Chemical Carcinogensis Flashcards
What is cancer
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
Paracelcus
Describes wasting disease of arsenic miners in Austria
Bernadino Ramazzini
Systematic analysis of diseases associated with different occupations
Able to link occupations with disorders (cancers)
Percival Pott
Links occupational exposure with increased incidence of scrotal cancer in English chimney sweeps
Ludwig Rehn
Links occupational exposure with increases risk of bladder tumors in dye factory workers
Yamagiwa Katsusaburo
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
Kennaway and Hieger
Identify benzo[a]pyrene as the major chemical carcinogen present in coal tar
Carcinogen
Any substance or agent that increases tumor incidence
3 differences between carcinogen and drugs
The biological effect is…
Persistent
Cumulative
Delayed
4 ways carcinogens and other drugs are similar
Exhibit clear dose-response relationships
Undergo metabolism
Response varies with species, sex, age
Interact with co-administered substances
2 things that determine where a drug acts
Root of exposure
Unique property of the tissue
2 main groups of chemical carcinogens
Polycyclic aromatic hydrocarbons (need metabolism to become carcinogenic) Alkylating agents (smaller, can cause cancer without activating)
Genotoxic Carcinogens
Cause damage to DNA (induces genetic damage)
Can cause DNA adducts, chromosome breakage, chromosome fusion and chromosome deletion
Non-Genotoxic carcinogens
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
4 steps in the multi-stage model of carcinogenesis
Initiation
Promotion
Conversion
Progression
Initiation
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
DNA adducts
DNA addition products
Where the carcinogen covalently binds to DNA
Promotion
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
Conversion
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
Progression
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
What is a primary defence against the accumulation of toxic chemicals within the body?
Liver metabolism
Goal of liver metabolism
Conversion of lipophilic substances to more water soluble metabolites that are more readily eliminated in urine and bile
Phase 1 metabolism
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
Phase 2 metabolism
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
Direct carcinogens
Those that are inherently reactive and can modify DNA without metabolic bioactivation
Indirect carcinogens
Bioactivation is required
3 stages for an indirect carcinogen to become activated
Procarcinogen
Ultimate carcinogen
Proximate carcinogen
Procarcinogen
Parent compound from which the ultimate carcinogen is derived
Ultimate carcinogen
The reactive metabolite which covalently modifies DNA (DNA adducts)
Proximate carcinogen
An intermediate metabolite between the pro- and ultimate carcinogen
What base does Benzo[a]Pyrene bind to?
Guanine
Where can the methyl carboninum ion bind?
O6 or N7 of guanosine
3 types of repair of DNA-Carcinogen Adducts
Nucleotide exicison
Base excision
O6-alkylguanine transferase
Nucleotide excision
Elicited by bulky adducts (Benzo[a]Pyrene)
Large stretch of DNA surrounding the adduct is removed (10-12 bp) and replaced
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
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
2 general classes of mutations you can get from faulty DNA repair
Substitution
Frameshift
Substitution reactions
A base is removed and replaced by a different one
Single amino acid substitution
Short protein (stop codon)
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)
2 classes of genes implicated in the onset of cancer
Proto-oncogenes
Tumour suppressor genes
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
2 types of mutations and their results via proto-oncogenes
- 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)
- Structural mutations (expression of a gene product with altered function/activity)
Ras proteins
Large family of membrane-bound G proteins
Exert a powerful proliferative influence in many cell types
Ras and Human cancers
Activation is common in cancer
Most mutations occur in the 12th or 61st codons
Amino acid substitution
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
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
2 types of mutations and their results via TSGs
- Regulatory mutations (reduced/absent expression of gene and levels of gene product)
- Structural mutations (expression of a gene product with reduced/absent function/activity)
p53 TSG
Most well studied TSG
Fully functional p53 can overcome the effects of one or more activated oncogenes
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
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
