PHYSICAL CARCINOGENS
1.RADIATION
2.NONRADIATION AGENTS
RADIATION
CARCINOGENESIS
1.ULTRAVIOLET LIGHT
2.IONISING RADIATION
1.ULTRAVIOLET LIGHT
MAIN SOURCE OF UV LIGHT IS
SUNLIGHT
OTHERS ARE UV LAMPS AND
WELDER’S ARCS
UV LIGHT PENETRATES ONLY FEW
MILLIMETRES OF THE SKIN
MELANIN PIGMENT PROTECTS
CAUSE VARIOUS FORMS OF SKIN
CANCERS
1.SQUAMOUS CELL CARCINOMA
2.BASAL CELL CARCINOMA
3.MALIGNANT MELANOMA
WHITE RACE
ASTRALIA
NEW ZEALAND AND THOSE
LIVING CLOSE TO THE
EQUATOR WHO RECEIVE MORE
SUNLIGHT
FARMERS AND OUTDOOR
WORKERS DUE TO THE EFFECT
OF ACTINIC LIGHT RADIATION
MECHANISM OF ACTION OF
UV LIGHT
DNA DAMAGE –MUTATION
NORMALLY DAMAGED DNA
GETS REPAIRED
CERTAIN RECESSIVE
HEREDITARY DISEASES
CHARACTERISED BY A
DEFECT IN DNA REPAIR
MECHANISM AND
ASSOCIATED WITH
INCREASE RISK OF CANCER
1. XERODERMA PIGMENTOSUM
SKIN CANCERS AT EARLY AGE
2.ATAXIA TELANGIECTASIA –
LEUKAEMIA
3. BLOOMS SYNDROMEPREDISPOSED TO ALL TYPES
CANCERS
4.FANCONI’S ANAEMIA WITH
INCREASED RISK TO DEVELOP
CANCER
MUTATION OF
PROTO-ONCOGENE RAS GENE AND
ANTI-ONCOGENE
TP53
2.IONISING RADIATION LIKE
a. X – RAYS
b. β – RAYS
c.GAMA RAYS
d.RADIOACTIVE ISOTOPES
e.PROTONS
f.NEUTRONS
THE RISK INCREASES WITH HIGHER
DOSAGE
X RAY WORKERS,RADIOTHERAPISTSKIN CANCERS
WATCH WORKERS ENGAGED IN
PAINTING THE DIALS WITH LUMINOUS
RADIUM
- OSTEOSARCOMA
MINERS WORKING WITH RADIOACTIVE
ELEMENTS
JAPANESE ATOM BOMB
SURVIVERS OF THE TWIN CITIES
OF HIROSHIMA AND NAGASAKI
AFTER WORLD WAR 2
CHERNOBYL NUCLEAR
POWER LEAKAGE-USSR(1985)
DAMAGE TO DNA DIRECTLY
OR BY FORMATION OF HIGHLY
REACTIVE FREE RADICALS
WHICH BRING ABOUT DNA
DAMAGE
NONRADIATION PHYSICAL
CARCINOGENS
MECHANICAL INJURY LIKE
STONES IN THE GALL
BLADDER,URINARY TRACT
HEALED SCARS,ASBESTOSIS
IMLANTS OF INERT MATERIALS
SUCH AS PLASTIC,GLASS IN
PROSTHESIS
VIRAL CARCINOGENESIS
ASSOCIATION WAS FIRST
OBSERVED BY ITALIAN
PHYSICIAN SANARELLI IN
1889
ONCOGENIC VIRUSES ARE
TRANSMITTED BY ONE OF 3
ROUTES
1.VERTICAL TRANSMISSIONGENETICALLY TRANSMITTED
2. HORIZONTAL TRANSMISSION
DIRECT CONTACT LIKE
CONTAGIOUS DISEASES
3.BY INOCULATION
1.DNA ONCOGENIC VIRUSES
2.RNA ONCOGENIC VIRUSES
DNA ONCOGENIC VIRUSES
5 GROUPS
1.PAPOVA VIRUSES
2.HERPES VIRUSES
3.ADENO VIRUSES
4.POX VIRUSES
5 HEPADNA VIRUSES
1.PAPOVAVIRUSES
A. PAPILLOMA VIRUSES
ABOUT 70 TYPES HAVE
BEEN IDENTIFIED
HIGH RISK HPV-16,18-CAUSE
INVASIVE SQUAMOUS CELL
CARCINOMA OF
CERVIX,ANUS,PERIANAL
REGION,VULVA,PENIS AND ORAL
CAVITY
LOW RISK HPV-1,2,4 AND 7
CAUSE SQUAMOUS CELL
PAPILLOMAS,
HPV 6 AND 11
CAUSE GENITAL WARTS
B.
SV 40 VIRUS A PAPOVA
VIRUS
?MESOTHELIOMA OF PLEURA
IN HUMAN BEINGS
2 . HERPES VIRUSES
A . EPSTEIN-BARR VIRUS(EBV)
a.BURKTT’S LYMPHOMA
( A B CELL LYMPHOMA)
FIRST NOTICED IN AFRICAN
CHILDREN BY BURKITT IN 1958.
90% BURKITT ‘S LYMPHOMA
TUMOUR CELLS HAVE EBV DNA
HIGH ANTIBODY TITERS.
OCCURS IN
IMMUNOSUPRESSION CASES
AS IN
MALARIA AND HIV.
b. ANAPLASTIC
NASOPHARYNGEAL
CARCINOMA-SOUTH EAST
ASIA
CHINA, ESKIMOS
100% CASES CARRY EBV DNA
IN TUMOUR CELLS.
HIGH TITERS OF ANTIBODY TO
EBV ANTIGENS
B . HUMAN HERPES VIRUS 8
(HHS 8) OR KAPOSI’S SARCOMA
ASSOCIATED HERPES VIRUS
(KSHS)
A VASCULAR NEOPLASM
COMMON IN AIDS PATIENTS
HHS8 VIRUS ALSO CAUSE B
CELL LYMPHOMA
. ADENOVIRUSES
NOT IN HUMAN BEINGS
3
4. POXVIRUS-SQUAMOUS CELL
PAPILLOMA
5.HEPADNAVIRUS
HBV BELONGS TO THIS
FAMILY
CAUSE HEPATOCELLULAR
CARCINOMA
CONTINUED HEPATOCYTE
DESTRUCTION
FOLLOWED BY PROLIFERATION
WHICH MAKES THEM VULNERABLE
TO THE ACTION OF AFLATOXIN
FROM ASPERGILLOUS FLAVUS
MUTATION-HCC
HCV – 50% CASES OF HCC
RNA ONCOGENIC VIRUS
RETROVIRUSES HAVING ENZYME
REVERSE TRANSCRIPTASE(RT)
3 SUB-GROUPS
1.ACUTE TRANSFORMING
VIRUSES
2 . SLOW TRANSFORMING VIRUSES
3.HUMAN T CELL LYMPHOTROPIC
VIRUSES(HTLV).
RNA VIRUSES HAVE 3 GENES
gag,pol,env genes
ACUTE TRANSFORMING
VIRUSES
TRANSFORM ALL THE INFECTED
CELLS
INTO MALIGNANT CELLS RAPIDLY.
THEY ARE DEFECTIVE VIRUSES
WHERE v-onc HAS SUBSTITUTED
gag,pol AND env AND THESE
DEFECTIVE VIRUSES CANNOT
REPLICATE BY THEMSELVES
UNLESS THE HOST CELL
IS INFECTED BY ANOTHER
HELPER VIRUS.
NOT FOUND TO BE
ONCOGENIC TO HUMANS.
2.SLOW TRANSFORMING
VIRUSES
MOUSE MAMMARY TUMOUR
VIRUS(BITTNER MILK FACTOR)
INSERTIONAL MUTAGENESISNEOPLASTIC
TRANSFORMATION
NOT ONCOGENIC TO HUMANS
3.HUMAN T CELL LYMPHOTROPIC
VIRUSES(HTLV)
ONLY RETROVIRUS IMPLICATED IN
HUMAN CANCER
1.HTLV 1- ADULT T CELL LEUKKAEMIA
LYMPHOMA SYNDROME
2.HTLV II –T CELL VARIANT OF HAIRY
CELL LEUKAEMIA
3. HTLV III (HTLV-III is an
outdated term for HIV-1
4. HTLV IV
IMMUNOSUPPRESSION PLAYS A
SUPPORTIVE ROLE IN NEOPLASTIC
TRANSFORMATION
NO v-onc gene MEDIATION
NO INSERTIONAL MUTAGENESIS
HTLV I - HAS tat gene IN
ADDITION TO gag,pol,env
genes
tat gene STIMULATES
NEOPLASTIC CELL
PROLIFERATION OF T
CELLS.
FIRST POLYCLONAL THEN
MONOCLONAL
PROLIFERATION LEUKAEMIA
LYMPHOMA
HTLV II - TRANSFORMATION
BY PROMOTER INSERTIONONCOGENESIS BY
ONCOGENES AND GROWTH
FACTORS
MODE OF DNA VIRAL
ONCOGENESIS
a . INFECTION –REPLICATIONCYTOLYSIS-RELEASE OF VIRUSES
b . INTEGRATION –VIRAL DNA
INTEGRATES INTO HOST DNANEOPLASTIC TRANSFORMATION
MODE OF RNA VIRAL
ONCOGENESIS
RETROVIRUS CONTAIN 2 IDENTICAL
RNA STRANDS
AND ENZYME REVERSE
TRANSCRIPTASE
RT ACTS AS A RNA DEPENDENT
DNA SYNTHETASE
ACT AS TEMPLATE TO
SYNTHESISE A
SINGLE STRAND OF MATCHING
VIRAL DNA.
SINGLE STRAND OF VIRAL DNA
IS THEN COPIED BY DNA
DEPENDENT DNA
POLYMERASE TO FORM
ANOTHER STRAND OF
COMPLIMENTARY DNA
THIS RESULTS IN DOUBLE
STRANDED VIRAL DNA
FORMATION OR
PROVIRUS FORMATION
PROVIRAL DNA GETS
INTEGRATED INTO HOST CELL
GENOME - NEOPLASM
SUMMARY OF VIRUSES AND HUMAN
CANCER
I.BENIGN TUMOURS
a.HUMAN PAPILLOMA VIRUS -HUMAN
WARTS
b.POXVIRUS - MOLLUSCUM
CONTAGIOSUM
MALIGNANT TUMOURS
1.BURKITT’S LYMPHOMA
EPSTEIN BARR VIRUS
2.NASOPHARYNGEAL
CARCINOMA-EPSTEIN BARR
VIRUS
3.HEPATOCELLULAR CARCI
NOMAHEPATITIS B AND C VIRUS
4.CERVICAL CARCINOMA –
HIGH RISK HUMAN PAPILLOMA
VIRUS-HPV 16 AND 18
5. KAPOSI’S SARCOMA –
HUMAN
HERPES VIRUS TYPE 8 (HHV8)
6. B CELL LYMPHOMA- (HHV8)
7. ADULT T CELL LEUKAEMIA AND
LYMPHOMA – HTLV I
8 .T CELL VARIANT OF HAIRY CELL
LEUKAEMIA – HTLV II
CHEMICAL CARCINOGENS
SIR PERCIVAL POTT IN 1775
OBSERVED HIGH INCIDENCE OF
CARCINOMA SCROTUM IN CHIMNEY
SWEEPS IN LONDON –
OCCUPATIONAL CANCER FROM
SOOT.
CHEMICAL CARCINOGENS
REPEATED PAINTING OF SKIN
WITH COAL TAR INDUCED
CANCER JAPANESE WORKERS
YAMAGIWA AND ICHIKAWA IN
1914
CHEMICAL CARCINOGENS
SINCE THEN A LARGE LIST
OF CHEMICAL CARCINOGENS
HAVE BEEN IDENTIFIED
STAGES OF CHEMICAL
CARCINOGENESIS
INDUCTION OF CANCER INFLUENCED
BY FACTORS LIKE
1.DOSE OF CARCINOGENIC
CHEMICAL
2.MODE OF ADMINISTRATION
3.INDIVIDUAL SUSCEPTIBILITY
4.PREDISPOSING FACTORS
CHEMICAL CARCINOGENESIS
CELLULAR TRANSFORMATION BY
CHEMICAL CARCINOGENS IS A
PROGRESSIVE PROCESS INVOLVING
2 DISTINCT SEQUENTIAL STAGES
1.INITIATION
2.PROMOTION
CHEMICAL CARCINOGENESIS
BASIC PATHOGENETIC
MECHANISM OF
CARCINOGENESIS IS MUTATION
IN PROTO-ONCOGENES AND
ANTI-ONCOGENES
INITIATION OF
CARCINOGENESIS
FIRST STAGE - INDUCED BY
INITIATOR CHEMICAL
CARCINOGENS.
CHANGE SO INDUCED IS SUDDEN
IRREVERSIBLE AND PERMANENT
INITIATOR CHEMICAL
CARCINOGENS
GROUPED INTO 2 CATEGORIES
1. DIRECT ACTING CARCINOGENS
INDUCE CELLULAR
TRANSFORMATION WITHOUT
UNDERGOING ANY PRIOR METABOLIC
ACTIVATION
EXAMPLES –ALKYLATING
AGENTS,ACYLATING AGENTS
INITIATOR CHEMICAL
CARCINOGENS –
INDIRECT ACTING
EXAMPLE - POLYCYCLIC AROMATIC
HYDROCARBONS,
AROMATIC AMINES,AZO DYES
NATURALLY OCCURING PRODUCTS
AND OTHERS
STEPS INVOLVED IN TRANSFORMING THE
TARGET CELL INTO INITIATED CELL.
A. METABOLIC ACTIVATION
B. REACTIVE ELECTROPHILS
C. TARGET MOLECULES
D. INITIATED CELL
INITIATOR CHEMICAL
CARCINOGENS
2.INDIRECT ACTING CARCINOGENS OR
PROCARCINOGENS –
REQUIRE METABOLIC
CONVERSION WITHIN THE BODY
TO BECOME ULTIMATE
CARCINOGENS
A .METABOLIC ACTIVATION
ACTIVATION OCCURS IN THE
LIVER
BY THE MONO-OXYGENASES
OF THE CYTOCHROME P450
SYSTEM IN THE ENDOPLASMIC
RETICULUM
PROCARCINOGENS
IN SOME CIRCUMSTANCES
PROCARCINOGENS MAY BE
DETOXIFIED AND RENDERED
INACTIVE METABOLICALLY
PROCARCINOGENS
POTENCY OF CHEMICAL
CARCINOGENS DEPENDS ON
FOLLOWING FACTORS
1.BALANCE BETWEEN ACTIVATION
AND INACTIVATION OF THE
CARCINOGENIC CHEMICAL
PROCARCINOGENS
2.GENES THAT CODE FOR P450
DEPENDENT ENZYMES INVOLVED
IN METABOLIC ACTIVATION
B.REACTIVE ELECTROPHILES-
INDIRECT ACTING CHEMICAL
CARCINOGENS BECOME ELECTRON
DEFICIENT (ELECTROPHILIC)AFTER
METABOLIC ACTIVATION
B.REACTIVE ELECTROPHILES
UNLIKE DIRECT ACTING CHEMICAL
CARCINOGENS
WHICH ARE INTRINSICALLY
ELECTROPHILIC
B.REACTIVE ELECTROPHILES
REACTIVE ELECTROPHILES OF
CHEMICAL CARCINOGENS BIND TO
ELECTRON RICH PORTION OF CELL
MOLECULES SUCH AS DNA,RNA AND
OTHER PROTEINS
C.TARGET MOLECULES
THE PRIMARY TARGET OF
ELECTROPHILES IS
DNA,PRODUCING MUTAGENESIS
C.TARGET MOLECULES
MUTATION MAY EITHER LEAD
TO THE INITIATED CELL OR
REPAIR OF THE MUTATION MAY OCCUR
C.TARGET MOLECULES
ANY GENE MAY BE TARGET
MOLECULE IN THE DNA
THE MOST FREQUENTLY
AFFECTED ONCOGENE IS RAS
AND ANTI-ONCOGENE TP 53.
THE INITIATED CELL
THE UNREPAIRED DAMAGE
PRODUCED IN THE DNA OF
THE CELL BECOMES
PERMANENT AND
IRREVERSIBLE
THE INITIATED CELL
ONLY IF THE ALTERED CELL
UNDERGOES AT LEAST ONE CYCLE
OF PROLIFERATION.
STIMULUS FOR PROLIFERATION
MAY COME FROM REGENERATION OF
SURVIVING CELLS,
VIRAL INFECTIONS , HORMONES etc
THE INITIATED CELL
THE INITIATED CELL BECOME
VULNERABLE TO THE ACTION OF
PROMOTERS OF CARCINOGENESIS
TUMOUR PROMOTERS ACT BY
FURTHER CLONAL
PROLIFERATION AND EXPANSION OF
INITIATED(MUTATED) CELLS
CLASSIFICATION CHEMICAL
CARCINOGENS IN HUMANS
1.DIRECT ACTING CARCINOGENS
A. ALKYLATING AGENTS
a .ANTICANCER DRUGS
(CYCLOPHOSPHOMIDE,
CHLORAMBUCIL,BUSULFAN,
MELPHALAN)
b. β PROPIOLACTONE
c .EPOXIDES
1.DIRECT ACTING CARCINOGENS
B. ACYLATING AGENTS –
ACETYL IMIDAZOLE
DIMETHYL CARBAMYL CHLORIDE
DIRECT ACTING CHEMICAL CARCINOGENS
CAUSE LYMPHOMAS AND LEUKAEMIAS
INDIRECT ACTING CARCINOGENSPROCARCINOGENS
A. POLYCYCLIC, AROMATIC
HYDROCARBONS –CANCER OF
LUNG,SKIN,ORAL CAVITY SARCOMAS.
(TOBACCO ,SMOKE, SOOT,MINERAL
OIL, SMOKED ANIMAL
FOODS,INDUSTRIAL AND
ATMOSPHERIC POLLUTANTS)-
INDIRECT ACTING CARCINOGENSPROCARCINOGENS
ANTHRACENES,
BENZAPYRENE,
METHYLCHOLANTHRENE
INDIRECT ACTING
CARCINOGENS
B. AROMATIC AMINES AND AZO DYES
β NAPHTHYLAMINE,BENZIDINE BLADDER CARCINOMA,
AZO DYES (BUTTER
YELLOW,SCARLET RED etc)HEPATOCELLULAR CARCINOMA
INDIRECT ACTING
CARCINOGENS
C.NATURALLY OCCURING PRODUCTSCAUSE HEPATOCELLULAR CARCINOMA
AFLATOXIN B1
ACTINOMYCIN D
MITOMYCIN C
BETEL NUTS - MOST PAAN CONTAINS
ARECA NUTS AS A FILLING - A SUBSTANCE
KNOWN TO CAUSE ORAL CANCER
AFLATOXINS
• AFLATOXINS ARE NATURALLY OCCURRING
MYCOTOXINS THAT ARE PRODUCED BY MANY
SPECIES OF ASPERGILLUS, A FUNGUS, THE MOST
NOTABLE ONES BEING ASPERGILLUS FLAVUS
AND ASPERGILLUS PARASITICUS. AFLATOXINS
ARE TOXIC AND AMONG THE MOST
CARCINOGENIC SUBSTANCES KNOWN AFTER
ENTERING THE BODY, AFLATOXINS MAY BE
METABOLIZED BY THE LIVER TO A REACTIVE
EPOXIDE OR HYDROXYLATED TO BECOME THE
LESS HARMFUL AFLATOXIN M.
ACTINOMYCIN D.
THE ACTINOMYCINS ARE A CLASS OF
POLYPEPTIDE ANTIBIOTICS ISOLATED FROM SOIL
BACTERIA OF THE GENUS STREPTOMYCES, OF
WHICH THE MOST SIGNIFICANT IS ACTINOMYCIN
D. ACTINOMYCIN-D IS A CHEMOTHERAPY DRUG
USED TO TREAT WILMS' TUMOR,
RHABDOMYOSARCOMA, GERM CELL TUMORS
AND OTHER CANCERS
MITOMYCIN C
ANTI-TUMOR ANTIBIOTIC THAT BINDS
COVALENTLY TO DNA.
ANTINEOPLASTIC ANTIBIOTIC
ISOLATED FROM THE BACTERIUM
STREPTOMYCES CAESPITOSUS
INDIRECT ACTING
CARCINOGENS
D. MISCELLANEOUS
a.NITROSAMINES AND NITROSAMIDES
CAUSE
GASTRIC CARCINOMA
b.VENYL CHLORIDE MONOMER CAUSE
HAEMANGIOSARCOMA OF LIVER- VINYL
CHLORIDE, FROM WHICH PVC IS
MANUFACTURED, IS A CARCINOGEN
INDIRECT ACTING
CARCINOGENS
ASBESTOS - BRONCHOGENIC
CARCINOMA,MESOTHELIOMA
ARSENICAL COMPOUND – BASAL CELL
CARCINOMA
METALS ( NICKEL,LEAD,
COBALT,CHROMIUM etC) – LUNG CANCER
INDIRECT ACTING
CARCINOGENS
INSECTISIDECIDES
FUNGICIDES,SACCHARIN AND
CYCLOMATES- CANCER IN
EXPERIMENTAL ANIMALS
PROMOTION OF
CARCINOGENESIS
PROMOTERS HAVE NO CARCINOGENIC
POTENTIAL
THEY ONLY PROMOTE THE PROLIFERATION OF
INITIATED CELL
PHENOLS,HORMONES,DIETARY FAT
( CARCINOMA COLON )
PROMOTION OF
CARCINOGENESIS
ARTIFICIAL SWEETENERS AND
DRUGS (PHENOBARBITAL),PHORBOL
ESTERS(PHORBOL ESTERS ARE
TUMOR-PROMOTING COMPOUNDS
ORIGINALLY DETECTED IN OIL
PREPARED FROM SEEDS OF CROTON
TIGLIUM)
PROMOTION OF
CARCINOGENESIS
DO NOT PRODUCE DAMAGE TO
DNA,SO NOT A MUTAGENIC.
ACT BY THE APPLICATION OR
ADMINISTRATION AFTER EXPOSURE
TO INITIATOR FOR SUFFICIENT TIME
AND SUFFITIENT DOSE.
TEST FOR
MUTAGENICITY(AMES’ TEST)
THE TEST EVALUATES THE ABILITY OF A
CHEMICAL TO INDUCE MUTATION IN THE
MUTANT STRAIN OF SALMONELLA
TYPHIMURIUM THAT
CAN NOT SYNTHESISE HISTIDINE.
SUCH STRAINS ARE INCUBATED WITH THE
POTENTIAL CARCINOGEN,
TEST FOR
MUTAGENICITY(AMES’ TEST)
TO WHICH LIVER HOMOGENATE IS
ADDED TO SUPPLY ENZYMES
REQUIRED TO CONVERT
PROCARCINOGEN TO ULTIMATE
CARCINOGEN.
TEST FOR
MUTAGENICITY(AMES’ TEST)
IF THE CHEMICAL IS MUTAGENIC,IT
WILL INDUCE MUTATION –TO
PRODUCE HISTIDINE AND ALLOWS
GROWTH OF THE BACTERIA.
NO METABOLIC ACTIVATION DIRECT ACTING CARCINOGEN
METABOLIC ACTIVATION
PROCARCINOGEN
TARGET CELL
REACTIVE ELECTROPHILS
TARGET MOLECULES(CHIEFLY DNA)
PERMANENT DNA DAMAGE
CLONAL PROLIFERATION OF INITIATED CELL
MALIGNANT TUMOUR