Carcinogenic agents Flashcards
1
Q
Adenoma-carcinoma sequence
A
Pathway for the development of colon cancer:
- Normal colon
- Inherited or acquired mutations of cancer suppressor genes are a “first hit” making the mucosa at risk
- A more susceptible mucosa takes a “second hit” from methylation abnormalities and inactivation of normal alleles
- Proto-oncogenes are mutated and adenomas form
- Homozygous loss of additional cancer suppressor genes => carcinoma
- Additional mutations and gross chromosomal alterations
2
Q
Describe the stepwise accumulation of mutations in cancer
A
- Normal cell gets carcinogen-induced initiating mutation
- Initiated precursor acquires genomic instability via a mutation affecting genomic integrity
- Precursor with mutator phenotype gets additional driver mutations “cancer hallmarks”
- Founding cancer cell continues to mutate
3
Q
Driver mutation vs passenger mutation
A
Driver: promotes growth and cancer transformation
Passenger: picked up along the way
4
Q
What are the types of carcinogens?
A
- chemical
- physical
- radiation
- oncogenic virus
5
Q
Direct vs. indirect carcinogens
A
Indirect carcinogens require metabolic activation
6
Q
Mouse two-stage skin carcinogenesis model
A
- Initiation = subcarcinogenic dose of initiating agent
- metabolic activation of procarcinogens
- mutation induction in critical target genes - Promotion = continual delivery of promoting agent
- increased DNA synthesis and inflammation
- altered gene expression and enzyme activity
- expansion of initiated population
- chronic cell proliferation begins
- papillomas = clonal outgrowths
- diploid lesions - Progression
- additional genetic events: aneuploidy, loss of heterozygosity
- dysplasia
- papilloma => squamous cell carcinoma
- invasion and metastasis
7
Q
How do chemical carcinogens lead to cancer?
A
- Initiation = rapid and irreversible DNA damage in critical gene
- Promotion = repeated exposure enhancers cell proliferation but alone doesn’t directly affect DNA; reversible
- Progression = genetic mutations accumulate => invasive and metastatic tumor
8
Q
Chemical properties of direct-acting carcinogens
A
- Electrophilic
- Bind nucleophilic DNA to form carcinogen-DNA adducts
9
Q
Name examples of direct-acting carcinogens
A
- Nitrogen mustards: chlorambucil, melphalan, cyclophosphamide
10
Q
What is the mechanism of action of an alkylating agent?
A
- self-cyclization to become a good electrophile
- nucleophilic attack of DNA or protein
- DNA base: nitrogen or carbonyl oxygen
- protein: sulfur or nitrogen - formation of DNA adduct that persists
11
Q
How can alkylating agents damage DNA?
A
“Initiate” DNA damage via:
- adduct misreading during replication and replacement with alternate base => mutation
- interstrand cross linking: prevent separation of dsDNA for replication and transcription => mutation or apoptosis
12
Q
Ames Test
A
- Tests carcinogenicity of a compound by testing its mutagenicity in bacteria (50-70% known carcinogens are mutagenic in this test)
- Histidine synthesis deficient bugs growth on histidine deficient media in the presence of compound => growth corresponds to mutagenicity
- Rat liver enzymes added to media to metabolize any indirect carcinogens
13
Q
Benzo[a]pyrene
A
- Indirect alkylating agent found in cigarettes
- Metabolized by cytochrome p450 oxidases and hydrolases to form electrophilic BPDE
- Forms adduct with guanine, which will be misread as A or T
14
Q
Ras
A
- One of the most commonly mutated genes in cancer
- Part of a growth factor signaling pathway
- Mutation for constitutive activity => uncontrolled growth via transcriptional activation, pro-growth metabolism, increased protein synthesis, and cell cycle progression
15
Q
p53
A
- Commonly mutated in cancer
- Normally initiates DNA damage repair cascade
- When mutated: no cell cycle arrest, DNA repair, or senescence in response to DNA damage
