Cancer 5 Flashcards
what is the nature of the DNA bases?
- they are flat carbon rings
- they are chemically reactive species able to react with other molecules
- they contain double bonds
- they are easily mutated

what is deamination?
- 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.

what causes hyper-reactive oxygen to be formed?
bases can undergo reactions which produce hyper-reactive oxygen as by-products
eg. singlet oxygen, peroxide radicals, hydrogen peroxide, and hydroxyl radicals
what causes modifications of DNA to be formed?
- ionising radiation
- hyper- reactive oxygen species
what is a common oxidation reaction?
- A common product of thymine oxidation is thymine glycol

what happens to the glycol?
- 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’
What is photodamage to the DNA?
- 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.
what are the types of DNA damage?
- 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

what can cause damage to DNA?
- 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

why is DNA damage important?
- DNA damage can lead to mutation
- mutation can lead to cancer
- •Damaging DNA is an important strategy in cancer therapy
how can carcinogens cause DNA damage?
- Base Dimers and Chemical Cross=Links
- Base Hydroxylations
- Abasic Sites
- Single Strand Breaks
- Double Strand Breaks
- DNA Adducts and Alkylation

explain base dimers and chemical cross-links ?
- This is where the DNA molecules are being chemically linked up
explain base hydroxylations?
- 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
explain abasic sites?
- 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
explain single-strand breaks?
- 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
explain double-strand breaks?
- 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
explain DNA adducts and alkylation?
- 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
what are polycyclic aromatic hydrocarbons?
- Polycyclic aromatic hydrocarbons are common environmental pollutants
- they are present in smoke

overview drug metabolism in the body?
- 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
what are the main enzymes in phase 1?
- Cyrochrome P450 enzymes
- responsible for oxidising chemicals
what is the two-step Oxidation of Benzo[a]pyrene (B[a]P)?
explain why the two-step oxidation of Benzo[a]pyrene (B[a]P) is dangerous?
- 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
explain why the metabolism of aflatoxin B1 is dangerous ?
- 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
explain why the metabolism of 2-naphthylamine is dangerous?
- 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




