signal

transduction

Carcinomas of

stomach, colon,

pancreas;

melanoma

Familial

adenomatous

polyposis coli/colon

cancer

PTEN PI-3 kinase signal

transduction

Endometrial and

prostate cancers

Unknown

SMAD 2

and SMAD

4

TGF- signal transduction

Colon, pancreas

tumors

Unknown

Nucleus RB Regulation of cell

cycle

Retinoblastoma;

osteosarcoma

carcinomas of

breast, colon, lung

Retinoblastomas,

osteosarcoma

p53 Cell-cycle arrest

and apoptosis in

response to DNA

damage

Most human

cancers

Li-Fraumeni

syndrome; multiple

carcinomas and

sarcomas

WT-1 Nuclear

transcription

Wilms tumor Wilms tumor

p16

(INK4a)

Regulation of cell

cycle by

inhibition of

cyclin-dependent

kinases

Pancreatic, breast,

and esophageal

cancers

Malignant

melanoma

BRCA-1

and BRCA-

2

DNA repair Unknown Carcinomas of

female breast and

ovary; carcinomas

of male breast

KLF6 Transcription

factor

Prostate Unknown

S . ,

RB ( - Gene Deletions )E2F , ,-S ,

91

, BR- BR- . . F2E -", tekcoP BR "

stsalboniteR BR- eniL-mreG

llamS, samotsalboilG -. , samocrasoetsO BR . , samonicraC lleC

BR- eniL-mreG , : BR ? samotsalboniteR ?

, BR aniteR- . , BR-,

samotsalboniteR BR- .

), BR (

, BR BR: , . , BR

D nilcyC. , BR " 4KDC D nilcyC .

. , sKDC - snilcyC " KDC

-) BR, 4KDC, D nilcyC, a4KNI61p ( BR- BR- . ,

.

103-203' BR - , ,

):63-7( , , " -FGT . -FGT

).KDC( 72p

, AND, , BR . , BR , , "

naimiS " . - AIE sesurivonedA -: T egraL surivamyloP 04 suriV

. BR -, 7E )VPH( surivamollipaP namuH, VPH. F2E tekcoP BR -

, 61 VPH , , F2E, BR- . ,

, .

" 35P eneG rosserppuS romuT - ).63-7 92-7( 12p -, KDC-

02

41q31 BR-. amotsalboniteR: 53-7 . BR . , laniteR -

, , - . aniteR - BR - . aniteR " BR-

12

. 4KDC-D-nilcyC - . BR :63-7 (). -, ( ) BR) 2KDC-E nilcyC (

( piK/piC -, 35p, -FGT. S/1G BR . , , BR ) FRA91p - a4KNI61p( a4KNI -) , 75p, 12p

. , BR- , . "

: 35p, 1.31p71 35p -

. %05-. , , , , 35p

35p . , ). , eniL mreG - (

, BR -. 35p " tiH "

, inemuarF-iL . , , . 05 52

-iL, BR , aimekueL, , samocraS . inemuarF

, . , inemuarF-iL

(?).

" - 35p - 35p - " " 35p -, " .

. . , (?) AND 35p -

35p %08" . 35p . AND-

) . noitatuM esnessiM, (AND, BR - " . 35p ,

, VPH 6E -, AND , . 35p -

22

" 35p, 2MDM 35p , " saimekueL - %05- %33- 2MDM -.

. 35p

35p - - " , AND 35p. AND-

, aixopyH , - . AND-

nietorP tnednepeD-AND. , 35p -, AND- . AND-) detatuM aisatcegnaleT-aixatA( MTA - esaniK

noitpircsnarT -, AND-, , 35p 35p). 73-7 ( rotcaF

" 1G - 35p . . 12p -: KDC - 35p-

. , AND- , BR -. , nitiuqibU) 02- ( 35p

" 35P . ), egamaD AND dna tserrA htworG( 54DDAG

35p -, 2MDM 35p , , AND -. AND). 92-7 , " (

, , 35p - , AND- " , ( , )

. 2-LCB, , : XAB. XAB . XAB,

303'

- . , AND 35p,

" AND 35p. AND, " AND 35p " AND. AND 1G

" ". 35p , ). 73-7 ( , , AND-, 35p

.

. AND- 35p -" (?) , ,

35p . AND samonicracotareT ralucitseT .

( ). , saimekueL citsalbohpmyL, 35p - ,

.

32

" , AND- " 35p - . 35p :73-7 , 54DDAG -, 12p-, KDC-, " AND- 1G -

XAB-, AND- , AND. , AND AND, 35p -. 35p

.

35p - . 35p

35p sesurivonedA -. 2MDM . FRA41p

( 37p -. enegitluM - 35p, 35p -

- %06 63p1), , 35p - . . 35p

42

" 35p. , 36p - .

403'

ninetaC-/CPA

romuT noitalugeR-nwoD . 1-FN - CPA - . seneG rosserppuS

) 2.11q71( 1-FN -) 12q5( CPA eniL mreG .

, CPA -

, sisopylop suotamoneda lailimaf ( )suotamonedA(). , , 71

. CPA -, seneG rosserppuS romuT -

. " samonedA , . . CPA - samonedA

%08-07, , , CPA - samonedA

. CPA

rosserppuS romuT - CPA CPA). 83-7( suponeX -" alihposorD "

, , . TNW TNW . TNW

) , ZRF( delzzirF . CPA - ninetaC-

-ninetaC - CPA. -ninetaC CPA- A: 7-83 - ninetaC-), TNW -. ( TNW-

B . -sninetaC - -ninetaC. CPA -

52

ninetaC-, , TNW " , FCR - , ninetaC- . -

-sninetaC . -ninetaC - , CPA C . ) , setavitcaoC (

.TNW -

. ninetaC- noitalugeR-nwoD CPA- , . " ninetaC- CPA, TNW

CPA-. ninetaC-, ninetaC- - , ninetaC- -

TNW CPA . , , FCT ninetaC- , . ninetaC-

. 1D nilcyC, CYM-c " ) " sisenegromuT ( ninetaC-/CPA

- -. ninetaC- - CPA . CPA " ninetaC

sninetaC- - , ninetaC-/CPA - . samonicraC ralullecotapeH - %02- samotsalbotapeH - %05-

, nirehdaC-E - ninetaC-, 3 .-

503'

. ninetaC-nirehdaC - . ninetaC-

srosserppuS romuT -

. , seneG rosserppuS romuT snoiteleD lamosomorhC -

seneG rosserppuS romuT -. HOL ):9-7 (

. samonaleM - %02- FRA/a4KNI - citaercnaP - %05- a4KNI61p - ,

, samonicraC lleC suomauqS - samonicraconedA a4KNI61p. samonicracoignalohC - ,

4KDC-D nilcyC a4KNI61p, , . BR

" , ( ).

%07- 2 epyT -FGT - -FGT - , CCPNH

), AND etilletasorciM (- -, 4DAMS. CCPNH

%05-, -FGT " noitcudsnarT langiS, , 2DAMS -,

citaercnaP nI deteleD( 4CPD - 4DAMS. , ).recnaC

1-FN - 1-FN - . samorbiforueN

- samorbiforueN -). 5( 1 epyT sisotamorbiforueN 1 epyT samorbiforueN. samocrasorbiforueN

, 1-FN -, nimorbiforueN. evreN citpO - samoilG

62

SAR -. SAR - noitcudsnarT langiS nimorbiforueN(). PTG) -( PDG

. - SAR , gnitavitcA-esaPTG . SAR, 1-FN

2-FN - eniL-mreG 2-FN - 2-FN, 5. 2 epyT sisotamorbiforueN

. , evreN citsuocA - - samonnawhcS. samomydnepE - samoignineM - 2-FN

, nilreM, 2-FN - ) niseoM & nixidaR ,nirzE( MRE-), 31( 1.4

, 44DC - , nitcA -, , nilreM . 2-FN -). 3 ( -

- nilreM , .-

p3) uadniL leppiH noV( LHV - eniL mreG LHV samotsalboignameH, samotycomorhcehP ,

( ) . aniteR -, LHV-). 02 ( LHV-

1-FIH. sesagiL nitiuqibU - . FGDP - FGEV), , 1 rotcaF noitpircsnarT elbicudnI aixopyH(

1-FIH noitanitiuqibU LHV . cinegoignA

) NETP( 01, P dna esatahpsohneTnis NETP noiteleD, 32q01

NETP. samotsalboilG - " NETP , .

. piK/piC 72p , , .NETP

, romuT smliW, 31p11, 1-TW - 1-TW , romuT smliW - .

1-TW - . 1-TW - .

. , emyhcneseM - 1-TW -

, 51p11, 2-TW, smliW . ).01( namedeiW-htiwkceB

-). 3 ( snietorpocylG snirehdaC , snirehdaC

snirehdaC-E . enil-mreG , , , , .

-E , nirehdaC-E - . nirehdaC

nirehdaC-E -. , nirehdaC-E - nirehdaC-E). , q61( snirehdaC -, , sninetaC-. ninetaC-

.

72

603'

- -FGT , 6FLK 6FLK 6FLK . %07- 6FLK . -FGT

, 12p piK/piC " . 12p. " 35p -

eneG rosserppuS romuT HCTP )HCTP( dehctaP -. gohegdeH), DEHCTAP(

-. FGDP - -FGT , DEHCTAP/gohegdeH lleC lasaB dioveN, nilroG HCTP

- HCTP). 62 ( amonicraC. amonicraC lleC lasaB %05 %02

. VU- "

" ,

. , " , " seneG rosserppuS romuT

. .

2-LCB. 1 .

samohpmyL lleC-B - %58, , 2-LCB -

- 2-LCB -, )12q:23q()81;41(t ) 41 ( ( 23q41 12q81

ttikruB - CYM - 2-LCB ). amohpmyL

2-LCB, 1. 2-LCB - ( setycohpmyL B. ,

worraM - yhtaponedahpmyL -), [?] 2-LCB samohpmyL -. noitartlifnI

samohpmyL -, , 2-LCB .

2-LCB. samohpmyL lleC-B 2-LCB ,

. . CYM - 35p :

35p. , 2-LCB " 35p - , " 35p. XAB -

, XAB, -, 2MDM- a4KNI - XAB .

, 2-LCB - -, DIB. 35p " , 2-LCB - CYM . 35p "

, 2-LCB- CYM : .

. , , , , . TKA/esaniK 3-IP

TKA". , " NETP eneG rosserppuS romuT - TKA -

. .

82

AND - , AND-" . "

, SOR- , , -, .

. AND- AND- , AND-

. , AND- , .

" AND . AND

AND . . ,

, AND . .

, . , AND. seneG rosserppuS romuT -

, .riapeR noitanibmoceR - riapeR noisicxE editoelcuN, riapeR hctamsiM

recnaC sisopylopnoN . CCPNH " riapeR hctamsiM

- muceC - " , AND hctamsiM ). 71( noloC lamixorP

. CCPNH noloC lamixorP -,

703' , , ,

, , CPA - eniL mreG . . CCPNH-

) " ". , hctamsiM (-, AND

- , T A, T G, -, , sredaerfoorP .

AND-. seneG rosserppuS romuT- " ), epytonehP rorrE noitacilpeR (

. AND- -

). 5 ( 6-1 - . -

, , - .

. riapeR hctamsiM --mreG , CCPNH 4, AND-

rof tnuocca hcaE( %03 -) 12p3( 1HLM -) 61p2( 2HSM - eniL 2SMP, SMP -. )sesac fo %03 yletamixorppa

, hctamsiM AND. hctamsiM - AND" . , tiH dnoceS" -

, seneG rosserppuS romuT - , , seneG rosserppuS romuT .

, CCPNH 05- , (

.AND- )

92

- , %4-2 - CCPNH - . %51-

-, II epyT -FGT CCPNH . seneG rosserppuS romuT -, XAB, ninetaC- - FCT

-, -FGT -FGT -, . XAB

musotnemgiP amredoreX

, AND, musotnemgiP amredoreX . VU

. AND, " enidimiryP gnikniL-ssorC - VU , riapeR noisicxE editoelcuN REN - " AND-

, REN-. VU " . musotnemgiP amredoreX -

-" AND

inocnaF - moolB, aisatceignaleT-aixatA , -aixatA, (AND-, " aimenA

). aimenA inocnaF( AND- gnikniL-ssorC), moolB aisatceignaleT), aisatceignaleT-aixatA (, ,

). moolB) ( aimenA inocnaF ( . moolB

.-" AND), esacileH MLB( esacileH - 51

, " aisatceignaleT-aixatA ( " aixatA rallebereC -) mullebereC ( ejnikruP

, ) . , MTA- , .

., - AND- esaniK MTA

, 35p MTA . MTA esaniK - . , , MTA . 1G -

AND , 35p " %1- MTA-.

, . , " . AND-

.

2-ACRB - 1-ACRB

, 31-21q31, 2-ACRB -, 12q71, 1-ACRB, seneG rosserppuS romuT - ). 42 (

. 2-ACRB - 1-ACRB - , 1-ACRB - eniL-mreG

. - ( 2-ACRB - ,

. samonaleM) (?) 1-ACRB %08- 2-ACRB - 1-ACRB - . %02-01-

. %3- , ) LHV ,1-FN ,35p ,BR ( seneG rosserppuS romuT -,

ACRB ,

03

2-ACRB - 1-ACRB - . , ( ) .-

. 2-ACRB - 1-ACRB

.

803'

rotavitcA-oC negortsE - 1-ACRB - 2-ACRB - 1-ACRB ( ).

, - AND-, 15DAR -. AND -ACRB). 32 gniledomeR nitamorhC (

, S/1G 2-ACRB - 1, 2-ACRB - 1-ACRB. AND-

, .

, ,

). 93-7 ( - " - AND- 1-ACRB) AND- " esaniK nietorP( 2KEHC - MTA

aimenA inocnaF. AND-, 15DAR , 1-DCNAF - 2-ACRB - ,

. aimenA inocnaF -

13

) detatuM aisatceignaleT-aixatA( MTA. AND :93-7 , 1-ACRB 2KEHC - MTA, " . AND- -

noitanitiuqibU -) G ,F ,E ,C ,A( aimenA inocnaF . , 15DAR 2-ACRB . 1-ACRB 2D nietorP inocnaF

-" AND- 15DAR - 2-ACRB, 1-ACRB . -" AND . 15DAR .

. , :04-7

.

23

, aimenA inocnaF - ACRB-, -" AND "

. AND

. MTA-

esaremoleT: - ), , 1 (

). ecnecseneS evitacilpeR " " (- "" ,

), . seremoleT( , 35p - ,

). , 04-7 ( ) , " slleC mreG . (

, . esaremoleT

903' , .

, esaremoleT . esaremoleT

, esaremoleT - ?

. , esaremoleT - , . %09 - esaremoleT) " sisenegromuT ( esaremoleT

esaremoleT. , .

, , . ,

rof gniwolla, ( . ??) sllec gnidivid ni gninetrohs eremolet lacitirc

esaremoleT). 04-7 ( .

) sisenegoignA (

, sisnegoignA , .

, mm 2-1 -, mm 2-1 - . ,

. , .

, - "

, sisenegoignA. FGDP - rotcaF htworG ekiL-nilusnI ( ). , sisatsateM -

.

? sisenegoignA). 3 (

" " , . , sisenegoignA -

) . 14-7 ( . , , FGEV

33

. , , . yrcimiM cinegolucsaV , " "

"

) . ( . rotcaF htworG tsalborbiF cisaB FGFb - FGEV ,

" " ( ) . FGEV. 3 sisenegoignA FGEV - FGFb

, .

,

. , sisenegoignA". hctiwS cinegoignA"- .

hctiwS cinegoignA - ) epyt dliw ( 35p -. , sisenegoignA

. - 1-nidnopsobmorhT" sisenegoignA) rotcaF elbicudnI aixopyH( 1-FIH- FGEV

( ), 35p-. DGEV " 1-FIH, FGEV , 1-nidnopsobmorhT -

. ,

. - , . sisenegoignA "

" , , 1-nidnopsobmorhT , - -, . nitatsmuT - nitatsodnE, nitatsoignA ,

) nitatsoignA( negonimsalP sisenegoignA ).nitatsmuT ,nitatsodnE (

, sisenegoignA -

. sisenegoignA nitatsodnE. nitatsmuT - nitatsodnE - "

- FGEV - -. . 2R-FGEV noitcudsnarT langiS, 2R-FGEV

)sisatsateM (

. . , ,

. , ). 24-7 ( , .

903"

sisatsateM dna noisavnI

) . sisatsateM) (noisavnI (

. ,

,

). 24-7(

.

Figure 7-42 The metastatic cascade. Schematic illustration of the sequential steps involved in the

hematogenous spread of a tumor.

013"

,

. ?

) 34-7A (

.

). 34-7C (

" -

". ,

, ,

). 34-7D(

.

. )2( MCE ) 1( :

xirtaM ralullecartxE fo noisavnI

. MCE

: MCE 3

) eussit evitcennoc laititsretni (

, 24-7 , , . MCE

. MCE

"

.

.

Figure 7-43 Mechanisms of metastasis development within a primary tumor. A nonmetastatic primary

tumor is shown (light blue) on the left side of all diagrams. Four models are presented: A, Metastasis is

caused by rare variant clones that develop in the primary tumor; B, Metastasis is caused by the gene

expression pattern of most cells of the primary tumor, referred to as a metastatic signature; C, A

combination of A and B, in which metastatic variants appear in a tumor with a metastatic gene

signature; D, Metastasis development is greatly influenced by the tumor stroma, which may regulate

angiogenesis, local invasiveness and resistance to immune elimination, allowing cells of the primary

tumor, as in C, to become metastatic.

113"

):44-7( MCE

.

MCE

. ,

E , .

,

. , ,

. E

E .

). 83-7 , (

E , . E

, .

, . MCE

. ,

. , ,

.

.

Figure 7-44 AD, Schematic illustration of the sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced

adhesiveness, and cells then attach to the basement membrane via the laminin receptors and secrete

proteolytic enzymes, including type IV collagenase and plasminogen activator. Degradation of the

basement membrane and tumor cell migration follow.

213"

(

) , ,

( ). ,

. ,

.

MCE

, , .

. ,

.

). 44-7 , ( MCE

MCE

. MCE

( )

.

.

. : , ,

4 PMM2 PMM9). PMM (

PMM .

:

, , .

.

. PMM

PMM

PMM . ,

.

.

,

,

.

, , sPMM.

4 PMM2 PMM9 .

. FGEV

313"

4

.

. ,

, , MCE PMM

. ,

.

noitanimessiD ralucsaVsllec romuT fo gnimoH dna

,

. .

). 24-7 , (

. ,

,

. ( )

, T 44DC.

.

) seluneV lailetodnE hgiH( VEH 44DC

. ,

.

.

. ,

,

. :

,

.

.

. ,

. , 7RCC 4RCXC

,

.

stnatcarttaomehc .

.II ro I rotcaf htworg ekil-nilusnI .

. , ,

.

,

.

poleveD sisatsateM fo sciteneG raluceloMtnem

?

.

. ,

, NIRZE

.

.SSIK 1-IAK, 32MN

orciM lamortSsisenegonicraC dna tnemorivne

. , MCE

5-, FGEV 4

FG MCE . PMM-2

( ) , .

, . FGF-b, FGT, FGDP

,

. MCE

. , ,"

" tsalborbif detaicossa amonicrac, "

. ) , FAC(

FAC . ,

cinegiromut-non tub dezilatrommi

detaitnereffid ylroop,

.

. ,

.

.

413"

recnaC fo noitalugersyD-seneG detaicossA

( )

). (

/"erutangis"" eliforp citeneg" -

segnahC lamosomorhC

.

. ,

.

()

.

. ,

-2 (

, ). BR,CPA) (LBA, LCB

.

ttikruB CYM-c aimekuel dioleym cinorhc LBA

. )23-7 ( amohpmyl

.

). 01-7 (

:

.

.

) ttikruB (

, 842q 3 .

CYM

CYM. ,

. ,

23 q41 8 CYM

). 33-7( HgI

, CYM , . )23q;42q()41:8(t

. ,

. CYM

.

.

. CYM

, ,

1131q 1D nilcyC llec eltnaM.

. , 23q41 HgI

. 2-LCB, , )12q;23q()81;41(t

. , B

T

. , T

. CYM

aimekuel dioleym cinorhc ,

,

22 9. ,

) noiger retsulc tniop kaerb( RCB) 9 (LBA-c

). 33-7( 22

noitacolsnarT yb detavitcA senegocnO fo selpmaxE detceleS -- 01-7 ELBAT

seneG detceffA noitacolsnarT ycnangilaM

43q9 1bA )11q;43q()22;9( aimekuel dioleym cinorhC

11q22 rcb

12q4 4FA )32q;12q()11;4( )LLA dna LMA( saimekuel etucA

LLM 32q11

72q6 6FA )32q;72q()11;6(

LLM 32q11

42q8 cym-c )23q;42q()41;8( amohpmyl ttikruB

HgI 23q41

31q11 D nilcyC )23q;31q()41;11( amohpmyl llec eltnaM

HgI 23q41

noitacolsnarT yb detavitcA senegocnO fo selpmaxE detceleS -- 01-7 ELBAT

seneG detceffA noitacolsnarT ycnangilaM

HgI 23q41 )12q;23q()81;41( amohpmyl ralucilloF

12q81 2-lcb

citsalbohpmyl etuca llec-T

aimekuel

42q8 cym-c )11q;42q()41;8(

RCT- 11q41

42q01 11 xoH )11q;42q()41;01(

RCT- 11q41

42q11 1-lF )21q;42q()22;11( amocras gniwE

SWE 21q22

.snoitacolsnart elpitlum ni devlovni era seneg denilrednU

.aimekuel citsalbohpmyl etuca ,LLA ;aimekuel dioleym etuca ,LMA

513"

. LBA-RCB

. LBA-RCB

, .

DK 012, aimekuel dioleym cinorhc

LBA-RCB-. DK091

. , ,

, SAR ,

.. LBA -RCB). 3( sTATS esanik 3-IP

, .

LLM . ,

52 32q11) aimekuel diohpmyl,dioleyM(

) SWE( amocraS gniwE). 01-7 (

)21;42q()22;11(t 21q22

). 62 ( amocraS gniwE

, SWE .

SWE, romut gniwE .

. ytiliba gnimrofsnart STE, ILF 1

noitacifilpmA eneG

.. .

.

.. . ,

: .

erutcurts ekil emosomorhC

.)smd( setunim elbuod

.)sRSH( snoiger gniniats suoenegomoh

,

dnab-G, nrettap gnidnab lamron

CYM-N). 43-7(

2B BRE %03 %52 CYM-N . 2B BRE

%02 2B BRE. sRSH smd,

CYM-N dna CYM-L ,CYM-C .

. gnul eht fo recnac llec llams

( , , 1D NILCYC

).

segnahC citenegipE

... .

. -...., GpC

a4KNI61p , FRA41p .

( 1HLM LHV , 1ACRB ,

gnitnirpmi cimoneg' ) .

..

. ,

.

.

,

.

slleC recnaC fo seliforP raluceloM

.

). , 1-7 .. () (

). .. : 54-7 .. (

. seliforp ralucelom ro erutangis noisserpxe eneG

). 1-7 (

serutangis ralucelom

etuca). 32 1-32 (

erutangis ralucelom .. aimekuel citsalbohpmyl

.

sisenegonicraC petsitluM fo sisaB raluceloM

, .

syarraorciM .srecnaC namuH fo seliforP noisserpxE eneG .1-7 xoB

scimoetorP dna

. ,

.

ANDc ( , yarraorcim

) . -

() - '

". spihc eneg, "

000,02-'

) ANDc . (

. '

- . ANDc), seborp(

). ' , (

:

/

. gniretsulc lacihcrareih.

.

. ,

,

erutpac resal .

. noitcessidorcim

:

.1

.2

.3

.4

.5

:

.

.

) 1. : ( 07

) 3 ( 5 ) 2 (

.

, ,

.

scimonetorp-

, .

. - '

) . sgat ytiniffa gnidoc-epotosi( TACI ,

.

,

. , -

.

.

Figure 7-45 Schematic representation of the steps required for the analysis of global gene expression

by DNA microarray. RNA is extracted from tumor and normal tissue. cDNA synthesized from each

preparation is labeled with fluorescent dyes (in the example shown, normal tissue cDNA is labeled

with a green dye; tumor cDNA is labeled with a red dye). The array consists of a solid support in which

DNA fragments from many thousands of genes are spotted. The labeled cDNAs from tumor and

normal tissue are combined and hybridized to the genes contained in the array. Hybridization signals

are detected using a confocal laser scanner and downloaded to a computer for analysis (red squares,

expression of the gene is higher in tumor; green square, expression of the gene is higher in normal

tissue; black squares, no difference in the expression of the gene between tumor and normal tissue). In

the display, the horizontal rows correspond to each gene contained in the array; each ventrical row

corresponds to single samples.

.

, ,

.

). noitomorp( ) noitaitini( :

-

.

"

.

SAR . ,

CYM.

. -

.

.

.

.

, ,

.

: 64-7

CPA .1

SAR .2

) 4DAMS- 2DAMS( q81 .3

.II rotpeceR FGT- 35p .4

amonicrac-amoneda eht hguorht srecnac latceroloc fo noitulove eht rof ledom raluceloM )elbaliavA toN erugiF( 64-7 erugiF

eht rof gnimit eht ,sisenegiromut fo ssecorp eht ni etal srucco 35p fo ssol dna tneve ylrae na si noitatum CPA hguohtlA .ecneuqes morf detpadA( .detsil segnahc eht fo lla evah ton yam sromut laudividni taht osla etoN .snoitairav wohs yam segnahc rehto

,kroY weN .recnaC namuH fo sisaB citeneG ehT :WK relzniK ,B nietslegoV nI .sromut latceroloC :WK relzniK ,B nietslegoV

).385 .p ,2002 ,lliH-warGcM

, ? ,

CPA

FGE- 2-XOC .

, CPA.

. 35p

, CPA-

. .

seneG rekateraC dna repeeketaG

(") repeeketag .

.

) . , semordnys ytilibitpecsus recnac(

:

BR- D, 4KNI BR- .1

)BR- (

.35p 2MDH, FRA41p 35p- .2

rekaterac

. hctamsim AND. seneg

,

-. , 'repeeketag

, . rekaterac

, repeeketag rekaterac

. repeeketag

-

.

,1-FN ,CPA ,.g.e( seneg repeeketag eht fo noitatum yb detatini ycnangilam fo syawhtap eht fo noitartsulli citamehcS 74-7 erugiF

.)2-ACRB ,1-ACRB ,2HSMh ,.g.e( seneg rekaterac ro )BR

epytonehP rotatuM

. AND

" . epytonehp rotatum "

, ( )

.

.

ytienegoreteh dna noissergorp romuT

.

-( citsalpoenerp - ( )

."noissergorp romut") , .

. noissergorp romut

) ( , ,

.

, , , ,

, . ,

, . ,

- .

noissergorp romut . ,

, . "

) sllec demrofsnart( "" .

35p , .

). riaper AND ". (

,

" , .

. "

. ,

, , .

, (

)21-7 gif( )

.

aretnI ralulleC riehT dna stnegA cinegonicraCsnoitc

.

:

.1

ygrene tnaidar .2

. .3

.

isenegonicraC lacimehCs

81-. ttoP lavicreP riS -

.

citamora cilcycylop eht ( ".

) , , snobracordyh

.

.

sisenegonicraC lacimehC ni devlovni spetS

. .84-7

-noitaitini

. ,)rotaitini (

) 1 ( noitaitini) 3- 2(

" () , nitaitini

3" ".

. (

)

sllec detaitini - srotpmorp

). , 5. ( cinegiromutnon

srotaitini - ) )stnega gnitomorp

)4( .

, srotaitini - ,

"

). sllec detaitini - -6(

,sllec detaitini -

.

84-7

fo sesahp noitomorp dna noitaitini eht gnitartsnomed stnemirepxE 84-7 erugiF

ylkeew-eciwt ta detaeper retomorp fo noitacilppa :2 puorG .ecim ni sisenegonicrac

lareves rof deyaled retomorp fo noitacilppa :3 puorG .shtnom lareves rof slavretni

ylhtnom ta deilppa retomorp :6 puorG .ylkeew eciwt deilppa neht dna shtnom

.slavretni

noitomorp - noitaitini -

2 , , , .

)94-7 (

sisenegonicraC lacimehC fo noitaitinI

: 2- ). 7-11 (

. -sdnuopmoc gnitca tcerid. 1

oviv ni -snegonicracorp sdnuopmoc gnitca-tceridni. 2

.

evitcaer ylhgih - : tcerid -

( ) selihportcele

). hcir nortcele=cilihpoelcun (

".

, ", "

, sllec detaitini - .

" .

snegonicraC fo noitavitcA cilobateM

tcerid stnega gnitalyca dna gnitalykla gnitca

, -

). 94-7 . (

) . , noitacifixoted(

,

.

054-P - "

. )sesanegyxo onom tnedneped 054-p emorhcotyc yb dezilobatem(

.

, "

1A1PYC - 054-p . :

%01 . snobracordyh citamora cilcycylop

, " "

7 .

, esarefsnart S enoihtatulg .

. . snobracordyh citamora cilcycylop

, %05

.

. ,

.

snegonicraC lacimehC fo stegraT raluceloM

,

- , ",

.tseT semA - . slacimehc gnitaitini

%09-%07 . ,

.oviv ni ortiv ni .

. "

"

" noitaitini -". "

" " . "

. .

musotnemgip amredorex"

"

. VU

"

SAR - , , .

. "

"tnirpregnif" .

. 35P- .

) VBH( B

. 1B nixotalfa

. C B

- C:G noisrevsnart %09 35P,

,. 942 T:A

. " " 942

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7-49:

Figure 7-49 General schema of events in chemical carcinogenesis. Note that

promoters cause clonal expansion of the initiated cell, thus producing a preneoplastic

clone. Further proliferation induced by the promoter or other factors causes

accumulation of additional mutations and emergence of a malignant tumor.

7-11

TABLE 7-11 -- Major Chemical Carcinogens

Direct-Acting Carcinogens

Alkylating Agents

-Propiolactone

Dimethyl sulfate

Diepoxybutane

Anticancer drugs (cyclophosphamide, chlorambucil,

nitrosoureas, and others)

Acylating Agents

1-Acetyl-imidazole

Dimethylcarbamyl chloride

Procarcinogens That Require Metabolic Activation

Polycyclic and Heterocyclic Aromatic Hydrocarbons

Benz(a)anthracene

Benzo(a)pyrene

Dibenz(a,h)anthracene

3-Methylcholanthrene

7,12-Dimethylbenz(a)anthracene

Aromatic Amines, Amides, Azo Dyes

2-Naphthylamine (-naphthylamine)

Benzidine

2-Acetylaminofluorene

Dimethylaminoazobenzene (butter yellow)

Natural Plant and Microbial Products

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