Antimetabolites Flashcards
What are antimetabolites
Drugs that interfere with the formation of key biomolecules within the cell - often targeting key enzymes
Hinder DNA replication and thus cell division and some interfere with RNA production
Several classes = Folate antagonist, pyrimidine antagonist and purine antagonists
what is folic acid
Pteroic acid with a glutamate
Water soluble B vitamine
Pregnant/lactating mothers require 400 micrograms per day or more
AMP and GMP =
dTMP =
- made from common precursorr IMP
- synthesised from dUMP
What does folates work in the body
Co-enzyme in the synthesis of nucleotide precursors
Acts as one-carbon donor, only active in a fully reduced form
How is dTMP synthesised
dUMP -> dTMP via thymidylate synthase
in conjunction to N5N10-methyleneTHF -> dihydrofolate
How is dihydrofolate recycled
dihydrofolate -> tetrahydrofolate via dihydrofolate reductase (in conjunction to NADPH+ -> NADP+)
How does tetrahydrofolate converted to N5N10-Methylene H4 folate
Serine -> Glycine - Serine hydroxymethyl transferase
How does intracellular polygultamation work ?
Gamma glutamyl hydrolase (folypolyglutamate synthetase)
Why do cells add glutamate molecules (poylgultamation)
- Makes structure bigger
- increases ability to be a co-factor
- allows cells to hang onto folate
- allows\selective retention
- enhances cofactor affinity TS and AICAR transformylase
Antifolates are _ _
Folate analogues
Methotrexate, Dihydrofolate
Name a commonly used antifolate
Methotrexate
- widely used in many tumour types, also used in non-malignant conditions
What is the main mechanism of action of methotrexate
analogue of dihydrofolate and therefore inhibits dihydrofolate reductase
Methotrexate is _
So also works by
- MTX/polyglutatmates are tight binding inhibitors of dihydrofolate reductase therefore there is a reduction in reduced folate pool
- Inhibits of the folate dependent enzymes GART & AICART inhibition of purine synthesis
MTX inhibition is _
reversibile - can out compete with Dihydrofolate or reduced folate
Describe the difference between Methotrexate and methotrexate polyglutamate
polyglutamates are better inhibitors of dihydrofolate reductase (slower dissociation half life)
- formation is higher in malignant cells
- have better retention
_% of methotrexate may be polyglutamated
80
What are the biochemical consequences of methotrexate
○ Active against rapidly dividing cells
○ Decreased dTTP and increased dUTP
○ inappropriate incorporation of uracil into DNA
○ Inhibition of chain elongation
○ Excision of uracil leads to strand breaks
○ repair and/or death (via p53)
How does methotrexate enter the cell
by an energy dependent, temperature sensitive and concentrative process
- using reduced folate carriers
Outline the clinical pharamacology of methotrexate
Oral/IV or intrathecal administration
Elimination half life of 3h in 1st phase, 8-10 in final
Low doese remaining can contribute to significant toxicity
Excretion = renal
What are the toxicites surrounding methotrexate
Myelosuppression, mucositis and nephrotoxicity
What is used to combat overdose/ toxic effect
leucovorin rescue
can prevent toxicity to bone marrow and GI tract
Acts as a competitor for transport/polyglutamation and targeted enzymes
_ _ may also decrease methotrexate toxicity
exogenous thymidine
Outline what we know about pralatrexate
- 10-fold greater affinity for the reduced folate carriers than methotrexate
- inhibits tumour cell growth at 30- to 40-fold lower extracellular concentrations than MTX
- higher polyglutamation.
- Approved for T-cell lymphoma
Outline what we know about pemetrexed
– readily transported into cells via the RFC
– Multitargeted antifolate, principally TS but also DHFR and GART
– Approved for mesothelioma
what is 5-fluorouracil
analogue of uracil but has fluorine atom on carbon 5 position
still used after 40 years, activity is colorectal, breast, head, neck and pancreatic cancer
what happens to 5-fluorouracil in the body
require intracellular metabolism to cytotoxic forms
- either uridine phosphorylase -> LUrd -> FUMP and incorporation into RNA
- either thymidine phosphorylase dFUrd -> FdUMP and incorporation into DNA
How does thymidylate synthase become inhibits
FrUMP inhibits TS in the presence of reduced folate cofactor (covalent complex)
- competes with dUMP for catalytic site
== dTMP depletion
How does are either incorparation effected by 5-fluorouracil
incorporation into RNA has a significant effect at higher concs and inhibits RNA processing
Incorporation into DNA, repaired and results in strand break
Outline 5-fluorouracil catabolism
Initial reduction mediated by dihydropyrimidine dehydrogenase
- then undergoes dihydropyrimidinase into a-fluoroureido-propionic acid
- then the final breakdown product is fluoro-B-alanine (via B-alanine synthase)
How does genotype effect 5-FU treatment
- Low DPD activity can lead to increased exposure to active metabolites and results in severe or even fatal toxicity
- DPD status should be determined before treatment with 5FU
Outline 5-FU clinical pharmacology
- poor oral bioavailability - massively improved with DPD inhibitor
- saturable 1st pass metabolism
- high clearance
- half life (10-20 mins) - with a DPD inhibitor hl = 5h
what is the clinical activity of 5-FU
- Adjuvant treatment of colorectal carcinoma
(with leucovorin) = Metabolism of 5-formyl-FH4 to CH2FH4 - Adjuvant treatment of early breast
carcinoma (with methotrexate and
cyclophosphamide) - Toxicities mainly GI (mucositis, diarrhoea)
- Hand-foot (palmar plantar) syndrome
