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Pharmacology II > Chemical Carcinogensis > Flashcards

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
Q

Direct carcinogens

A

Those that are inherently reactive and can modify DNA without metabolic bioactivation

26
Q

Indirect carcinogens

A

Bioactivation is required

27
Q

3 stages for an indirect carcinogen to become activated

A

Procarcinogen
Ultimate carcinogen
Proximate carcinogen

28
Q

Procarcinogen

A

Parent compound from which the ultimate carcinogen is derived

29
Q

Ultimate carcinogen

A

The reactive metabolite which covalently modifies DNA (DNA adducts)

30
Q

Proximate carcinogen

A

An intermediate metabolite between the pro- and ultimate carcinogen

31
Q

What base does Benzo[a]Pyrene bind to?

A

Guanine

32
Q

Where can the methyl carboninum ion bind?

A

O6 or N7 of guanosine

33
Q

3 types of repair of DNA-Carcinogen Adducts

A

Nucleotide exicison
Base excision
O6-alkylguanine transferase

34
Q

Nucleotide excision

A

Elicited by bulky adducts (Benzo[a]Pyrene)

Large stretch of DNA surrounding the adduct is removed (10-12 bp) and replaced

35
Q

Base excision

A

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
Q

O6-alkylguanine transferase

A

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
Q

2 general classes of mutations you can get from faulty DNA repair

A

Substitution

Frameshift

38
Q

Substitution reactions

A

A base is removed and replaced by a different one
Single amino acid substitution
Short protein (stop codon)

39
Q

Frameshift mutations

A

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
Q

2 classes of genes implicated in the onset of cancer

A

Proto-oncogenes

Tumour suppressor genes

41
Q

Proto-oncogenes

A

Normal cellular genes that control cell growth, specialization, and death
Almost all encode signal transduction proteins
Activated into an oncogene by genetic change

42
Q

2 types of mutations and their results via proto-oncogenes

A
  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
Q

Ras proteins

A

Large family of membrane-bound G proteins

Exert a powerful proliferative influence in many cell types

44
Q

Ras and Human cancers

A

Activation is common in cancer
Most mutations occur in the 12th or 61st codons
Amino acid substitution

45
Q

Why is Ras mutated at the two specific codons? (3)

A

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
Q

Tumour Suppressor Genes

A

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
Q

2 types of mutations and their results via TSGs

A
  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
Q

p53 TSG

A

Most well studied TSG

Fully functional p53 can overcome the effects of one or more activated oncogenes

49
Q

p53 mutations

A

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
Q

Function effect of mutations in p53 at codon 249 (4)

A

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

Pharmacology II (24 decks)

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