Chemo agents acting on nucleic acids Flashcards
What is the moa of alkylating agents (Cyclophosphamide)?
- Forms a highly reactive aziridinium ion that can be attacked by nucleophilic DNA bases e.g. guanine
- In this reaction, the alkyl groups are transferred to nucleophilic sites of DNA bases
- this can occur twice leading to cross linked DNA
- Damage caused cannot be repaired so cancer cells can no longer proliferate
What is the moa of intercalating agents (Doxorubicin, Mitoxantrone)?
- Insert themselves into the space between successive DNA base pairs
- Leads to unwinding of DNA helix
- Altering the DNA structure which causes functional changes
- transcription and replication cant happen
- causes cells to die
- MUST have planar aromatic rings
What is the main side effect of Doxorubicin and how does this occur?
Cardiomyopathy
generates ROS which can pair with other oxygen radicals to form hydrogen peroxide which causes cardiac damage
- therefore there is a lifetime max dose of 450mg/m2 for all anthracycline (-icin)
What is the moa of non intercalating topoisomerase inhibitors (Etoposide, Tenoposide)?
- Stabilises the covalent intermediate between DNA and topoisomerase 2
- This means DNA strands are not rejoined therefore not repaired
- This damage causes cytotoxic effects
What is the role of topoisomerase?
DNA replication
Transcription
Chromosome separation
DNA repair
Give 2 examples of non intercalating agents and explain which one is better
Etoposide
Tenoposide - is lipophilic/hydrophobic which increases cytotoxic effect than etoposide
What is prescribed alongside a non intercalating agent and why?
DNA disruptors
As they are useless if the DNA is not damaged
How does Bleomcyin and dactinamcyin work?
Drugs can bind in major (bleomycin) /minor (dactinomycin) groove of DNA
drugs have high affinity/selectivity with DNA
How does Bleomycin resistance occur?
Bleomcyin hydrase is an enzyme present in all tissues except in skin and lung
converts amide group in bleomycin into inactive carboxylate ionised metabolite
therefore bleomycin hydrase destroys bleomycin
What does bleomycin cause and why?
Pulmonary and skin toxicities e.g., Raynaud’s
it is broken down by bleomycin hydrase in all tissues except skin and lungs
How does O6 methylation of guanine occur?
Drugs methylate O6 position of guanine
forms O6 methylguanine
whihc preferentially pairs with thymine
this is a mispair as guanine should pair with cytosine
this leads to a mutation and cancer cell destruction
Name 3 drugs that are known to methylate O6 position of guanine
Procarbazine
Dacrabazine
Temozolomide
How does Procarbazine methylate O6 guanine?
- it alkylates the DNA via a radical based mechanism
- oxidation occurs to form methylhydrazine
- which produces a methyl radical
- which methylates O6 position of guanine
What does Procarbazine inhibit?
monoamine oxidase
enzymes involved in ethanol metabolism
How does dacarbazine and Temozolimde methylate O6 guanine
Methylate guanine via diazomethane and/or methyl carbocations generated in situ
How does Temozolimide resistance occur?
- due to an enzyme called MGMT which is over expressed in tumours
- it binds to DNA and flips methylated DNA base out of helix
- and into catalytic site
- which catalyses the transfer of the methyl group to cytosine residue in active site
- alkylation caused by temozolimide is overcome
Name the alkylating agents
Cylcophosphamide
Procarbazine, dacarbazine, Temozolimide
Busulfan
What is the moa of busulfan?
- causes N7 methylation
- where one or both methylsulfonate esters can be displaced
- causing monoalkylation and/or cross linked DNA
Name 3 examples of organoplatinum complexes
Cisplatin
Carboplatin
Oxaliplatin
what is the moa of platins?
- Platins contain electron deficient metal atom
- which attracts e- rich DNA nucleophiles
- before reacting w DNA, e- donating ligand (Cl)
- is displaced by cellular water
- platins are bifunctional and can accept 2 DNA nucleophiles
- and intrastrand cross links occur between adjacent guanines
- which distorts the DNA and it cannot repair the damage
- cell goes into cell cycle arrest
- triggers apoptosis
What does platins cause?
Kidney toxicity as platins are eliminated by the kidneys
How can kidney toxicity be managed with platins?
Sodium thiosulfate - to neutralise the active drug in the renal tubules
aggressively hydrate
use diuretics
