Chemo agents acting on antimetabolites

Question 1

What is the moa of antimetabolites?

Answer 1

• Are false substrates for critical nucleotides biosynthesis enzymes
• They cause a chemical entrapment that entice enzymes to bind irreversibly instead of endogenous substrate
• nucleotides are not synthesised
• DNA not synthesised
• tumour growth arrested

Question 2

What are the types of antimetabolites

Answer 2

Pyrimide antagonists (Fluoruracil, Capecitabine)
Purine antagonists (Mercaptopurine, Thioguanine)
Folate antagonists (Methotrexate)
DNA polymerase and elongation inhibitors (Gemcitabine)

Question 3

How does 5-FU work?

Answer 3

• A pyrimidine antagonist
• Inhibits thymidylate synthase
• dUMP can’t be converted to dTMP
• No thymidine
• No DNA
• apoptosis
  (irreversible)

Question 4

What is the difference between Capecitabine and 5-FU?

Answer 4

Capecitabine is the pro-drug of 5 FU

• it is converted to 5-FdUMP in vivo inhibiting thymidylate synthase
• Capecitabine is given orally whereas 5FU is IV ad

Question 5

Name 2 purine antagonists

Answer 5

Mercaptopurine

Thioguanine

Question 6

How do purine antagonists work?

Answer 6

• Prodrugs converted to ribonucleotides in vivo
• they target amidophopshorobosyl transferase
• inhibits adenylic acid and guanylic acid synthesis
• which inhibits further elongation
• promotes apoptosis

Question 7

How do folate antagonists work? Give an example

Answer 7

Methotrexate

• binds to dihydrofolate reductase instead of 7,8-dihydrofolate binding to DHFR
• DHFR cant reduce mtx
• stops synthesis dTMP
• no thymine
• no DNA
• apoptosis

Question 8

How do DNA polymerase and elongation inhibitors work?

Answer 8

• inhibitors taken up into cells via selective nucleotide transporter protein
• specific kinases conduct phosphorylation
• inhibitor incorporated into the growing DNA chain
• arrests further elongation (chain terminator)
• or inhibits enzymes essential for DNA synthesis