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PHAM02 > Wk 14: Antimetabolites > Flashcards

Wk 14: Antimetabolites Flashcards

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
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2
Q

Is folic acid (b9) active?

A

No - converted to dihydrofolic + tetrahydrofolic acid

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3
Q

What does lack of dietary folic acid lead to in pregnant women?

A

Neural tube defects in embryos

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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
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5
Q

Is folic acid used in leukaemia patients?

A

No - decline in health

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6
Q

How does folic acid help in DNA synthesis?

A

Provides essential 1 carbon donors:

  • Formyl donor: purine biosynthesis
  • Methyl donor: pyrimidine biosynthesis
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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
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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
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9
Q

Other than inhibiting DHFR, what does methotrexate also inhibit?

A

Folate dependent enzymes:

  • Accumulation of methotrexate polyglutamates
  • Accumulation of dihydrofolate polyglutamate
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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
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11
Q

What is 5-fluorouracil?

A
  • Pro-drug
  • In vivo: converted unto 5-FdUMP
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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
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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
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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
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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
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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
Q

How do you screen for DPD deficiency?

A
  • PCR + DNA analysis
  • Phenotype: measure uracil in plasma, measure DPD/TS activity in mononuclear cells, measure dihydrouracil in blood, urine or saliva
26
Q

What is raltitrexed?

A
  • Folic acid analogue
  • Blocks folate binding of thymidine synthetase by mimcing N5, N10 methylenetetrahydrofolate
  • Inhibits thymidylate synthase activity
27
Q

What is the mechanism of action of pemetrexed?

A

Inhibits:
- TS

  • DHFR
  • GARFT: catalyses formation of glycinamide ribonucleotide
28
Q

What is the mechanism of action of cytarabine?

A
  • 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
Q

What is the mechanism of action of gemcitabine?

A
  • 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
Q

What is the mechanism of action of azacitidine?

A

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
Q

What is the mechanism of action of decitabine?

A
  • Metabolised to triphosphate + incorporated into DNA
  • Covalent binding w/ DNA methyltransferase preventing DNA synthesis
32
Q

What is the mechanism of action of cladribine?

A
  • Mimics adenosine inhibiting adenosine demaines
  • Interfere w/ DNA processing
  • Activated by lymphocytes
33
Q

What is the mechanism of action of fludarabine?

A
  • Interferes w/ ribonucleotide reductase + DNA polymerase
  • Active against dividing + resting cells
  • Ionised at physiological pH
34
Q

What is the mechanism of action of lonsurf?

A

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
Q

What is the mechanism of action of mercaptopurine?

A
  • 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

PHAM02 (35 decks)

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