Carcinogens By Dr Tajdar Husain Khan. What is a carcinogen? A carcinogen is any substance or agent that, because of the way it affects cell DNA, can.

Carcinogens

By Dr Tajdar Husain Khan

What is a carcinogen?

A carcinogen is any substance or agent that, because of the way it affects cell DNA, can cause cancer

Carcinogens may be chemical substances; physical agents, such as asbestos dust; or biological agents, such as certain viruses and bacteria

In the workplace, carcinogenic substances may be inhaled, absorbed through the skin or even ingested in some cases

A carcinogen can alter or damage a cell’s DNA…

Cancer is a multi-stage process, involving the creation and unchecked growth of abnormal cells

A carcinogens may be the initiator — the agent that alters or damages DNA, the basic coding system of cells

They may also be promoters — encouraging out-of-control cell growth

Many carcinogens are known

• Under a 1986 California law known as Proposition 65, the state maintains a list of substances shown scientifically to cause cancer

• There are 627 chemicals currently on that list

OVERVIEW

• Three Classes of Carcinogens– Chemical– Radiation– Viral

• Tumor Immunology– Tumor Antigens– Antitumor Effector Mechanisms– Immunosurveillance– Immunotherapy

CHEMICAL CARCINOGENS

• Natural and Synthetic Agents• Highly reactive electrophiles (electron

deficient)– React with RNA, DNA or cellular proteins– Direct –Acting– Indirect-Acting

CHEMICAL CARCINOGENS

Kumar et al. Basic Pathology 6th ed. Table 6-7

Direct Acting Agents

• Weak carcinogens• Require no chemical transformation– Chemotherapeutic drugs• Alkylating agents

– Cyclophosphamide, chlorambucil, nitrosoureas

• Second malignancy decades later

– Acylating agents• 1-Acetyl-imidazole, Dimethylcarbamyl chloride

Indirect Agents• Require metabolic conversion before they become active.

– Procarcinogen- initial chemical– Ultimate carcinogen: active end product

• Examples– Polycyclic hydrocarbons: fossil fuels, active epoxides bind DNA

• Benz[a]anthracene: skin cancer• Benzo[a]pyrene: cigarette smoke- lung cancer

Indirect Agents Continued

• Examples– Aromatic amines and azo dyes

• Converted in liver by P-450– Beta-naphthylamine: Bladder ca in rubber factories– Azo dyes: developed for food color

• Nitrosamines and amides– Formed endogenously in acid environment of stomach

» GI cancers?• Aflatoxin B

– Aspergillus in grains» Hepatocellular cancer

Mechanism of Action of Chemical Carcinogens

• Mutagenic– Ras mutations in rodents

• Promoter– Augmenting agents by themselves not carcinogenic

• Produce cell proliferation• Must follow mutagenic chemical “initiator”

– Tetra-decanoylphorbol-acetate (TPA)» Activate protein kinase C

• Patients at High risk– Genetic disorders i.e.. HNPCC

Radiation Carcinogenesis

• Types of radiation– Ultraviolet rays of sunlight

• Melanoma, Squamous cell carcinoma, basal cell carcinoma

– X-rays• Early developers: skin

cancer• ENT ca with irradiation:

thyroid cancer– Nuclear fission

• Survivors of nuclear bomb: leukemia

– Radionuclides• Miners: lung cancer Ionizing radiation: chromosome breakage,

translocations and point mutations

MECHANISMS OF VIRAL CARCINOGENESIS

• ONCOGENES– Carry oncogenes in viral DNA

• INSERTIONAL MUTAGENESIS– Altering structure and/or function of host

genome.

TUMOR VIRUSES

• RNA VIRUSES (RETROVIRUSES)• DNA VIRUSES• Important for both types of viruses is that the

infection not kill the cell

RNA TUMOR VIRUSES

• RETROVIRUSES– ONLY CANCER CAUSING RNA VIRUSES

• PROTOTYPE RETROVIRUS:– GAG (CORE PROTEINS)– POL (REVERSE TRANSCRIPTASE)– ENV (ENVELOPE PROTEINS)

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GENETIC MATERIAL• DNA– Primary function permanent storage of

information– Does not normally change– Mutations do occur

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MUTATIONS• Mutation– Heritable change in the genetic

material– Permanent structural change of

DNA• Alteration can be passed on to

daughter cells• Mutations in reproductive cells

can be passed to offspring

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MUTATIONS• Mutations– Provide allelic variation• Ultimate source of genetic variation• Foundation for evolutionary change

– Various phenotypic effects• Neutral• Harmful• Beneficial

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MUTATIONS• Mutations– Most mutations are neutral– More likely to be harmful than beneficial to the

individual• More likely to disrupt function

than improve function

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MUTATIONS• Mutations– Many inherited diseases result from mutated

genes– Diseases such as various cancers can be caused by

environmental agents known to cause DNA mutations• “Mutagens”

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TYPES OF MUTATIONS

• Types of mutations– Chromosome mutations• Changes in chromosome structure

– Genome mutations• Changes in chromosome number

– Single-gene mutations• Relatively small changes in DNA

structure• Occur within a particular gene• Focus of study in this chapter

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MUTATIONS• Point mutations– Change in a single base pair within the DNA– Two main types of point mutations• Base substitutions

– Transition– Transversion

• Small deletions or insertions

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MUTATIONS

• Two types of base substitutions– Transition

• Pyrimidine changed to another pyrimidine– e.g., C T

• Purine changed to another purine– e.g., A G

– Transversion• Purines and pyrimidines are

interchanged– e.g., A C

• More rare than transitions

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EFFECTS OF MUTATIONS

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MUTATION TYPES

• Genetic terms to describe mutations– Wild-type

• Relatively common genotype• Generally the most common allele

– Variant• Mutant allele altering an organism’s phenotype

– Forward mutation• Changes wild-type allele into something else

– Reverse mutation• “Reversion”• Restores wild-type allele

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MUTATION TYPES

• Genetic terms to describe mutations– Deleterious mutation

• Decreases an organism’s chance of survival

– Lethal mutation• Results in the death of an organism• Extreme example of a deleterious

mutation

– Conditional mutants• Affect the phenotype only under a

defined set of conditions• e.g., Temperature-sensitive (ts) mutants

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CHROMOSOME STRUCTURE• Altered chromosome structure can alter gene

expression– Inversions and translocations commonly have no

obvious phenotypic effects– Phenotypic effects sometimes occur• “Position effect”

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CHROMOSOME STRUCTURE

• Altered chromosome structure can alter gene expression and phenotype– Breakpoint may occur within a gene

• Expression of the gene is altered

– Breakpoint may occur near a gene• Expression is altered when moved to a new location• May be moved next to regulatory elements influencing the

expression of the relocated gene– i.e., Silencers or enhancers

• May reposition a gene from a euchromatic region to a highly condensed (heterochromatic) region– Expression may be turned off

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CHROMOSOME STRUCTURE• Altered chromosome structure

can alter gene expression and phenotype– An eye color gene relocated to a

heterochromatic region can display altered expression• Gene is sometimes inactivated• Variegated phenotype results

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SOMATIC VS. GERM-LINE

• The timing of mutations in multicellular organisms plays an important role– Mutations may occur in gametes or a fertilized egg– Mutations may occur later in life• Embryonic or adult stages

• Timing can affect – The severity of the genetic effect– The ability to be passed from parent to offspring

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SOMATIC VS. GERM-LINE• Animals possess germ-line and somatic cells– Germ-line cells• Cells giving rise to gametes

– Somatic cells• All cells of the body

excluding the germ-line cells– e.g., Muscle cells, nerve cells,

etc.

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SOMATIC VS. GERM-LINE• Germ-line cells– Germ-line mutations can occur in

gametes– Germ-line mutations can occur in a

precursor cell that produces gametes

– All cells in the resulting offspring will contain the mutation

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SOMATIC VS. GERM-LINE• Somatic cells– Somatic mutations in embryonic

cells can result in patches of tissues containing the mutation• Size of the patch depends on the

timing of the mutation• Individual is a genetic mosaic

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CAUSES OF MUTATIONS

• Two causes of mutations– Spontaneous mutations• Result from abnormalities in biological

processes• Underlying cause lies within the cell

– Induced mutations• Caused by environmental agents• Cause originates outside of the cell

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CAUSES OF MUTATIONS

• Causes of spontaneous mutations– Abnormalities in crossing over– Aberrant segregation of chromosomes during

meiosis– Mistakes by DNA polymerase during replication– Alteration of DNA by chemical products of normal

metabolic processes– Integration of transposable elements– Spontaneous changes in nucleotide structure

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CAUSES OF MUTATIONS• Induced mutations are caused by mutagens– Chemical substances or physical agents originating

outside of the cell– Enter the cell and then alter the DNA structure

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CAUSES OF MUTATIONS

•

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CAUSES OF MUTATIONS

• Spontaneous mutations are random events– Not purposeful– Mutations occur as a matter of chance• Some individuals possess beneficial mutations

– Better adapted to their environment– Increased chance of surviving and reproducing

• Natural selection results in differential reproductive success– The frequency of such alleles increases in the population

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CAUSES OF MUTATIONS• Mutation rate– Likelihood that a gene will be altered

by a new mutation– Expressed as the number of new

mutations in a given gene per generation• Generally 1/100,000 – 1/billion

– 10-5 – 10-9

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CAUSES OF MUTATIONS

• Mutation rate– Mutation rate is not a constant number• Can be increased by environmental

mutagens– Induced mutations can increase beyond

frequency of spontaneous mutations

• Mutation rates vary extensively between species– Even vary between strains of the

same species

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CAUSES OF MUTATIONS

• Mutation frequency– Number of mutant alleles of a given gene divided

by the number of alleles within a population– Timing of mutations influences mutation

frequency• Timing does not influence mutation rate

– Mutation frequency depends both on mutation rate and timing of mutations

– Natural selection and genetic drift can further increase mutation frequencies

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CAUSES OF MUTATIONS

• Spontaneous mutations: Depurination– Most common type of naturally occurring

chemical change– Reaction with water removes a purine (A or G)

from the DNA• “Apurinic site”

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CAUSES OF MUTATIONS

• Spontaneous mutations: Depurination– ~10,000 purines lost per 20 hours at 37oC in a

typical mammalian cell• Rate of loss increased by agents causing certain base

modification– e.g., Attachment of alkyl

(methyl, ethyl, etc.) groups

– Generally recognized by DNA repair enzymes• Mutation may result if

repair system fails

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CAUSES OF MUTATIONS• Spontaneous mutations: Deamination of

cytosines– Other bases are not readily deaminated– Removal of an amino group from the cytosine base

• Uracil is produced

– DNA repair enzymes generally remove this base• Uracil is recognized as an inappropriate base

– Mutation may result if repair system fails• Uracil hydrogen bonds with A, not G

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CAUSES OF MUTATIONS

• Spontaneous mutations: Deamination of cytosines– Methylation of cytosine occurs in many eukaryotic

species as well as prokaryotes– Removal of an amino group from the 5-methyl

cytosine produces thymine– DNA repair enzymes cannot determine which is

the incorrect base• Hot spots for mutations are produced

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CAUSES OF MUTATIONS

• Spontaneous mutations: Tautomeric shifts– Common, stable form of T and G is the keto form• Interconvert to an enol form at a low rate

– Common, stable form of A and C is the amino form• Interconvert to an imino form at a low rate

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CAUSES OF MUTATIONS

• Spontaneous mutations: Tautomeric shifts– Enol and imino forms do not conform to normal

base-pairing rules• AC and GT base pairs are formed

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CAUSES OF MUTATIONS

• Spontaneous mutations: Tautomeric shifts– Tautomeric shifts immediately prior to DNA

replication can cause mutations• Resulting mismatch

could be repaired• Mutation may result if

repair system fails

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CAUSES OF MUTATIONS

• Certain non-mutagenic chemicals can be altered to a mutagenically active form after ingestion– Cellular enzymes such as oxidases can activate

some mutagens• Certain foods contain chemicals acting as

antioxidants– Antioxidants may be able to counteract the effects

of mutagens and lower cancer rates