Anti-Metabolitites

Question 1

What are the hallmarks of cancer?

Answer 1

Self sufficient in growth signals
Insensitive to anti growth signals 
Evasion of programmed cell death 
Limitless replicative potential 
Sustained angiogenesis 
Tissue invasion and metastasis

Question 2

How do antimetabolites kill cancer cells?

Answer 2

By inhibiting a critical cellular process.

Question 3

Why are most antimetabolites inhibitors of critical enzymes involved in DNA biosynthesis?

Answer 3

Because biosynthesis of DNA is essential to proliferation of tumour cells.

Question 4

What are the four main groups of antimetabolite drugs?

Answer 4

Folate antagonists eg methotrexate
Pyrimidine antagonists eg 5-Flurouracil
Purine antagonists eg 6-Mercaptopurine
Sugar modified nucleosides eg Cytarabine

Question 5

What is folate?

Answer 5

Folate is vitamin b9. It is an essential vitamin and cannot be synthesised by the body. Folic acid is converted to folate by the body and used as a dietary supplement. Folate is required by the body for the synthesis of DNA and RNA and to metabolise amino acids.

Question 6

What are the mechanisms of resistance to methotrexate?

Answer 6

Mutations of the DHFR enzyme, modifying folate binding site.
Multidrug resistance phenotype causing active efflux of drug
Mutations to RFC, reducing uptake

Question 7

What is methotrexate?

Answer 7

It is an analogue of dihydrofolate which binds to DHFR at folate binding site.
It is a very potent competitive inhibitor of DHFR.
It is too polar for passive diffusion into cells and is taken up by reduced folate carrier. It must be polyglutamylated to be restrained in cells.
Often used in high dose regimen with leucovorin rescue of normal cells.
It is widely used against many cancer types.

Question 8

What are anti metabolites lipophilic antifolates?

Answer 8

Nolatrexed – inhibits DHFR and TS active against carcinoma.
Piritrexim – potent lipophilic inhibitor of DHFR, active in several tumour types.
Methylbenzoprim – very potent experimental lipophilic inhibitor of DHFR.
Pyrimethamine – inhibits DHFR of many species, mainly used as antibacterial

Question 9

What are anti-metabolities, inhibitors of thymidylate synthase?

Answer 9

Pemetrexed and Raltitrexed, they are competitive inhibitors of TS and binding at the 5, 10-CH2 tetrahydrofolate biding site.

Question 10

What is Azacytidine?

Answer 10

A weak inhibitor of TS.
Phosphorylated to form azacytidine triphosphate then incorporated into RNA.
Mimics C in RNA but unstable and decomposes causing damage to RNA.
It inhibits DNA methyltransferases.

Question 11

What are examples of sugar modified nucleosides?

Answer 11

Cytarabine – converted to triphosphate
Fludarabine – converted to triphosphate
Gemcitabine – converted to triphosphate F2dCTP and diphosphate F2dCDP.
Triphosphate inhibits DNA polymerase as an analogue of dCTP.