Anti-Metbolites

Question 1

What are anti-metabolites?

Answer 1

They are chemicals that inhibit the use of a metabolite where the metabolite is a naturally occurring chemical that is part of normal metabolism. Thus, they are similar in structure to the metabolite they interfere with.

Question 2

Comment on the selectivity of anti-metabolites.

Answer 2

They are similar in structure to the metabolite they interfere with. Because of this, they have poor selectivity and are also effective against healthy tissues.

Question 3

Chemically, what are anti-metabolites often?

Answer 3

They are often purine, pyridine, and pteridine (folate) analogues.

Question 4

During what phase of the cell replication cycle do anti-metabolites have an effect?

Answer 4

The S phase.

Question 5

Why is it often necessary to give supplements with anti-metabolite therapy?

Answer 5

It is often required to give supplements to reduce the effect of these anti-metabolites on healthy cells.

Question 6

Are anti-metabolites restricted to use in the treatment of cancer?

Answer 6

No. Sulphonamides are also antimetabolites and they are used as antibacterials.

Question 7

Describe fludarabine.

Answer 7

Fludarabine is a purine anti-metabolite given orally or IV. It interferes with ribonucleotide reductase and DNA polymerase enzymes. It is active against both dividing and resting cells.

Question 8

Describe the structure of fludarabine.

Answer 8

It is a fluorinated analogue of adenine attached to an arabinose sugar C2’ OH has the beta configuration (up) compared with ribose (down).

Question 9

Fludarabine is used in the treatment of non-Hodgkin’s lymphomas in combination with which drugs?

Answer 9

Cyclophosphamide, mitoxantrone, dexamethasone, rituximab.

Question 10

Describe cyclophosphamide.

Answer 10

A DNA alkylator acting at the N7 of guanine.

Question 11

Describe mitoxantrone.

Answer 11

Topoisomerase II inhibitor, interferes with DNA replication/repair.

Question 12

Describe dexamethasone.

Answer 12

A steroid to counteract the side effects of chemotherapy.

Question 13

Describe rituximab.

Answer 13

A monoclonal antibody, destroys excessive, overactive B lymphocytes.

Question 14

Describe purine anti-cancer agents.

Answer 14

Purine bases are prodrugs that exploit the purine salvage pathway.

Question 15

What are purine anti-cancer agents used against?

Answer 15

Purine anticancer agents are used against leukaemia and non-Hodgkin’s lymphoma, as well as others.

Question 16

What drug has an interaction with mercaptopurine? What is the result of this reaction?

Answer 16

There is a drug interaction with allopurinol (a xanthine oxidase inhibitor) that can exacerbate mercaptopurine toxicity.

Question 17

Describe anti-folates.

Answer 17

These are agents which mimic the structure of folic acid and inhibit dihydrofolate reductase. They are made up of a section that mimics the folic acid base, and a section that mimics the side chain.

Question 18

Describe methotrexate.

Answer 18

This is an anticancer agent which is the most tightly binding DHFR inhibitor. It is an irreversible DHFR antagonist.

Question 19

Describe premetrexed.

Answer 19

This is an agent used to treat lung cancer. It is combined with cisplatin and the steroid dexamethasone.

Question 20

Describe leucovorin (folinic acid).

Answer 20

This is an agent used in rescue therapy. It combats the toxicity caused by the use of methotrexate and purine antimetabolits. It kickstarts the ‘folate pool’.

Question 21

By what other name is leucovorin known?

Answer 21

Folinic acid.

Question 22

What compound is also known as folinic acid?

Answer 22

Leucovorin.

Question 23

5-FU is a prodrug, what is it converted to? By what mechanism does this occur?

Answer 23

5-FU is a prodrug that is converted to active 5-FdU by pyrimidine salvage.

Question 24

How does 5-FdU inhibit thymidylate synthase?

Answer 24

The molecule has an F atom. The removal of the F+ is impossible as it can’t accept a positive charge. Hence, the compound stays in the enzymes active site and the reaction remains incomplete.

Question 25

What enzyme does 5-FdU inhibit?

Answer 25

Thymidylate synthase.