Chemical Carcinogensis Flashcards

1
Q

What is cancer

A

A disease in which cells of the body divide and proliferate in an uncontrolled manner
Associated with a loss of normal cell cycle control
Genetic mutation is a required event

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2
Q

Paracelcus

A

Describes wasting disease of arsenic miners in Austria

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3
Q

Bernadino Ramazzini

A

Systematic analysis of diseases associated with different occupations
Able to link occupations with disorders (cancers)

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4
Q

Percival Pott

A

Links occupational exposure with increased incidence of scrotal cancer in English chimney sweeps

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5
Q

Ludwig Rehn

A

Links occupational exposure with increases risk of bladder tumors in dye factory workers

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6
Q

Yamagiwa Katsusaburo

A

Direct demonstration of tumor development in rabbits after exposure to coal tar
First experiments that were designed to test the linkage between compounds and disease

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7
Q

Kennaway and Hieger

A

Identify benzo[a]pyrene as the major chemical carcinogen present in coal tar

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8
Q

Carcinogen

A

Any substance or agent that increases tumor incidence

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9
Q

3 differences between carcinogen and drugs

A

The biological effect is…
Persistent
Cumulative
Delayed

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10
Q

4 ways carcinogens and other drugs are similar

A

Exhibit clear dose-response relationships
Undergo metabolism
Response varies with species, sex, age
Interact with co-administered substances

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11
Q

2 things that determine where a drug acts

A

Root of exposure

Unique property of the tissue

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12
Q

2 main groups of chemical carcinogens

A
Polycyclic aromatic hydrocarbons (need metabolism to become carcinogenic)
Alkylating agents (smaller, can cause cancer without activating)
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13
Q

Genotoxic Carcinogens

A

Cause damage to DNA (induces genetic damage)

Can cause DNA adducts, chromosome breakage, chromosome fusion and chromosome deletion

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14
Q

Non-Genotoxic carcinogens

A

Generally act to promote the development of cancers
Results in altered signal transduction
Work by causing inflammation, immunosuppression, oxygen radicals, receptor activation
Increase the proliferation of both normal and initiated cells, but initiated cells have an exaggerated growth response

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15
Q

4 steps in the multi-stage model of carcinogenesis

A

Initiation
Promotion
Conversion
Progression

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16
Q

Initiation

A

Genetic damage cause by an exposure to a genotoxic chemical carcinogen is a required event
Faulty repair of this damage leads to a change in gene structure (mutation)
Results in increased/decreased levels of gene expression or protein products with altered function

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17
Q

DNA adducts

A

DNA addition products

Where the carcinogen covalently binds to DNA

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18
Q

Promotion

A

Mutations in genes that control cell growth increase the rate of proliferation or initiated cell (clonal expansion)
Expansion of initiated cells to form a preneoplastic lesion

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19
Q

Conversion

A

Transformation from preneoplastic state to malignant state (tumour cell)
Associated with additional genetic change and clonal expansion of tumour cell
Facilitated by genotoxic and non-genotoxic chemicals

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20
Q

Progression

A

Progression of a malignant tumor to a more aggressive state
Associated with additional genetic change and expansion of tumor
Invasion beyond the primary tumor site is common
Genotoxic and non-genotoxic agents facilitate this process

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21
Q

What is a primary defence against the accumulation of toxic chemicals within the body?

A

Liver metabolism

22
Q

Goal of liver metabolism

A

Conversion of lipophilic substances to more water soluble metabolites that are more readily eliminated in urine and bile

23
Q

Phase 1 metabolism

A
Predominant liver metabolism pathway
Usually precedes Phase 2
Creation or unmasking of small polar or reactive functional groups
Most common outcome is deactivation
Occasionally bioactivation occurs
24
Q

Phase 2 metabolism

A

Addition of large polar groups to exposed functional groups
Produces more water soluble metabolites
Most common outcome is detoxification
Compounds are rarely bioactivated this way

25
Direct carcinogens
Those that are inherently reactive and can modify DNA without metabolic bioactivation
26
Indirect carcinogens
Bioactivation is required
27
3 stages for an indirect carcinogen to become activated
Procarcinogen Ultimate carcinogen Proximate carcinogen
28
Procarcinogen
Parent compound from which the ultimate carcinogen is derived
29
Ultimate carcinogen
The reactive metabolite which covalently modifies DNA (DNA adducts)
30
Proximate carcinogen
An intermediate metabolite between the pro- and ultimate carcinogen
31
What base does Benzo[a]Pyrene bind to?
Guanine
32
Where can the methyl carboninum ion bind?
O6 or N7 of guanosine
33
3 types of repair of DNA-Carcinogen Adducts
Nucleotide exicison Base excision O6-alkylguanine transferase
34
Nucleotide excision
Elicited by bulky adducts (Benzo[a]Pyrene) | Large stretch of DNA surrounding the adduct is removed (10-12 bp) and replaced
35
Base excision
Elicited by small DNA adducts (alkylating agents) | Removal and replacement of a single modified base or a very short stretch of DNA surrounding the adduct
36
O6-alkylguanine transferase
Specifically removed alkyl groups from the O6-position of modified guanosine bases (ex: methylcarbonium ion) No DNA is removed or replaced Just takes the methyl group off
37
2 general classes of mutations you can get from faulty DNA repair
Substitution | Frameshift
38
Substitution reactions
A base is removed and replaced by a different one Single amino acid substitution Short protein (stop codon)
39
Frameshift mutations
Damaged base is removed, and either nothing is replaced or 2 bases are inserted Shifts the reading frame of that sequence - everything downstream is effected Multiple amino acid substitutions Short protein (stop codon)
40
2 classes of genes implicated in the onset of cancer
Proto-oncogenes | Tumour suppressor genes
41
Proto-oncogenes
Normal cellular genes that control cell growth, specialization, and death Almost all encode signal transduction proteins Activated into an oncogene by genetic change
42
2 types of mutations and their results via proto-oncogenes
1. Regulatory mutations (overexpression of gene and increased amount/activity of product, expression of gene at inappropriate time/context, expression of gene in an inappropriate cell type) 2. Structural mutations (expression of a gene product with altered function/activity)
43
Ras proteins
Large family of membrane-bound G proteins | Exert a powerful proliferative influence in many cell types
44
Ras and Human cancers
Activation is common in cancer Most mutations occur in the 12th or 61st codons Amino acid substitution
45
Why is Ras mutated at the two specific codons? (3)
The mutatuons have a tangible functional outcome Get reduced or absent GTPase activity, persistent activity in the absence of growth factor stimulation, and growth advantage to cells possessing the mutation
46
Tumour Suppressor Genes
Normal cellular genes that limit tissue growth and contribute to the destruction of cells with damaged genomes Almost all TSGs encode signal transduction proteins Deactivation occurs through genetic change
47
2 types of mutations and their results via TSGs
1. Regulatory mutations (reduced/absent expression of gene and levels of gene product) 2. Structural mutations (expression of a gene product with reduced/absent function/activity)
48
p53 TSG
Most well studied TSG | Fully functional p53 can overcome the effects of one or more activated oncogenes
49
p53 mutations
Point mutations resulting in amino acid substitutions or short proteins are extremely common in cancer Chemical carcinogens frequently cause mutations at codon 249 Result in protein with reduced or absent function
50
Function effect of mutations in p53 at codon 249 (4)
Reduced or absent protein activity (deactivation) Removes a key negative control on cell growth Growth advantage to cells possessing mutation Allows cells with damaged genomes to proliferate