Anti-Metbolites Flashcards
What are anti-metabolites?
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.
Comment on the selectivity of anti-metabolites.
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.
Chemically, what are anti-metabolites often?
They are often purine, pyridine, and pteridine (folate) analogues.
During what phase of the cell replication cycle do anti-metabolites have an effect?
The S phase.
Why is it often necessary to give supplements with anti-metabolite therapy?
It is often required to give supplements to reduce the effect of these anti-metabolites on healthy cells.
Are anti-metabolites restricted to use in the treatment of cancer?
No. Sulphonamides are also antimetabolites and they are used as antibacterials.
Describe fludarabine.
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.
Describe the structure of fludarabine.
It is a fluorinated analogue of adenine attached to an arabinose sugar C2’ OH has the beta configuration (up) compared with ribose (down).
Fludarabine is used in the treatment of non-Hodgkin’s lymphomas in combination with which drugs?
Cyclophosphamide, mitoxantrone, dexamethasone, rituximab.
Describe cyclophosphamide.
A DNA alkylator acting at the N7 of guanine.
Describe mitoxantrone.
Topoisomerase II inhibitor, interferes with DNA replication/repair.
Describe dexamethasone.
A steroid to counteract the side effects of chemotherapy.
Describe rituximab.
A monoclonal antibody, destroys excessive, overactive B lymphocytes.
Describe purine anti-cancer agents.
Purine bases are prodrugs that exploit the purine salvage pathway.
What are purine anti-cancer agents used against?
Purine anticancer agents are used against leukaemia and non-Hodgkin’s lymphoma, as well as others.
What drug has an interaction with mercaptopurine? What is the result of this reaction?
There is a drug interaction with allopurinol (a xanthine oxidase inhibitor) that can exacerbate mercaptopurine toxicity.
Describe anti-folates.
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.
Describe methotrexate.
This is an anticancer agent which is the most tightly binding DHFR inhibitor. It is an irreversible DHFR antagonist.
Describe premetrexed.
This is an agent used to treat lung cancer. It is combined with cisplatin and the steroid dexamethasone.
Describe leucovorin (folinic acid).
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’.
By what other name is leucovorin known?
Folinic acid.
What compound is also known as folinic acid?
Leucovorin.
5-FU is a prodrug, what is it converted to? By what mechanism does this occur?
5-FU is a prodrug that is converted to active 5-FdU by pyrimidine salvage.
How does 5-FdU inhibit thymidylate synthase?
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.
What enzyme does 5-FdU inhibit?
Thymidylate synthase.
