Anti-folate drugs

Question 1

Example drug

Answer 1

Methotrexate

Question 2

Mechanism of action

Answer 2

Main function of MTX/MTXPG: is inhibition of the enzyme dihydrofolate reductase (DHFR) and other enzymes such as ATIC involved in purine synthesis pathways
- which converts dihydrofolate (DHF) to tetrahydrofolate (THF). THF is essential for de novo purine synthesis results in impaired DNA formation and repair

The effect of MTX depends on the function and expression of several other enzymes in the folate pathway, including Thymidylate synthetase (TS). TS converts THF with addition of deoxyuridine monophosphate (dUMP) back to DHF and deoxythymidine monophosphate (dTMP)

Compared with MTX, the active metabolites MTXPGs induce stronger inhibition of the target enzymes (i.e., TS and DHFR) and further inhibit key enzymes ATIC in the de novo purine synthesis pathway.

Question 3

Metabolism

Answer 3

Methotrexate is administered orally, IV or intrathecally.
It is rapidly eliminated by renal excretion and metabolism withe a half life of 3-10 hours and 8-15 hours (dose dependent)

Inside the cells, MTX is converted to active methotrexate polyglutamates (MTXPGs) by folylpolyglutamate synthetase (FPGS), which adds glutamate residues to MTX.

It has prolonged cellular retention as it is polyglutamated.

Question 4

Drug resistance

Answer 4

Bertino et al 1996, different resistance mechanisms have been described in cells that survive MTX treatment:

1) decreased retention as a consequence of lack of polyglutamate formation;
2) an increase in DHFR: an important mechanism of resistance of cells to MTX is an increase in DHFR activity due to amplification of the DHFR gene
3) an increased level of a lysosomal enzyme, γ-glutamyl hydrolase, that hydrolyses MTX polyglutamates

Question 5

Tumor types

Answer 5

Breast cancer
Leukaemia
Lung cancer
Lymphoma 
Osteosarcoma

Question 6

Toxicity

Answer 6

1. Myelosuppression
2. Muscositis
3. Nephrotoxicity