Chapter 4

Question 1

Define tumour initiation?

Answer 1

Interaction of reactive chemical species with DNA to produce damage which could lead to erroneous DNA replication and fixation of DNA mutation

Question 2

Which 3 factors are important in determining likelihood of tumour initiation?

Answer 2

Rate of procarcinogenic activation, efficiency and fidelity of DNA repair, capacity for cell proliferation.

Question 3

Define tumour promotion?

Answer 3

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.

Question 4

What are tumour promoting agents?

Answer 4

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

Question 5

Name examples of tumour promoting substances

Answer 5

TCDD, TPA, phenobarbital

Question 6

Define tumour progression?

Answer 6

Benign lesions acquire the ability to grow, invade and establish metastasis.

Question 7

Name the 6 hallmarks of cancer

Answer 7

Self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, potential for metastasis/tissue invasion

Question 8

Name some substances that are known carcinogens?

Answer 8

Nitrogen mustard, aflatoxinB1

Question 9

How can carcinogenic substances contribute to cancer development?

Answer 9

By contributing to genetic, epigenetic or microenvironmental alterations

Question 10

what is the most common property of a genotoxic carcinogen?

Answer 10

directly electrophilic (electron seeking) or being capable of conversion to electrophils. These substances interact with DNA and proteins, forming covalent adducts or oxidative damage.

Question 11

Which enzyme system has been implicated in bioactivation of carcinogens?

Answer 11

CYP-450, but oxidative procarcinogen bioactivation may be also be catalyzed by NADPH quinone oxidoreductase, aldo-keto reductase and peroxidases

Question 12

Name the 3 most studied classes of chemical carcinogens that require activation?

Answer 12

PAHs, aromatic amines, nitrosamines

Question 13

Which fungus produce Aflatoxin B1?

Answer 13

Aspergillus

Question 14

Name the two most common mechanisms of DNA damage caused by carcinogenic chemicals?

Answer 14

Carcinogen adduct covalently bound to DNA or oxidative DNA damage

Question 15

Which oxidized form of a nucleotide base has been used as a marker of oxidative DNA damage?

Answer 15

8-oxo-deoxyguanosine

Question 16

How can reactive oxygen species be produced?

Answer 16

exposure to exogenous chemicals, byproduct of CYP, endogenous processes (inflammatory processes or oxidative phosphorylation)

Question 17

Name 3 mutational events that may take place if DNA repair does not occur before DNA replication occurs?

Answer 17

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

Question 18

Are the mutations occurring after chemical exposure random?

Answer 18

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.

Question 19

What is the mutation associated with hepatocellular carcinoma secondary to alfatoxin exposure in people?

Answer 19

Codon 249 mutation in p53

Question 20

What is the MOA for TPA?

Answer 20

Its an proinflammatory agent and inducer of oxidative stress, providing a microenvironment promoting proliferation of initiated cells.

Question 21

What is the MOA for TCDD?

Answer 21

Inhibit apoptosis of initiated cells

Question 22

What is the MOA of phenobarbital?

Answer 22

Alter pattern of DNA methylation, modifying epigenetic control of gene expression in cancer cells.

Question 23

How does inflammation contribute to tumour progression?

Answer 23

1. Supply with growth factors and signals to the tumor microenvironment
2. induce signals that support EMT - such as TGF beta, PDGF, HGF, Wnt, EGF
3. ROS production that are mitogenic

Question 24

Name the 2 emerging hallmarks of cancer

Answer 24

Modified energy metabolism and immune escape

Question 25

Name 2 enabling mechanisms

Answer 25

genomic instability and inflammation

Question 26

Name 2 important proinflammatory interleukins?

Answer 26

IL-6, TNF-alpha

Question 27

Name an important oxidant-generating enzyme?

Answer 27

nicotinamide adenine dinucleotide phosphate oxidase (NADPH) - important for the function of respiratory bursts

Question 28

What is an Ames test?

Answer 28

A short-term mutagenesis assay where salmonella strains are used to evaluate the frequency of carcinogen induced DNA mutations

Question 29

Give an example of a biomarker which can be used for measuring exposure a carcinogen?

Answer 29

CYP1A1 expression is correlated with exposure to cigarette smoke and the risk of developing lung cancer

Question 30

Does genetic variation impact risk of cancer development after exposure to a carcinogen?

Answer 30

Yes, it is suspected that genetic polymorphism in drug-metabolizing enzymes may be associated with altered susceptibility to cancer

Question 31

Defect in which DNA repair genes are associated with significantly increased sensitivity to any carcinogenic exposure?

Answer 31

BRCA1/2 (breast cancer), xeroderma pigmentosum (XP), werner syndrome, turcot syndrome

Question 32

What are the main two mechanisms of DNA damage caused by carcinogenic chemical?

Answer 32

A carcinogenic adduct covalently bound to DNA or oxidative DNA damage

Question 33

What are the emerging Hallmarks of cancer?

Answer 33

1. Deregulating cellular energetics

2. Avoiding immune destruction

Question 34

By which 3 processes can pro carcinogenic substances be activated?

Answer 34

1. Phase 1 metabolism - Hydroxylation CYP-P450- oxidative procarcinogen bioactivation, some become active in phase 2 though conjugation
2. Multiple enzymes may contribute to carcinogenic transformation
3. Non-enzymatic spontaneous chemical decomposition

Question 35

Define tumour initiation?

Answer 35

The interaction between reactive chemical species and DNA which cause damage - result in erroneous DNA replication with fixation of mutations if not repaired

Question 36

Name 3 cellular functions important for determining the likelihood of tumour initiation?

Answer 36

Procarcinogen activation, efficacy and fidelity of DNA repair and capacity for cell proliferation.

Question 37

Define tumour promotion?

Answer 37

Clonal expansion of an initiated cell as a consequence of events that alter gene expression which has provided the cell with selective proliferative advantage.