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lec 6 chemical carcinogenesis - READY TO REVIEW! :D Flashcards

1
Q

whats the dif between a genotoxic and non genotoxic carcinogen

but both of them are a ______

A

genotoxic interacts with the DNA and leads to mutation

non geno modifies gene expression, without actually damaging the DNA

but both are a carciongen - a phys/chem agent that induces growth of new tissue (neoplasia)

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2
Q

t/f: every single cancer is caused by a carcinogen

A

false. many are spont with no clear exposure, but about half have carcinogenic causes

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3
Q

what does it mean that cancers are monoclonal?

what happens with each mutation?

A

it starts with one cell that acquires a somatic mutation. then one of its offspring has that mutation. then that leads to more cells with that mutation (sequential mutations/hits).

each mutation –> further proliferative / survival advantage –> clonal expansion, tumour development

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4
Q

HRAS is an example of a

A

protooncogene

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5
Q

TP53 is an example of a

A

tumour supp gene

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6
Q

whats the difference between protooncogenes and tumour suppressor genes

A

mutating a proto onco leads to oncogenes that drive abnormal cell prolif (proto onco = positive reg of cell prolif)

mutating a tumour sup means cells lose their negative regulation –> cancer (tumour supp = negative reg of cell prolif)

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7
Q

what type of mutation (gain or loss of function) lead to protooncogene activation

A

gain of fucntion

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8
Q

what type of mutation (gain or loss of function) lead to tumour suppressor activation

A

loss of function

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9
Q

what are clastogens

A

mutations that cause gross chromosomal rearrangements

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10
Q

what is the mutation in the philadelphia chromosome, what cellular consequence does it have, and what cancer does it lead to?

A

chromosome 9 (ABL1) and 22 (BCR) fuse together. this forms the BCR-ABL1 fusion gene (philly chromosome).

it leads to a constitutively activated tyrosine kinase signalling protein.

leads to chronic myeloid leukemia

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11
Q

what are the three stages of the multistage model of carcinogenesis?

A

the initiation stage
the promotion stage
the progression stage

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12
Q

what happens in the initiation phase in MMoC?

A

the normal cell acquires DNA damage. if it can’t REPAIR, the normal cell becomes an initiated cell.

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13
Q

what happens in the promotion phase of the MMOC.

A

the initiated cell undergoes selective clonal expansion. if it cannot initiate APOPTOSIS, it’ll proliferate into a focal lesion

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14
Q

What happens in the progression phase in the MMoC?

A

the focal lesion undergoes malignant transformation. if it cannot initiate apoptosis it proliferates and develops into CANCER

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15
Q

is there a threshold for genotoxicity (ie: a dose where you know that NO genotoxic damage will occur)

A

no! genotoxicity can occur even at a small dose.

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16
Q

whats the difference between treatment requirements of the initiation, promotion, and progression stage.

A

a single treatment can induce the mutation in the initiation phase

multiple treatments / prolonged treatment is necessary in the promotion phase

the number treatments needed in the progression phase is unknown

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17
Q

describe how the initiation, promotion, and progression phase differ wrt to:
1. DNA mods
2. genotoxicity
3. mutations
4. reversibility

A
  1. I: DNA gets modified. Prom: no direct DNA mod. prog: DNA mod
  2. I: genotoxic. Prom: non genotoxic. Prog: genotoxic
  3. I: Muts. Prom: no direct muts. Prog: mutation and chromosomes disarrangement
  4. I: IRREVERSIBLE! Prom: Reversible. Prog: irreversible
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18
Q

does order and time of promoters vs initiators matter wrt tumour development ?

A

YES! initiator needs to come before the promoter, and the promoter needs to be relatively close together

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19
Q

this model is a well established in vivo model for studying sequential development of tumours:

A

MOUSE SKIN MODEL!

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20
Q

describe how MMoC is studied in mouse skin models.

A

initiation - you apply a sub carcinogenic dose of a carcinogen (like DMBA which targets the proto onco HRAS1)

promotion: repeatedly apply a tumour promoting agent to induce tumour development

progression: the papillomas progress into invasive squamous cell carcinoma

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21
Q

procarcinogens need to undergo ___ before they can modify DNA

A

metabolic activation

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22
Q

t/f: xenobiotics always directly lead to ox stress/mutations/tox/cancer

A

FALSE! some undergo phase 1 enzyme mods then lead to that, some undergo phase 1 and 2 enzyme mods then lead to that

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23
Q

ultimate carcinogens are:

A

the biologically reactive form of procarcinogens

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24
Q

t/f: detoxification will always lead to non toxic/non carcinogenic products

A

FALSE! detox can either lead to excretion

or, it gets cleaved by enzymes in the kidney/colon to produce mutagens / carcinogens, which cause further ox stress, mutations, tox, cancer

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25
t/f: dose response is the same in all the tissues of an organism
FALSE! dif tissues have dif levels of metabolic enzymes, and metabolism will affect metabolic activation
26
how is metabolic activation related to tissue specific toxicity
the distribution of metabolic enzymes varies across tissues. the location of where the metabolic enzymes are changes where metabolic activation can happen, which changes where DNA damage can occur.
27
cyp1a1 is found
liver, urinary bladder
28
cyp1a2 is found
liver
29
cyp2e1 is found
liver
30
cyp3a4 is found
liver, small intestine, duodenum
31
how does the need metabolic activation lead to individual variability in response to carcinogens
ppl have genetic variations in metabolic enzymes. dif genetic variations, dif enzymes, dif ability to process carcinogens on individual basis.
32
t/f: all individuals will have the same response to carcinogens
FALSE!
33
is the multistage carcinogenesis model actually relevant to human cancers? what are the limitations of this model?
relevance: - long latency: model says there is an extended period between when carcinogen exposure happens, and when cancer actually develops. this is also reflected in humans (low doses repeatedly delivered over months/years --> cancer dev) - multiple events: just like the model, human cancers usually result from multiple mutations, not just one event - enviro factors: human cancers impacted by combo of genetic and enviro factors limitations: - the model over simplifies carcinogenesis - humans are exposed to mixtures of agents that act at multiple stages, not exclusively to one agent like the model suggests - the mouse skin model doesn't reflect the complexity of human cancers
34
what type of carcinogen is mutagenic, causes direct DNA damage and adduct formation, requires metabolism, and has no threshold?
GENOTOXIC!
35
which type of carcinogen is non mutagenic, has no direct DNA damage, has a threshold, may function in the tumour promotion stage, and displays tissue and species specificity?
non genotoxic
36
are polycyclic aromatic hydrocarbons genotoxic or non genotoxic?
genotoxic
37
describe the metabolic pathway from procarcinogen benzo(a)pyrene to the ultimate carcinogen (key enzymes, intermediates)
1. the procarcinogen benzoapyrene metabolized by CYP1A1 to form the proximate carcinogen benzoapyrene 78 epoxide. 2. this prox carcinogen gets detoxified by epoxide hydrolase to form benzoapyrene 78 dihydrolol 3. this gets metabolised by CYP1A1 again to form the ultimate carciongen benzoapyrene 78 diol 910 epoxide (BPDE) 4. BPDE gets metabolised by glutathion s transferase to form the glutathione conjugate for elimination
38
what is a key feature of the carcinogenic structure of benzo(a)pyrene. what can this structural feature lead to?
the carcinogenic structures have an EPOXIDE. - this epoxide leads to cellular damage by reacting with DNA and proteins. - enzymes that can undo the epoxide (epoxide hydrolase, glutathion s transferase) can detoxify it
39
what is the significance of the bay region in benzo(a)pyrene 7,8 diol 9,10, epoxide?
the bay region is a portion that is resistant to being hydrolysed by epoxide hydrolase.
40
t/f: all carcinogenic agents lead to the same type of mutation
FALSE!
41
BPDE leads to what mutation
G:C to T:A transversion (purine to pyrimidine, pyrimidine to purine)
42
nitrosamines lead to what mutation
G:C to A:T transition (purine to purine, pyrimidine to pyrimidine)
43
cigarette smoke condensate leads to what mutation
80% G:C to T:A (transversion), 20% G:C to A:T (transition)
44
are alkylating agents genotoxic or non genotoxic? do all alkylating agents require metabolic activation?
genotoxic not all; you have direct acting which don't, and indirect acting which do.
45
whats the difference between direct acting and indirect acting alkylating agents? examples?
direct: doesn't require metabolic activation. ie: alkylalkanesulfonates indirect: requires metabolic activation ie: N-nitrosamines (the n nitrosamine needs to be activated into a carbenium ion!)
46
what happens upon metabolic activation of NDEA
you get a carbenium ion, which can then alkylate the DNA
47
t/f (and correct it if false): alkylating agents only react with DNA at one site
FALSE! they react with DNA at more than 12 sites.
48
what are the two most common alkylating sites
N7 Guanine N3 Adenine
49
are aromatic amines and amides genotoxic or non genotoxic carcinogens
genotoxic
50
what are the primary sources of aromatic amines and amides
dye, cigarette smoke
51
what type of metabolism do aromatic amines and amides undergo?
both phase 1 and phase 2
52
what do phase 1 reactions of amines/amides lead to?
phase 1 leads to hydroxylated metabolites, these are the ones assoc with adduct formation in proteins and DNA, leading to liver and bladder carcinogenicity
53
do nongenotoxic chemical carcinogens physically damage the dna?
NO
54
what are the 6 modes of action of non-genotoxic carcinogens?
- cytotoxic - receptor mediated toxocity - alter methylation - microRNA -immunosuppression - oxidative stress NOTE! none of these things are actually altering the DNA!!
55
explain how cytotoxicity leads to tumourogenicity example ?
TLDR: cytotox --> regenerative hyperplasia 1. a cytotoxic chemical kills a bunch of cells 2. in attempts to replace these killed cells, you get persistent regenerative growth 3, but in the porcess, the likelyhood of spontaneous squisition of mutated cells increases. and these cells accumulate, proliferate. 4. so, inducing cytotox --> compensatory hyperplasia --> contributes to the tumourigencity seen at high doses. example: - chloroform --> liver + kidney tumours. - melamine --> bladder tumours
56
explain receptor mediated non genotoxic mode of action (ie: how it leads to tumour growth) --> two examples?
FIRST: PPAR - the toxin can activate the PPAR nuclear receptor. this leads to enzyme induction, altered lipid metabilism, altered cell growth, increased DNA synthesis, tumour promotion SECOND: HORMONAL - activation of the hormone receptors can lead to tumour growth - ie: admin of 17 beta estradiol -> increased mammary tumours in mice. - ie2: diethylstilbestrol (estrogenic chemical) --> mammary cancer, cervical cancer.
57
explain how altered methylation can lead to cancer causing gene expression in TSGs vs oncos
either way, when a gene is methylated, transcription is blocked at that site. in TSGs: normally, no methylation. in tumour cells, theres methylation (focal hypermethylation), blocked transcription, and the TSG is silenced --> cancer in oncogenes: normally, methylation, transcription blocked. but, upon global HYPOmethylation, the oncogene gets demethylated, and the oncogene is expressed.
58
is methylation always cancer causing? when is it not?
no. it is NOT cancer causing when the methylation is blocking the transcription of an oncogene.
59
are miRNAs always oncogenic?
NO!
60
how do miRNAs act in normal tissue ?
the mature miRNA binds to and blocks some gene, leading to normal cell growth, prolif, diffr, cell death
61
how do miRNA function as tumour suppressor genes vs oncogenes?
TSG: - it ACTS as a TSG, when it BLOCKS an oncogene. thus the miRNA regulates oncos that control proliferation, diffr, apoptosis. ONCO: - is ACTS as an onco when it BLOCKS TSGs - it negatively regualtes the TSG, which should normally control cell prolif, diffr, apop --> so we get tumour formation as a result.
62
whats the difference between cold and hot tumours?
cold tumours are ones that don't have CD8+ and NK cells in the tumour, but have IMMUNOSUPPRESSIVE cells in the tumour, thus the immune system doesnt recognize the tumour, the cancer is "safe", and it doesn't respond well to immunotherapy HOT tumours have CD8 and NK cells present in the tumour. they SUPPRESS the immunosuppressive cells. the immune system is effective at battling the cancer
63
is a hot or cold tumour more responsive to immunotherapies?
HOT!
64
is there only one way by which oxidative stress can lead to tumourigenesis? describe
NO! - ROS can lead to the MAPK kinase cascade, which activates transcription factors, leading to cell prolif, diffr, apop - ROS can also lead to dissoc of IKB from NFKB, leading to active NFKB, leading to transcription of prolif, cytokines, adhesion molecules.
65
how can ionizing radiation directly vs indirectly cause DNA damage?
DIRECTLY: ionizes the atom making up the DNA INDIRECTLY: interacts with surrounding water molecules, generates ROS which damages the DNA
66
how can UV radiation damage DNA
leads to pyrimidine dimers, which eventually leads to a CC-TT transition.
67
what are the three big categories of DNA repair pathways
direct reversal excision repair double strand break repair
68
what DNA repair category does BER fall into -- what happens in BER?
excision repair - dna glycosylases like OGG 1 recognizes and removes the damaged bases - you get a gap in th e DNA called an AP site - the gap gets cleaved by an AP endonuclease - the gap gets filled by DNA polymerase and sealed with DNA ligase.
69
what DNA repair category does NER fall into? what happens in NER?
excision repair - this happens with bulky adducts and cross lins - a whole fragment of nucleotides containing the damaged lesion is removed. - a new strand gets synthesized using the undamaged strand as the template.
70
what DNA repair category does MMR fall into? what happens in MMR?
still in excision repair! - the mismatch repair complex comes in and removes the mismatched bases, correcting the insertion and deletion of short stretches of DNA - results in minimal mutations
71
what happens in cells that have MMR mutations?
they cant fix the mismatched base pair; resulting in more mutations ie: colorectal cancer, 15/20% of cases involve MMR mutations.
72
why do DSBs need to be repaired quickly?
to avoid cell death, chromosomal abberations, mutations, cancer initiation
73
what are the two types of DSB repair?
homologous recomb non homologous end joining
74
what are the ideal qualities of a test for mutagens? do any test meet all these qualities?
fast, cheap, sensitive, human / ethical, relevant to human bio no! :(
75
what happens in in vitro genotoxicity assays? 4 examples?
ames test - done on bacteria - you have them be defected before. then treat with a substance. if the substance mutates the bac, it reverses the previous defect MLA/HPRT - on rodent/human cells - detects gene mutations micronucleus test - rodent / human - detects nucleus abberations / changes in the structure or number of chromosomes chromosomal abberation test - rodents / humans - detetcts changes in the structure of chromosomes.
76
what are the limitations of in vitro genotoxicity assays?
it tells you whether something is genotoxic, but not whether you'll see cancer as the end result.
77
what is the gold standard test for carcinogen detection?
the 2 year rodent bioassay
78
what happens in the 2 year rodent bioassay
you chronically admin the tox at the maxmium tolerable dose and at half that dose, about n = 50 per dose, per sex admin in the same route of exposure as humans asses tumour incidence in all tissues
79
rodent bioassays, unlike in vitro tests respond to :
non mutagenic carcinogens (ie: tumour promoters)
80
what does the IARC classification tell you?
the level of certainty that a substance will cause cancer.
81
in IARC classification, a higher group number means?
higher number = lower level of certainty
82
tobacco somking, solar radition, alcohol, ionizing radation, fall into which IARC group? what does this mean?
1 carcinogenic they have sufficient evidence for cancer in humans
83
emissions from high temp frying, DDT, red meat, night shift work are in which IARC group? meaning?
2A probably carcinogenic limited cancer evidence in humans, but sufficient in experimental animals
84
gasoline, occ exposure as hairdresser or barber, lead, are in which IARC group? meaning?
2B possible carcinogenic limited evidence in humans less than sufficient evidence in experimental animals
85
coffee, crude oil, mercury, paracetamol are in which IARC group? meaning?
3 not classifiable as to its carcinogenicity to humans inadequate evidence in humans inadequate evidence in animals.
86
are tumours hetero or homo genous? They contain clones initially derived from (many/single) cell(s)
hetero single
87
BaP is an AhR ligand. how does AhR activation contribute to the genotoxic effects of BaP?
the procarconigen acts on the nuc receptors, leading to transcription of more CYP1A1. more CYP1A1 means more generation / metabolic activation into the ultimate carcinogen
88
monoalkylation, intercalation, intrastrand cross linking, inter strand cross linking; there are all examples of
DNA alkylation patterns
89
benzocaine is an example of which family of genotoxic agents
benzocaine

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