carcinogens Flashcards

1
Q

what are carcinogens?

A

chemical or physical sources that initiate or promote carcinogenesis

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2
Q

what is a DNA damage?

A

abnormal chemical structure in DNA which causes changes

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3
Q

what is a genotoxin?

A

a physical or chemical agent that can induce DNA damages

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4
Q

what is a mutation?

A

an alteration of the nucleotide sequence in the genome

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5
Q

what is a mutagen?

A

a physical or chemical agent that can induce mutations

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6
Q

what types of genotoxins are there? What do they cause?

A

Mutages (DNA adducts and mutations)

clastogens (chromosome breaks)

Aneugens (mitotic spindle)

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7
Q

what are the key characteristics of carcinogens?

A
  • is genotoxic
  • alters DNA repair
  • causes genomic instability
  • induces oxidative stres
  • induces chronic inflammation
  • is immunosuppressive
  • models receptor mediated effects
    -causes immortalization
    -alters cell proliferation/ cell death/ nutrient supply
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8
Q

what is the difference between genotixic carcinogens and non-genotoxic carcinogens?

A

genotoxic: initiate tumor formation by DNA damage and DNA mutagenesis. Is not concentration dependent. DNA damage is reversible but mutation is not. mutagenic

non-genotoxic: promote tumor formation by pathways other than DNA damage –> cell proliferation, cytotoxicity, hormonal effects
is concentration dependent, reversible and non-mutagenic –> provides growth advantage

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9
Q

Give examples for genotoxins and non-genotoxins

A

genotoxin: Aflatoxin B1, Formaldehyde, Nitrosamine, Vinyl Chloride

non-genotoxic: Asbestos, Dioxins, Estradiol, Phenobarbital

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10
Q

what are common types of DNA damage?

A

8-oxo-2’-deoxyguanosine: oxidative lesion in duplex DNA

ß-N-glycosidic bond between base and deoxyribose is hydrolyzed

Single Strand break: : directly or indirectly (BER)

double strand breaks

O6-MG: alkylation of oxygen antom of guanine –> repaired by suicide enzyme MGMT

spontaneous hydrolysis reaction of cytosine into Uracil

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11
Q

What is MGMT and how does it work?

A

is a suicide enzyme that is synthesized if DNA damage is detected: Transfers CH3 group of DNA to its self and is then degraded

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12
Q

how can genotoxic carcinogens be activated? what are direct and indirect genotoxins?

A

many genotoxins are not genotoxic by themselves but can form genotoxic metabolites through cellular metabolism: eg cytochrome P450 enzymes

direct genotoxins: active without metabolic activation

indirect: carcinogenic after metabolic activation

Procarcinogens are concerted by phase I enzymes. They then either form inactive metabolites which are secreted or ultimate carcinogens which are active and can lead to DNA damage

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13
Q

is DNA damage random?

A

No, each carcinogen has its specific pattern how it reacts with the DNA bases

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14
Q

how can DNA adducts be detected?

A

32P Postlabeling
Immunoassay
CG/MS and LC/MS

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15
Q

what is the relation between DNA damage, mutation and cell division?

A

cell division is required to fix a DNA damage

once a DNA damage is fixed in a mutation, it cannot be repaired

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16
Q

which mutations are more likely: transition mutation or transversions of bases?

A

transition more likely than transversion

17
Q

what can lead to specific mutational patterns?

A

chemical exposures and DNA repair defects

18
Q

why is tumor formation a rare event even though a lot of DNA damages occur per day per cell?

A

-efficient DNA repair systems
-many mutations are silent (introns, third base of codon)
-possibility of neutral mutation
-most gnees are not involved in cancer

19
Q

is DNA damage sufficient for carcinogenesis?

A

no, but it is a prerequisite

20
Q

what are the effects of genotoxic and non-genotoxic mechanisms?

A

genotoxic: DNA adducts; chromosome fusion, deletions, breackage, mis- segregation, non-disjunction

non-genotoxic: inflammation, immunosuppression, ROS, receptor activation, epigenetic silencing –> altered signal transduction

21
Q

what is assesed in safety testing of drugs?

A

carcinogetic properties are evaluated in mutagenicity and carcinogenicity studies –> most time and cost consuming

22
Q

how are carcinogens regulated? What is paracelsus principle?

A

paracelsus principle: any poison can be non-toxic if the dose is below an appropiate threshold

–> but no threshold at any exposure level for genotoxic carcinogens

–> drug development stopped if genotoxicity Tests are positive, but non-genotoxic carcinogens may be used

23
Q

how does carcinogenicity testing work?

A

2-years rodent bioassay:
-rats
-male and female
-400 to 600 animals per study
-one control and three dosis groups

24
Q

how does genotoxicity testing work?

A

several in vivo and in vitro tests

assessing genotoxicity via detection of mutations, chromosome abnormalities or DNA breaks

–>bacteria: Ames Test
–>rodent/human cells: MLA/HPRT, Micronucleus test, chromosomal aberrations

–> in vivo test as follow up

25
Q

how does the Ames test work?

A

salmonella or e coli which are auxotrophic for an essential amino acid

incubation of tester strains with a potential genotoxin

induced mutations lead to increase in number of revertants –> are able to grow on minimal essential amino acid medium

26
Q

how does the mammalian mutagenicity tesing (MLA TK test) work?

A

in vitro gene mutation assay:

nucleoside analogues are incorporated into DNA in TK-positive cells –> cytotoxic

genotoxin induced mutaions in TK lead to resistance –> survival

27
Q

how does the micronucleus test work? What does it test for?

A

it tests for: clastogenic and aneugenic chemicals

cytokinesis blocking using cytochalsain B (inhibits actin polymerization) –> binucleate cells –> staining using DNA specific dyes/flourescent labelled DNA probes

28
Q

How can chromosome aberrations be tested?

A

Analysis of structural abnormalities:

exposure to test substance –> cells are treated with a metaphase-arresting substance –> chromosome preparation (hypotonic treatment, fixation, staining)

29
Q

how can single strand or double strand breaks be detected? what is the name of the assay and how does it work?

A

Comet assay:

-exposed single cells are seeded into an aqueous gel matrix
-direct current electric filed is established
-DNA migration towards anode
-DNA fragments induced by DNA strand breaks migrate faster than whole chromosomes
-

30
Q

What are the limitations of the comet assay?

A

-very sensitive
-high concentration of test substance often give positive results because necrosis or apoptosis can induce DNA damage

31
Q

What is MOE? what does it determine?

A

Margin of exposure:

MOE=TD10/estimated human exposure

with TD10= dose to give tumors to 10 % rats or mice

32
Q

What is the ALARA principle?

A

carcinogen exposure As Low As Reasonably Achievable

33
Q

At which MOE is the existing carcinogenic risk to be low?