Chemo agents acting on nucleic acids

Question 1

What is the moa of alkylating agents (Cyclophosphamide)?

Answer 1

• 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

Question 2

What is the moa of intercalating agents (Doxorubicin, Mitoxantrone)?

Answer 2

• 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

Question 3

What is the main side effect of Doxorubicin and how does this occur?

Answer 3

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)

Question 4

What is the moa of non intercalating topoisomerase inhibitors (Etoposide, Tenoposide)?

Answer 4

• Stabilises the covalent intermediate between DNA and topoisomerase 2
• This means DNA strands are not rejoined therefore not repaired
• This damage causes cytotoxic effects

Question 5

What is the role of topoisomerase?

Answer 5

DNA replication
Transcription
Chromosome separation
DNA repair

Question 6

Give 2 examples of non intercalating agents and explain which one is better

Answer 6

Etoposide

Tenoposide - is lipophilic/hydrophobic which increases cytotoxic effect than etoposide

Question 7

What is prescribed alongside a non intercalating agent and why?

Answer 7

DNA disruptors

As they are useless if the DNA is not damaged

Question 8

How does Bleomcyin and dactinamcyin work?

Answer 8

Drugs can bind in major (bleomycin) /minor (dactinomycin) groove of DNA
drugs have high affinity/selectivity with DNA

Question 9

How does Bleomycin resistance occur?

Answer 9

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

Question 10

What does bleomycin cause and why?

Answer 10

Pulmonary and skin toxicities e.g., Raynaud’s

it is broken down by bleomycin hydrase in all tissues except skin and lungs

Question 11

How does O6 methylation of guanine occur?

Answer 11

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

Question 12

Name 3 drugs that are known to methylate O6 position of guanine

Answer 12

Procarbazine
Dacrabazine
Temozolomide

Question 13

How does Procarbazine methylate O6 guanine?

Answer 13

• 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

Question 14

What does Procarbazine inhibit?

Answer 14

monoamine oxidase

enzymes involved in ethanol metabolism

Question 15

How does dacarbazine and Temozolimde methylate O6 guanine

Answer 15

Methylate guanine via diazomethane and/or methyl carbocations generated in situ

Question 16

How does Temozolimide resistance occur?

Answer 16

• 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

Question 17

Name the alkylating agents

Answer 17

Cylcophosphamide
Procarbazine, dacarbazine, Temozolimide
Busulfan

Question 18

What is the moa of busulfan?

Answer 18

• causes N7 methylation
• where one or both methylsulfonate esters can be displaced
• causing monoalkylation and/or cross linked DNA

Question 19

Name 3 examples of organoplatinum complexes

Answer 19

Cisplatin
Carboplatin
Oxaliplatin

Question 20

what is the moa of platins?

Answer 20

• 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

Question 21

What does platins cause?

Answer 21

Kidney toxicity as platins are eliminated by the kidneys

Question 22

How can kidney toxicity be managed with platins?

Answer 22

Sodium thiosulfate - to neutralise the active drug in the renal tubules
aggressively hydrate
use diuretics