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Carcinogensis + Anticancer drugs > Antimetabolites > Flashcards

Antimetabolites Flashcards

1
Q

What are antimetabolites

A

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

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2
Q

what is folic acid

A

Pteroic acid with a glutamate
Water soluble B vitamine
Pregnant/lactating mothers require 400 micrograms per day or more

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3
Q

AMP and GMP =
dTMP =

A
  • made from common precursorr IMP
  • synthesised from dUMP
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4
Q

What does folates work in the body

A

Co-enzyme in the synthesis of nucleotide precursors
Acts as one-carbon donor, only active in a fully reduced form

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5
Q

How is dTMP synthesised

A

dUMP -> dTMP via thymidylate synthase
in conjunction to N5N10-methyleneTHF -> dihydrofolate

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6
Q

How is dihydrofolate recycled

A

dihydrofolate -> tetrahydrofolate via dihydrofolate reductase (in conjunction to NADPH+ -> NADP+)

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7
Q

How does tetrahydrofolate converted to N5N10-Methylene H4 folate

A

Serine -> Glycine - Serine hydroxymethyl transferase

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8
Q

How does intracellular polygultamation work ?

A

Gamma glutamyl hydrolase (folypolyglutamate synthetase)

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9
Q

Why do cells add glutamate molecules (poylgultamation)

A
  • 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
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10
Q

Antifolates are _ _

A

Folate analogues
Methotrexate, Dihydrofolate

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11
Q

Name a commonly used antifolate

A

Methotrexate
- widely used in many tumour types, also used in non-malignant conditions

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12
Q

What is the main mechanism of action of methotrexate

A

analogue of dihydrofolate and therefore inhibits dihydrofolate reductase

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13
Q

Methotrexate is _
So also works by

A
  • 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
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14
Q

MTX inhibition is _

A

reversibile - can out compete with Dihydrofolate or reduced folate

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15
Q

Describe the difference between Methotrexate and methotrexate polyglutamate

A

polyglutamates are better inhibitors of dihydrofolate reductase (slower dissociation half life)
- formation is higher in malignant cells
- have better retention

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16
Q

_% of methotrexate may be polyglutamated

A

80

17
Q

What are the biochemical consequences of methotrexate

A

○ 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)

18
Q

How does methotrexate enter the cell

A

by an energy dependent, temperature sensitive and concentrative process
- using reduced folate carriers

19
Q

Outline the clinical pharamacology of methotrexate

A

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

20
Q

What are the toxicites surrounding methotrexate

A

Myelosuppression, mucositis and nephrotoxicity

21
Q

What is used to combat overdose/ toxic effect

A

leucovorin rescue
can prevent toxicity to bone marrow and GI tract
Acts as a competitor for transport/polyglutamation and targeted enzymes

22
Q

_ _ may also decrease methotrexate toxicity

A

exogenous thymidine

23
Q

Outline what we know about pralatrexate

A
  • 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
24
Q

Outline what we know about pemetrexed

A

– readily transported into cells via the RFC
– Multitargeted antifolate, principally TS but also DHFR and GART
– Approved for mesothelioma

25
Q

what is 5-fluorouracil

A

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

26
Q

what happens to 5-fluorouracil in the body

A

require intracellular metabolism to cytotoxic forms
- either uridine phosphorylase -> LUrd -> FUMP and incorporation into RNA
- either thymidine phosphorylase dFUrd -> FdUMP and incorporation into DNA

27
Q

How does thymidylate synthase become inhibits

A

FrUMP inhibits TS in the presence of reduced folate cofactor (covalent complex)
- competes with dUMP for catalytic site
== dTMP depletion

28
Q

How does are either incorparation effected by 5-fluorouracil

A

incorporation into RNA has a significant effect at higher concs and inhibits RNA processing
Incorporation into DNA, repaired and results in strand break

29
Q

Outline 5-fluorouracil catabolism

A

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)

30
Q

How does genotype effect 5-FU treatment

A
  • 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
31
Q

Outline 5-FU clinical pharmacology

A
  • 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
32
Q

what is the clinical activity of 5-FU

A
  • 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

Carcinogensis + Anticancer drugs (16 decks)

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