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PED3006 Carcinogenesis > Antimetabolites > Flashcards

Antimetabolites Flashcards

1
Q

Describe antimetabolites

A

Drugs that interfere w formation of key biomolecules within the cell
Several classes

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2
Q

What are three classes of antimetabolites

A

Folate antagonists
Pyrimidine antagonists
Purine antagonists

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3
Q

Describe folic acid

A

Essential water-soluble B vitamin
Acquired through diet, body can’t synthesise it
Require 400mg per day

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4
Q

Describe folates as coenzymes

A

Help in the synthesis of nucleotide precursors
One carbon donors
Only active in fully reduced form

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5
Q

Describe the de novo synthesis reaction of dUMP to dTMP via folate

A

Catalysed by thymidylate synthase
Folate in tetra hydrofolate form donates carbon group -> dihydrofolate

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6
Q

What is the fully reduced form of folate called

A

Tetrahydrofolate

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7
Q

What is the role of dihydrofolate reductase

A

Reduced dihydrofolate -> tetrahydrofolate to make the folate fully reduced so it can be used again
Uses NADPH as co factor to reduce fol

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8
Q

Describe folates involvement in purine synthesis

A

Co factor in de novo purine synthesis to form IMP -> GMP and AMP

Alongside GAR and AICAR transformylases

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9
Q

Describe intracellular polyglutamation

A

Via folypolyglutamate synthetase
Adds glutamate residues to folate to make it larger and anionic = intracellular accumulation and retention

Enhances cofactor affinity in purine pathway

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10
Q

Describe antifolates

A

Folate analogues
Tight binding inhibitor not substrate for dihydrofolate reductase

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11
Q

What is methotrexate

A

Antifolate
Widely used in many tumour types
Used in non-malignant conditions

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12
Q

Describe the mechanism of action for MTX

A

Glutamated by folypolyglutamate
Inhibits dihydrofolate reductase
= inhibits thymidylate synthesis
= build up of dUMP and dihydrofolate

= can’t generate dDTPs
= inhibits GART and AICART

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13
Q

When is MTX a stronger inhibitor of thymidylate synthetase

A

When it has been glutamated

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14
Q

Why is there better retention of MTX In tumour cells

A

High polyglutamation formation in malignant cells
= 80% MTX polyglutamated

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15
Q

What are the biochemical consequences of MTX

A

Decreased dTTP and increased dUTP
= inappropriate incorporation of U into DNA
Inhibition of chain elongation
-> excision of U = strand breaks -> death

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16
Q

How does MTX enter the cells

A

Via passive diffusion at high concs
= temp sensitive and energy dependent

Via reduced folate carrier

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17
Q

How does folic acid enter the cell

A

Via the folate receptor

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18
Q

How does serum folate enter the cell

A

Via folate receptors or the reduced folate carrier

19
Q

How can malignant cells affect the folate carrier to form resistance to MTX

A

Decrease expression = reduced amount of MTX into cell

20
Q

How can malignant cells reduced the amount of glutamate MTX to form resistance

A

Enhanced levels of gammaGH or decreased levels of FPGS enzyme activity

MTX not well retained and has less affinity for enzymes

21
Q

How does a malignant cells form resistance against MTX via DHFR

A

Specific mutation = decreased DHFR binding to MTX but still allow dihydrofolate bind

22
Q

How can malignant cells affect gene expression to form resistance to MTX

A

Amplification of DHFR at gene level
= more protein
= not enough MTX to sufficiently inhibit

23
Q

Describe the pharmacology of MTX

A

Oral/IV or intrathecal administration
1st phase half life = 3 hours
Final phase half life = 8-10 hours

24
Q

How is MTX excreted

A

Renal

25
Q

What toxicities are expected with MTX

A

Myelosuppression, mucositis and nephrotoxicity

26
Q

What does require LV rescue

A

Intermediate and high
100mg/m2 +

27
Q

What is the role of LV

A

Prevents/ rescues cells from toxic effects of MTX
Can prevent toxicity to bone marrow and GI tract

28
Q

What is the mechanism of action for LV

A

Competitor for transport/ polyglutamation and targeted enzymes

29
Q

Is MTX inhibition reversible

A

Yes
Can be out competed with FH2 or reduced folates

30
Q

What else can be used to rescue cells instead of LV

A

Thymidine

31
Q

Name 2 new antifolates

A

Pralatrexate
Pemetexed

32
Q

Describe pralatrexate

A

10x greater affinity for RFC than MTX
Higher polyglutamation
Inhibits tumour cell growth at lower conc

33
Q

Describe Pemetrexed

A

Readily transported into cells via RFC
Multitargeted antifolate, mainly TS but also DHFR and GART

34
Q

Describe purine and pyrimidine anti-metabolites

A

Analogues for bases and nucleosides
= Inhibits DNA synthesis

35
Q

Name pyrimidine anti-metabolites

A

5-flurouracil
Cytosine arabinoside

36
Q

Name purine anti-metabolites

A

Mercaptopurine
Thiogunaine

37
Q

Describe 5-fluorouracil

A

Analogue of uracil with F atom on C5
Causes replication errors
Requires intracellular metabolism to cytotoxic forms

38
Q

What can be used to inhibit thymidylate synthase

A

FdUMP
In the presence of folate cofactor
Competes with dUMP for catalytic site

39
Q

What is another mechanism that 5-FU uses

A

Incorporates into RNA
Inhibits RNA processing
Incorporated into DNA - strand breaks

40
Q

Describe the catabolism of 5-FU

A

Initial reduction by DPD
Final breakdown product is FBAL

41
Q

What can low DPD activity cause

A

Increased exposure to active metabolites
= results in severe or fatal toxicity

42
Q

What is advised prior to 5FU treatment

A

DPD status e.g enzyme activity and SNP presence

43
Q

Describe the pharmacology of 5FU

A

Poor oral bioavailability (25-45%)
-> DPD inhibitor = 100%
Saturable first pass metabolism
High clearance
Half life 10-20mins -> 5hrs

PED3006 Carcinogenesis (9 decks)

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