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Oncology > Anti-metabolites > Flashcards

Anti-metabolites Flashcards

1
Q

What is the active metabolite of the prodrug 5-FU?

A

5 F-dump

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2
Q

What is the normal function of thymidylate synthase?

A

converts dUMP to dTMP by breaking C5-H bond

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3
Q

How does 5 FdUMP inhibit thymidylate synthase?

A

C5-F bond cannot be broken by TS

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4
Q

What is the MOA of 5-FU?

A

irreversible, covalent inhibition of thymidylate synthase

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5
Q

Why is Leucovorin given with 5-FU?

A

increases clinical efficacy by helping 5 F-dUMP bind stronger to thymidylate synthase; precursor to folate

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6
Q

How long before 5-FU should Leucovorin be given?

A

60 min

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7
Q

What is needed for 5-FdUMP to inhibit thymidylate synthase?

A

folate

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8
Q

Why is Capecitabine a top 200 drug compared to other antimetabolites?

A
  1. oral
  2. more selective toxicity for cancer cells
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9
Q

How does Capecitabine have greater selectivity for cancer cells?

A

thymidylate phosphorylase needed for activation of the Capecitabine prodrug has a higher concentration in cancer cells

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10
Q

What enzyme is responsible for carrying out the natural detoxifying metabolism of fluoropyrimidines?

A

DPD (dihydropyrimidine dehydrogenase)

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11
Q

How can genetic variations in the DPYD gene affect DPD enzyme?

A
  1. decreased activity of DPD
  2. complete lack of DPD
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12
Q

What are patients with partial or complete DPD deficiency at an increased risk for?

A

5 F- dUMP mediated myelosuppression

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13
Q

What is the purpose of folic acid in the body?

A

used as cofactors for enzymes that catalyze one-carbon transfer reactions

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14
Q

What enzyme do anti-folates inhibit?

A

DHFR (dihydrofolate reductase)

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15
Q

What part of the cell cycle do anti-folates act?

A

s phase

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16
Q

What type of cells do anti-folates tend to have a greater effect on?

A

have a greater cytotoxic effect on rapidly dividing cancer cells; rate theory

17
Q

What reactions do anti-folates inhibit?

A

protein/ enzyme synthesis
DNA/ RNA synthesis and repair

18
Q

What drug is used to inhibit folate metabolism?

A

Methotrexate

19
Q

What is the difference between MTX and natural substrates for DHFR?

A

MTX binds to DHFR 1000 times stronger than natural substrates

20
Q

When MTX inhibits DHFR, what products are not being made?

A
  1. dTMP
  2. purines (A,G) and pyrimidines (C, T, U)
  3. amino acids
21
Q

What usually follows high-dose MTX?

A

Leucovorin rescue

22
Q

Does Leucovorin show selectivity in its “rescue” properties?

A

no; rescues normal and cancer cells

23
Q

What is another name for Leucovorin?

A

folinic acid

24
Q

How is Levoleucovorin dosed differently then racemic leucovorin?

A

use 1/2 the dose of racemic leucovorin

25
Q

What type of MTX must be used if administered intrathecally?

A

preservative-free

26
Q

What side effects is MTX known for?

A

nephrotoxicity
crystalluria

27
Q

What metabolizes anti-metabolites?

A

kidneys

28
Q

What is given with high dose MTX to reduce nephrotoxicity and crystalluria?

A

hydration and IV sodium bicarbonate

29
Q

Is the ionized form or unionized form of MTX more likely to cause crystalluria?

A

unionized

30
Q

What enzyme is used as the MTX antidote of last resort?

A

Glucarpidase VOROXAZE

31
Q

How does VOROXAZE work to reverse MTX toxicity?

A

converts extracellular MTX to less toxic metabolites that are handled by the liver and not the kidneys

32
Q

What are other ways to reverse MTX overdose?

A
  1. Leucovorin
  2. alkalinize the urine
33
Q

What drugs interact with high-dose MTX?

A
  1. high dose salicylate NSAIDs
  2. PPIs
  3. sulfonamide ABX
  4. beta-lactam ABX
  5. Probenecid
34
Q

Why do these drugs interact with MTX?

A

compete with MTX in the kidneys for organic transporter proteins that facilitate renal elimination of MTX; leading to increased nephrotoxicity

35
Q

What structure does Pemetrexed mimic?

A

folic acid

36
Q

What 3 enzymes needed for purine and pyrimidine synthesis are inhibited by pemetrexed?

A
  1. TS
  2. DHFR
  3. GARFTase
37
Q

What is supplemented to reduce the frequency of adverse events with pemetrexed?

A

vitamin B12 and folic acid

38
Q

What is given to prevent skin rashes with pemetrexed infusion?

A

dexamethasone

Oncology (22 decks)

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