Chemical carcinogensis

Question 1

How can chemicals cause cancer?

Answer 1

It can initiate carcinogenesis or promote proliferation of the initiated cells, or induce progression of these proliferated cells to become malignant and are selected for. If these damages are not repaired or the cells do not apoptose to control the damage muations can occur in tumour suppressor genes and oncogenes.

Question 2

How genotoxic chemicals can cause cancer?

Answer 2

They can cause genotoxic damage; for example chemicals are electrophiles that can bind covalently to DNA and form adducts, DNA repair doen’t fix this and it will proliferate

Question 3

What are the different mechanisms of action of non-genotoxic chemical carcingens?

Answer 3

It modulates cell growth and death it can on:
The endocrine via receptor or without receptors
Inflammatory processes and immune response- berillium accumulates CD4 t-cells
Immunosuppresants- Cyclosporine inhibits IL-2
Inhibit gap junction communications -TCDD
Induce tumour promoters of tissue specific toxicity-arsenic compunds induce oxidative damage, cytotoxicity

Question 4

How can we screen for chemical carcinogens?

Answer 4

Genotoxic:Human epidemiological studies
classicla 2 year rodent assays
in vivo assays- create genetically engineered animals that are sensitive 
invitro assays-ames test
in silico analysis
Non genotoxic:
epidemiological
in vitro cell transformation assays
inhibition of gap junction
toxigenomics- expose and then profile gene expression

Question 5

What is epidemiology?

Answer 5

The study of determinants and distribution of health related states or events and using it to control diseases

Question 6

What are some of the problems with epidemiological studies?

Answer 6

Difficult to isolate other factors
Sensitive against low background but insesitive to common cancer
Small studies are confounded with sampling error
Difficult to draw causative link

Question 7

What are the two types of carcoinogens? What’s the difference?

Answer 7

Direct-attach alkyl group to DNA bases

and non direct-procarcinogens need to go through metabolic conversion before they become reactive carcinogens

Question 8

Give example of direct carcinogens. How is it formed? What can inhibit their formation absorbic acids? Where is it found?

Answer 8

Nitrosamines- nitrites formed from nitrates and join with amines. It’s found in food.

Question 9

What kind of mutation does nitrosamine form when it bind to DNA? Why is it a mutation?

Answer 9

O6-methyl guanine. Because it binds to thymine instead of cystine

Question 10

How does nitrosamine form the muation?

Answer 10

It undergoes oxidizaton and the methyl group is released, the methyl group is highly reactive and can form O6-methyl guanine

Question 11

Give example of an indirect carcinogen?

Answer 11

Benz(a)pyrene

Question 12

What is benzo(a)pyrene? Where is found and how is it a carcinognen?

Answer 12

It a polycyclic aromatic hydrocarbon, it is found in organic combusted material.
It’s a procarcinogen that becomes carcinogen when converted because it binds to N2 position of guanine forming an adduct DNA and block replicative polymerase

Question 13

How is bezo(a)pyrene made?

Answer 13

Through oxidation reaction catalyzed cytochrome P450 and other cytochrome enzyme, it forms BDPE.

Question 14

What repair system tries to fix the o6 methyl guanine adduct? What base does it remove? Why not another repair system?

Answer 14

Mismatch repair; base excision repair . It removes thymine.

Because non bulky adduct

Question 15

How is base excision repair done?

Answer 15

DNA glycosylate cleaves the mismatched base leaving an AP site, APE1 will cleave the DNA back bone, DNA pol will insert the correct base and synthisize the cleaved backbone and ligase seals it together it.

Question 16

What type of repair is used for bulky adducts? Where do adducts tend to bind on the DNA and why?

Answer 16

NER

non coding regions, because it’s not subject to transcription coupled repair

Question 17

What are the main steps of NER?

Answer 17

Incision, excision and ligation

Question 18

What are the key characteristics of carcinogenesis?

Answer 18

acts as electrophile either directly or after metabolic activation
be genotoxic
induce epigenetic alterations
alter DNA repair and genomic stability
induce oxidative stress
immunosuppresive-
inflammatory response and immune response
modulate receptor mediated effects
cause immortilization 
alter cell proliferation

Question 19

T/F

Most of carcinogens are nongenotoxic

Answer 19

False, most are genotoxic

Question 20

Give an example of a non genotoxic carcinogen. Where is it found? How does it act as a carcinogen?

Answer 20

TCDD, found in environment and food. It inhibit GAP junction communication.

Question 21

Give another example of a non genotoxic carcinogen and a way BBDE can acts as a non genotoxic carcinogen?

Answer 21

PAH activates AHR complex which translocates into nucleas and activates toxic, cytochrome genes. BBDE can directly bind to AhR and transcibes those genes

Question 22

Pros and cons of 2 year rodent model assay

Answer 22

\+:
Direct dose effect relationship
long lasting
-:
expensive
tumour responses can be species specifc
very high dosages can't be translated to humans
Don't know mechanism of action

Question 23

In vivo assay pros and cons?

Answer 23

\+:
few animals 
short term
-:
Can exhibit metabolic alterations 
The mutation can influence tumour that develops differently in that specific study

Question 24

How does the in vitro test for carcinogens work? What is good about this technique? What is bad about it?

Answer 24

they use an ames test where they plate cells on without an essential bacteria needed to survive, add carcinogen and if they survive then they were mutated and if not then they’re not mutated from the carcinogens compare to control(no carcinogen added)
Can be used on many different cells(humans vs prokaryotes)
Has high correlation rate between mutagenicity in vitro and carcinogens in vivo

Question 25

How can adducts be measured?

How is DNA damage measured?

Answer 25

immunocytochemistry
labelling followed by HPLC and MS
comet assay
sister chromatid exchange assays

Question 26

What is in silico modelling?

Answer 26

Uses physiology and metabolism to assess if a substance is carcinogenic, based on stucture and it’s interaction with different molecules, this is modelled on a computer

Question 27

What are the chemical carcinogens categories

Answer 27

Category1- Known carcinogen
1A-known carcinogen based on human evidence
1B-Known carcinogen and animal evidence
2-Suspected human carcinogen