Wk 14: Antimetabolites Flashcards
(35 cards)
1
Q
What is an antimetabolite?
A
- Structurally similar to essential metabolite but cannot take its place
- Analogue of natural substrate + changed biosterically
- Interfere w/ normal cellular function, affects nucleotide production
- Interacts with all rapidly dividing cells
2
Q
Is folic acid (b9) active?
A
No - converted to dihydrofolic + tetrahydrofolic acid
3
Q
What does lack of dietary folic acid lead to in pregnant women?
A
Neural tube defects in embryos
4
Q
What is folic acid essential for in the body?
A
- Nucleotide biosynthesis
- DNA synthesis
- DNA repair
- Cofactor in bio reactions
- Prod healthy RBC
5
Q
Is folic acid used in leukaemia patients?
A
No - decline in health
6
Q
How does folic acid help in DNA synthesis?
A
Provides essential 1 carbon donors:
- Formyl donor: purine biosynthesis
- Methyl donor: pyrimidine biosynthesis
7
Q
What does methotrexate do at low doses?
A
- Interferes w/ inflammatory actions of IL-1
- Stims adenosine release
- Apoptosis + death of activated T-lymphocytes
8
Q
What does methotrexate do at high doses?
A
- Dihydrofolate reductase inhibitor
- DHFR - regenerates folic acid cofactors required for DNA synthesis
- Binds to DHFR upside down relative to dihydrofolate
- Depletes formyl + methyl 1 carbon donors
- Inhibits pyrimidine + purine biosynthesis
9
Q
Other than inhibiting DHFR, what does methotrexate also inhibit?
A
Folate dependent enzymes:
- Accumulation of methotrexate polyglutamates
- Accumulation of dihydrofolate polyglutamate
10
Q
What is used fo rescue therapy in methotrexate toxicity?
A
Folinic acid (N5-formyltetrahydrofolate)
- Readily converted to reduced folic acid derivatives
- Doesn’t require DHFR for conversion: unaffected by DHFR inhibition + allows purine/pyrimidine synthesis in presence of DHFR inhibition
11
Q
What is 5-fluorouracil?
A
- Pro-drug
- In vivo: converted unto 5-FdUMP
12
Q
What does 5-FdUMP do?
A
- Directly inhibits enzyme thymidylate synthase, tf inhibits DNA synthesis
- Resistance: down regulation of enzymes needed to add deoxyribose phosphate to form 5-FdUMP
13
Q
What is the mechanism of 5-FU?
A
- Fl = electronegative
- C-F is polarised
- Base from thymidylate synthase cannot abstract proton from 5-FU
- 5-H in dUMP replaced by 5-F in 5-FdUMP
- Fδ- + base on TS repel each other
- C-F bond strong
- F+ not leaving group
- 5-FU covalently bonded to thymidylate synthase
- Cells unable to make dTMP = inhibits DNA synthesis
14
Q
How does 5-FU cause apoptosis?
A
- Mimic pyrimidine nucleotide, producing abnormal variant: Unstable DNA, Vital cellular function interfered, Leads to apoptosis (S phase)
- Inhibits TS, depletes cell of dTTP, accumulation of dUMP, inc uracil misincorporation in DNA
15
Q
How does 5-FU cause sustained inhibition?
A
- TS, FdUMP + active folate cofactor covalently bind
- Mechanism dependent on cofactor conc
- Boost cofactor conc + 5-FU activity using folinic acid
16
Q
What is in tegafur-uracil?
A
- Tegafur: 5FU prodrug - converted by orate phosphoribosyltransferase, greater conversion in tumour cells
- Uracil: inhibits 5-FU breakdown, dihydropyrimidine dehydrogenase inhibitor
17
Q
What is in tegafur-gimeracil-oteracil?
A
- Tegafur: 5FU prodrug
- Gimeracil: inhibits 5-FU metabolism by reversibly blocking dihydropyrimidine dehydrogenase
- Oteracil: remains in GI tract due to low permeability, red 5-FU prod by blocking metabolism of tegafur, lower 5-FU in GI = lower GI toxicity
18
Q
How does resistance of 5-FU occur?
A
- Red uptake of 5-FU in cell
- Red expression of enzymes that activate prodrug
- Inc expression of thymidylate synthase
- More discriminating target enzymes
- Low folate cofactor levels
19
Q
What is capecitabine?
A
- Oral prodrug of 5-FU
- More selective: Thymidine phosphorylase found in higher levels in tumour tissue
20
Q
What is given following an overdose of fluropyrimidine treatment?
A
Uridine triacetate
21
Q
What increases the risk of toxicity in patients receiving fluoropyrimidine treatment?
A
Inherited DPD deficiency
22
Q
When would you not need DPYD screening when using fluoropyrimidine treatment?
A
- Topical fluorouracil cream: systemic abs low
- Flucytosine: severe fungal infections shouldn’t be delayed
23
Q
What would you do if a patient is partially DPD deficient?
A
- Dose red
- Inc monitoring
24
Q
How many DPYD variants are associated with DPD deficiency?
A
4
25
How do you screen for DPD deficiency?
- PCR + DNA analysis
- Phenotype: measure uracil in plasma, measure DPD/TS activity in mononuclear cells, measure dihydrouracil in blood, urine or saliva
26
What is raltitrexed?
- Folic acid analogue
- Blocks folate binding of thymidine synthetase by mimcing N5, N10 methylenetetrahydrofolate
- Inhibits thymidylate synthase activity
27
What is the mechanism of action of pemetrexed?
Inhibits:
- TS
- DHFR
- GARFT: catalyses formation of glycinamide ribonucleotide
28
What is the mechanism of action of cytarabine?
- OH inverted at C-2 compared to ribose, araC phosphorylated to araCTP, competes w/ dCTP for DNA
- Blocks strand elongation + repair mechanism
- Inhibits reduction of CDP to dCDP
- Orally inactivated: cytidine deaminase in intestinal mucosa
29
What is the mechanism of action of gemcitabine?
- Phosphorylation by deoxycytidine kinase = dFdCMP
- dFdCMP = ribonucleotide reductase inhibitor, inhibits DNA synthesis
- Additional phosphorylation = active metabolite dFdCTP
- dFdCTP inhibits DNA polymerase + chain elongation
- dFdCTP added to growing DNA causing strand termination + apoptosis
30
What is the mechanism of action of azacitidine?
Metabolised to triphosphate + incorporated into RNA/DNA
RNA
- Dissembly polyribosome
- Defective methylation + acceptor function of transfer RNA
- Inhibits protein prod
DNA
- Covalent binding w/ DNA methyltransferase preventing DNA synthesis
31
What is the mechanism of action of decitabine?
- Metabolised to triphosphate + incorporated into DNA
- Covalent binding w/ DNA methyltransferase preventing DNA synthesis
32
What is the mechanism of action of cladribine?
- Mimics adenosine inhibiting adenosine demaines
- Interfere w/ DNA processing
- Activated by lymphocytes
33
What is the mechanism of action of fludarabine?
- Interferes w/ ribonucleotide reductase + DNA polymerase
- Active against dividing + resting cells
- Ionised at physiological pH
34
What is the mechanism of action of lonsurf?
Trifluridine:
- Monophosphate: binds covalently to tyrosine 146 active site of TS, inhibiting the enzyme
- Triphosphate: incorporated in DNA
Tipiracil:
- Prevents degradation of trifluridine via TD
35
What is the mechanism of action of mercaptopurine?
- Biosteric change = aspartic acids doesn't react to mercaptopurine as C isn't electrophilic enough
- Competes w/ IMP, blocking AMP production
- Also converted to XMP, blocking GMP synthesis
- Mimics IMP + converted to thioGMP: unstable nucleic acids + interferes w/ replication
