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Year 2 - Cancer > Cancer 5 > Flashcards

Cancer 5 Flashcards

1
Q

what is the nature of the DNA bases?

A
  • they are flat carbon rings
  • they are chemically reactive species able to react with other molecules
  • they contain double bonds
  • they are easily mutated
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2
Q

what is deamination?

A
  • The primary amino groups of nucleic acid bases are somewhat unstable
  • deamination is the removal of an amine group
  • They can be converted to keto-groups
  • Other deamination reactions include conversion of adenine to hypoxanthine, guanine to xanthine, and 5-methyl cytosine to thymine.
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3
Q

what causes hyper-reactive oxygen to be formed?

A

bases can undergo reactions which produce hyper-reactive oxygen as by-products

eg. singlet oxygen, peroxide radicals, hydrogen peroxide, and hydroxyl radicals

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4
Q

what causes modifications of DNA to be formed?

A
  • ionising radiation
  • hyper- reactive oxygen species
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5
Q

what is a common oxidation reaction?

A
  • A common product of thymine oxidation is thymine glycol
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6
Q

what happens to the glycol?

A
  • they react with chemical species which favor it
  • these reactants can be carcinogens
  • the addition of a larger molecule produces what we call an ‘adduct’
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7
Q

What is photodamage to the DNA?

A
  • Ultraviolet light is absorbed by the nucleic acid bases
  • the resulting influx of energy can induce chemical changes
  • photoproducts are formed as a consequence of bond formation between adjacent pyrimidines within one strand.
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8
Q

what are the types of DNA damage?

A
  • base pair mismatch

this is when one base is normal and the matching base is abnormal it causes a slight bulge

  • thymine dimer
  • radioactive damage
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9
Q

what can cause damage to DNA?

A
  • endogenous means from within the body

eg mitochondria produce reactive oxygen species that have the ability to damage DNA

  • Diet is strongly associated with cancer (about 40=45% of human cancers)
  • Medical treatments, such as radiotherapy, can also damage DNA and increase the risk of cancer
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10
Q

why is DNA damage important?

A
  • DNA damage can lead to mutation
  • mutation can lead to cancer
  • •Damaging DNA is an important strategy in cancer therapy
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11
Q

how can carcinogens cause DNA damage?

A
  • Base Dimers and Chemical Cross=Links
  • Base Hydroxylations
  • Abasic Sites
  • Single Strand Breaks
  • Double Strand Breaks
  • DNA Adducts and Alkylation
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12
Q

explain base dimers and chemical cross-links ?

A
  • This is where the DNA molecules are being chemically linked up
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13
Q

explain base hydroxylations?

A
  • An oxidative reaction occurring on one of the DNA bases and this can cause problems
  • This could mean that the DNA has to get repaired and during the repair process, it could become mutated
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14
Q

explain abasic sites?

A
  • during the repair process the entire DNA base has been removed so the sugar backbone is maintained but we have removed the base from the mutagenic molecule
  • During replication, the missing base will cause problems
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15
Q

explain single-strand breaks?

A
  • These are very common and can be very useful
  • There are physiological enzymes that are responsible for making single-strand breaks
  • Topoisomerase is involved in the relaxing and unwinding of DNA
  • it works by chopping the strand of DNA and allowing the strand to unwind and we can gain access to the DNA as the strand is re- annealed
  • So we can deal with single strand breaks in DNA
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16
Q

explain double-strand breaks?

A
  • These are a bit of a disaster
  • After the double-strand breaks, there is a tendency for the two bits of DNA to drift apart and this is intolerable from the cell’s point of view
  • There are a number of DNA repair mechanisms that attempt to amend this, but sometimes the DNA repair can go wrong and introduce DNA damage
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17
Q

explain DNA adducts and alkylation?

A
  • This is generally the type of damage that is caused by chemicals
  • Some chemicals tend to be metabolically activated into electrophiles
  • DNA is very rich in electrons because of all the nitrogens in the bases
  • The electrophiles bind to the DNA and form a covalent bond
  • this causes issues in DNA replication due to the binding of the big bulky chemical
  • In short, DNA polymerase cannot recognise the base because of the chemical adduct
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18
Q

what are polycyclic aromatic hydrocarbons?

A
  • Polycyclic aromatic hydrocarbons are common environmental pollutants
  • they are present in smoke
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19
Q

overview drug metabolism in the body?

A
  • Phase 1: introduce or unmask functional groups that can be used in Phase 2
  • Phase 2: we use the functional groups (made available by phase 1) to conjugate it with an endogenous molecule to make it water-soluble so that it can be excreted in the urine

overall purpose is to make something that is lipophilic more polar to get rid of it

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20
Q

what are the main enzymes in phase 1?

A
  • Cyrochrome P450 enzymes
  • responsible for oxidising chemicals
21
Q

what is the two-step Oxidation of Benzo[a]pyrene (B[a]P)?

A
22
Q

explain why the two-step oxidation of Benzo[a]pyrene (B[a]P) is dangerous?

A
  • B[a]P is a substrate for CYP450, which oxidizes it to form an oxide (Benzo[a]pyrene-7,8-oxide) (toxic)
  • This oxide is reactive and wants to find electrons (it is an electrophile)
  • There is a defence mechanism in the body = epoxide hydroxylase cleaves the three membered strained ring of the oxide to form a dihydrodiol (this is NOT toxic)
  • the non-toxic dihydrodiol metabolite is also a substrate for P450
  • So P450 converts this non-toxic metabolite into another oxide
  • This is very reactive and is desperate to find some electrons to react with
  • the best source of electrons is DNA, so DNA adducts are formed
23
Q

explain why the metabolism of aflatoxin B1 is dangerous ?

A
  • aflatoxins are produced from fungi aspergillus fungi
  • grow on foodstuffs that are not maintained well and peanuts
  • aflatoxin B1 is not a carcinogen
  • cytochrome P450 converts it to an apoxite
  • this apoxite is very reactive with DNA
  • it reacts with the guanine in DNA at the N7 position
  • we end up with an adduct formation on the guanine that will cause mutation
  • this is very carcinogenic for hepatic cancers
24
Q

explain why the metabolism of 2-naphthylamine is dangerous?

A
  • 2- naphthylamine is a part component of dye-stuffs
  • Benzidine is another important past component of dye- stuffs
  • Both benzidine and 2- naphthylamine are potent BLADDER carcinogens
  • 2- naphthylamine is a substrate for CYP450, which converts the amino group to form a hydroxylamine
  • Hydroxylamines are reactive
  • in the liver when this reactive hydroxylamine is formed it is glucuronidated ( detoxifying reaction)
  • This glucuronidation is done by glucuronyl transferase
  • The inactive metabolite is excreted by the liver and it goes into the bladder and mixes with the urine
  • Urine is ACIDIC, and, under acidic conditions, the glucuronides are hydrolysed
  • This releases the hydroxylamine derivative which in acidic conditions rearranges to form a positively charged nitrogen
  • The nitrenium ion is an electrophile, which then goes and binds to the DNA and forms adducts
  • The bladder isn’t as capable of detoxifying the hydroxylamine derivative as the liver
25
Q

how does solar radiation cause cancer?

A
  • UV radiation can lead to the formation of pyrimidine dimers
  • if there are two pyrimidines next to each other in the presence of UV radiation they can covalently link
  • this might form skin cancer
26
Q

how does ionizing radiation cause cancer?

A
  • Examples of ionising radiation: gamma, X=ray, beta particles
  • They can all generate free radicals
  • Oxygen- free radicals are produced by normal biochemistry and there are good defence mechanisms for dealing with them = however, ionising radiation can overwhelm the defence mechanisms
27
Q

what is a superoxide radical?

A
  • a superoxide radical is very powerful
  • this is a molecule of oxygen that has an extra electron so it is very reactive
28
Q

what is a hydroxyl radical?

A
  • a hydroxyl group that has grabbed an extra electron
  • this is even more reactive than the superoxide radical
  • these radicals are electrophiles
  • DNA is electron-rich
29
Q

how do oxygen free radicals attack DNA?

A
  • single strand breaks are not very damaging
  • double-strand breaks are more dangerous
  • when the base has been oxidized by an oxygen free radical and the DNA repair enzymes come and cut out the base itself it leaves behind the sugar- phosphate backbone with gaps
  • these gaps are called apurinic / apyrimidic sites
  • You can also get base modifications:

Ring- opened guanine + adenine

Thymine + cytosine glycols

8- hydroxyadenine + 8- hydroxyguanine (mutagenic)

30
Q

what is the role of P53 in dealing with cellular stress?

A
  • P53 is a crucial tumour suppressor gene
  • it is normally tied to MDM2 which keeps the P53 inactive
  • when it is released from MDM2 it forms a dimer which activates many different pathways
  • If we have mild physiological stress = p53 carries out a transcriptional series of events and activates proteins that help repair the problem
  • if there is severe stress = p53 can activate an apoptotic pathway by directly interacting with apoptosis proteins
31
Q

what are the 4 main types of DNA repair?

A
  • direct reversal of DN damage
  • base excision repair
  • nucleotide excision repair
  • during or post replication repair
32
Q

explain direct reversal of DNA damage?

A

Photolyases

  • specific group of enzymes called photolyases can reverse cytlobutane- pyrimidine dimers
  • Photolyase looks specifically for cytlobutane=pyrimidine dimers and cuts them to restore the normal sequence
  • this allows repair of the DNA to occur

Methyltransferases and alkyltransferases

  • Methyltransferases and alkyltransferase remove alkyl and methyl groups from bases to restore the identity of the base
  • these enzymes then destroy themselves
33
Q

what is DNA mismatch repair?

A
  • mismatch repair involves scrutinisation of of DNA for apposed bases that do not pair properly
  • Mismatches that arise during replication are corrected by comparing the old and new strands (proofreading)
  • this is in place as there is a large rate of error that takes place in DNA replication
34
Q

why does guanine often form adducts?

A
  • The most electron=rich base is guanine
  • if we introduce an electrophile it will probably target guanine and form a covalent bond, this is toxic and the cell must remove this
35
Q

what is the base excision repair pathway?

A
  • DNA glycosylase hydrolyses between the sugar and the DNA base
  • Then an AP- endonuclease splits the DNA strand so there is a gap in the backbone
  • DNA polymerase then fills in the missing base
  • DNA Ligase then seals the DNA to form intact DNA
36
Q

what is nucleotide excision repair?

A
  • Endonuclease makes two cuts in the DNA on either side of the site of damage
  • These patches can be long (100 - 200 nucleotides) or short (10 - 20 nucleotides)
  • Helicase will then remove this patch, leaving the double stranded DNA with a patch missing
  • DNA Polymerase then replaces the bases that have been removed using the complementary strand as a template
  • DNA Ligase then joins the DNA up again
  • this process is energy demanding and requires a lot of proteins
37
Q

what is Xeroderma Pigmentosum?

this is the main disease to remember

A
  • this is a disease in which nucleotide excision repair does not work properly
  • causes severe light sensitivity
  • severe pigmentation irregularities
  • early onset of skin cancer and GI cancer at high incidence
  • frequent neurological defects
  • this disease is not curable - only managed, must AVOID UV night
38
Q

what is Trichothiodystrophy?

A

this is a disease in which nucleotide excision repair does not work properly

  • sulphur deficient brittle hair
  • facial abnormalities
  • short stature
  • ichthyosis (fish-like scales on the skin)
  • light sensitivity in some cases
39
Q

what is cockaynes syndrome?

A

this is a disease in which nucleotide excision repair does not work properly

  • dwarfism
  • light sensitivity in some cases
  • facial and limb abnormalities
  • neurological abnormalities
  • early death due to neurodegeneration
40
Q

when do DN A double-strand break repairs happen?

A
  • Under physiological conditions during somatic recombination and transposition
  • During Homologous Recombination.
  • As a result of ionizing radiation and oxidative stress induced DNA damage.
41
Q

how to join DNA after DN double-strand break repair?

A

there are two main methods

homologous recombination and nonhomologous DNA end-joining

homologous recombination =

  • Direct joining of the broken ends.
  • This requires proteins that recognize and bind to the exposed ends and bring them together for ligating.
  • this happens with complementary nucleotides

non homologous recombination = (more complicated)

  • 3 DNA ends are picked up by KU proteins
  • KU holds the DNA together and you force the DNA to link up
42
Q

what are the estimated rates of endogenous damage and repair?

A
  • It appears that human cells have plenty of spare capacity to deal with both endogenous and exogenous damage
  • errors occur, especially with greater age
  • If the damage is poorly repaired, then there is greater risk of carcinogenesis
43
Q

what happens if the cell has too much damage?

A

If the DNA damage is excessive, the cells will commit to apoptosis

44
Q

at what point do most issues occur resulting in cancer?

A
  • However, most problems occur between excessive damage and small amounts of damage
  • This could lead to incorrect repair
  • this results in fixed damage in the daughter cells (permanent mutations)
45
Q

how to test for DNA damage in cells?

A
  • You firstly look at the structure of the chemical to see if there are any functional groups that could cause problems
  • The simplest way to see whether an agent can cause mutation is to introduce it to bacteria and see whether it causes mutation
  • if it damages bacteria DNA it might damage human DNA
  • Then you test it on Mammalian Cells
  • then you test it on mammals using bone marrow micronucleus tests
  • bone marrow is used because it contains pleuripotent stem cells
  • This means that you can look at the formed elements of the blood as a mechanism of what is happening in the bone marrow
46
Q

what is the bacterial Ames test for mutagenicity of chemicals?

A
  • Normally, Salmonella typhimurium is used for this assay
  • we take chemical and make it metabolically active
  • to do this we incubate the chemical with a preparation of rat liver enzymes (containing P450 enzymes) and that generates the reactive chemical
  • The bacteria are genetically engineered so that they can NOT produce histidine (amino acid)
  • This means that these bacteria require exogenous histidine to be able to grow
  • However, using the chemical mutagens, these cells can be mutated so that they regain the ability to produce histidine, thus meaning that it can grow in the absence of histidine
  • So you mix the bacteria with the activated chemical and put them on a plate (which doesn’t have any histidine on it)
  • Anything that has NOT been mutated will need exogenous histidine to grow and hence will die on the plate
  • So the more the DNA damaging capability of the chemical, the more colonies will grow in the absence of histidine
47
Q

how to detect DNA damage in mammalian cells?

A
  • We can look at what is happening to the chromosomes themselves
  • Chemicals can cause double strand breaks that leads to fragmentation of chromosomes
  • This is very labour intensive investigation
48
Q

how to use in vitro micronucleus Assays?

A
  • Mammalian cells are treated with the chemical in vitro and allowed to divide
  • We are trying to measure the ability of the chemical to break up DNA into fragments,
  • then we can count the fragments
  • We need the cell to go through one replication cycle and then stop it when a binucleus is formed
  • Cytochalasin=B is used to block cytokinesis
  • Then the binucleate cells are assessed for the presence of micronuclei
  • The kinetochores of the chromosomes can be stained to determine if chemical

treatment caused:
o Clastogenicity = chromosomal breakage
o Aneuploidy = chromosomal loss/change in the number of chromosomes

  • both of these cause cancer
  • The cell on the left has NOT been damaged by the chemical
  • The cell on the right has extra nuclear material
49
Q

how to carry put bone marrow micronucleus in mice or rats?

A
  • You are using the pluripotent nature of the bone marrow in producing blood cells
  • The animals are treated with the chemical and the bone marrow cells or peripheral erythrocytes are examined for the presence of micronuclei
  • The erythrocytes normally remove the nucleus during development but it CAN NOT remove small fragments of DNA (micronucleus)
  • so presence of micronucleus indicates DNA damage which could cause cancer

Year 2 - Cancer (15 decks)

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