Chapter 4 Flashcards
Define tumour initiation?
Interaction of reactive chemical species with DNA to produce damage which could lead to erroneous DNA replication and fixation of DNA mutation
Which 3 factors are important in determining likelihood of tumour initiation?
Rate of procarcinogenic activation, efficiency and fidelity of DNA repair, capacity for cell proliferation.
Define tumour promotion?
Clonal expansion of an initiated cell, as a result of events that alter gene expression as to provide the cell with a selective proliferation advantage.
What are tumour promoting agents?
Usually non-genotoxic, but cause direct or indirectly cells to divide = survival and proliferation of preneoplastic cells an formation of benign lesions such as papillomas
Name examples of tumour promoting substances
TCDD, TPA, phenobarbital
Define tumour progression?
Benign lesions acquire the ability to grow, invade and establish metastasis.
Name the 6 hallmarks of cancer
Self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, potential for metastasis/tissue invasion
Name some substances that are known carcinogens?
Nitrogen mustard, aflatoxinB1
How can carcinogenic substances contribute to cancer development?
By contributing to genetic, epigenetic or microenvironmental alterations
what is the most common property of a genotoxic carcinogen?
directly electrophilic (electron seeking) or being capable of conversion to electrophils. These substances interact with DNA and proteins, forming covalent adducts or oxidative damage.
Which enzyme system has been implicated in bioactivation of carcinogens?
CYP-450, but oxidative procarcinogen bioactivation may be also be catalyzed by NADPH quinone oxidoreductase, aldo-keto reductase and peroxidases
Name the 3 most studied classes of chemical carcinogens that require activation?
PAHs, aromatic amines, nitrosamines
Which fungus produce Aflatoxin B1?
Aspergillus
Name the two most common mechanisms of DNA damage caused by carcinogenic chemicals?
Carcinogen adduct covalently bound to DNA or oxidative DNA damage
Which oxidized form of a nucleotide base has been used as a marker of oxidative DNA damage?
8-oxo-deoxyguanosine
How can reactive oxygen species be produced?
exposure to exogenous chemicals, byproduct of CYP, endogenous processes (inflammatory processes or oxidative phosphorylation)
Name 3 mutational events that may take place if DNA repair does not occur before DNA replication occurs?
1) error-prone replication resulting in a nucleotide substitution resulting in incorporation of the wrong complementary base
2) frame shift mutations
3) DNA strand breaks
Are the mutations occurring after chemical exposure random?
No, there is a selectivity at the DNA for mutations, often seen on oncogenes or tumour suppressor genes. The mutations occur at discrete hot spots.
What is the mutation associated with hepatocellular carcinoma secondary to alfatoxin exposure in people?
Codon 249 mutation in p53
What is the MOA for TPA?
Its an proinflammatory agent and inducer of oxidative stress, providing a microenvironment promoting proliferation of initiated cells.
What is the MOA for TCDD?
Inhibit apoptosis of initiated cells
What is the MOA of phenobarbital?
Alter pattern of DNA methylation, modifying epigenetic control of gene expression in cancer cells.
How does inflammation contribute to tumour progression?
- Supply with growth factors and signals to the tumor microenvironment
- induce signals that support EMT - such as TGF beta, PDGF, HGF, Wnt, EGF
- ROS production that are mitogenic
Name the 2 emerging hallmarks of cancer
Modified energy metabolism and immune escape
Name 2 enabling mechanisms
genomic instability and inflammation
Name 2 important proinflammatory interleukins?
IL-6, TNF-alpha
Name an important oxidant-generating enzyme?
nicotinamide adenine dinucleotide phosphate oxidase (NADPH) - important for the function of respiratory bursts
What is an Ames test?
A short-term mutagenesis assay where salmonella strains are used to evaluate the frequency of carcinogen induced DNA mutations
Give an example of a biomarker which can be used for measuring exposure a carcinogen?
CYP1A1 expression is correlated with exposure to cigarette smoke and the risk of developing lung cancer
Does genetic variation impact risk of cancer development after exposure to a carcinogen?
Yes, it is suspected that genetic polymorphism in drug-metabolizing enzymes may be associated with altered susceptibility to cancer
Defect in which DNA repair genes are associated with significantly increased sensitivity to any carcinogenic exposure?
BRCA1/2 (breast cancer), xeroderma pigmentosum (XP), werner syndrome, turcot syndrome
What are the main two mechanisms of DNA damage caused by carcinogenic chemical?
A carcinogenic adduct covalently bound to DNA or oxidative DNA damage
What are the emerging Hallmarks of cancer?
- Deregulating cellular energetics
2. Avoiding immune destruction
By which 3 processes can pro carcinogenic substances be activated?
- Phase 1 metabolism - Hydroxylation CYP-P450- oxidative procarcinogen bioactivation, some become active in phase 2 though conjugation
- Multiple enzymes may contribute to carcinogenic transformation
- Non-enzymatic spontaneous chemical decomposition
Define tumour initiation?
The interaction between reactive chemical species and DNA which cause damage - result in erroneous DNA replication with fixation of mutations if not repaired
Name 3 cellular functions important for determining the likelihood of tumour initiation?
Procarcinogen activation, efficacy and fidelity of DNA repair and capacity for cell proliferation.
Define tumour promotion?
Clonal expansion of an initiated cell as a consequence of events that alter gene expression which has provided the cell with selective proliferative advantage.
