A. FOLIC ACID ANALOGUES: METHOTREXATE, PEMETREXED
Mechanisms of Action
- competitive inhibitors of dihydrofolate reductase (DHFR) and the folate-dependent enzymes of purine and thymidylate synthesis in all species
- MTX causes depletion of cellular TH4 stores
- PEMETREXED and PRALATREXATE are better antagonists of thymidylate synthase and of purine synthesis than of DHFR
- net result:
- inhibition of DNA synthesis by blocking BOTH purine and deoxythymidylate synthesis
- this is the key requirement for antineoplastic action
- decreased methionine synthesis
- decreased amino acid metabolism
- inhibition of DNA synthesis by blocking BOTH purine and deoxythymidylate synthesis
- in order to be effective, folic acid analogues must have glutamates added - this causes more potent binding to folate-dependent enzymes and also prevents the drugs from leaving cell
- tumour cells are more capable of polyglutamating à selective toxicity