Anti-metabolites

Question 1

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

Answer 1

5 F-dump

Question 2

What is the normal function of thymidylate synthase?

Answer 2

converts dUMP to dTMP by breaking C5-H bond

Question 3

How does 5 FdUMP inhibit thymidylate synthase?

Answer 3

C5-F bond cannot be broken by TS

Question 4

What is the MOA of 5-FU?

Answer 4

irreversible, covalent inhibition of thymidylate synthase

Question 5

Why is Leucovorin given with 5-FU?

Answer 5

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

Question 6

How long before 5-FU should Leucovorin be given?

Answer 6

60 min

Question 7

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

Answer 7

folate

Question 8

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

Answer 8

1. oral
2. more selective toxicity for cancer cells

Question 9

How does Capecitabine have greater selectivity for cancer cells?

Answer 9

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

Question 10

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

Answer 10

DPD (dihydropyrimidine dehydrogenase)

Question 11

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

Answer 11

1. decreased activity of DPD
2. complete lack of DPD

Question 12

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

Answer 12

5 F- dUMP mediated myelosuppression

Question 13

What is the purpose of folic acid in the body?

Answer 13

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

Question 14

What enzyme do anti-folates inhibit?

Answer 14

DHFR (dihydrofolate reductase)

Question 15

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

Answer 15

s phase

Question 16

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

Answer 16

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

Question 17

What reactions do anti-folates inhibit?

Answer 17

protein/ enzyme synthesis
DNA/ RNA synthesis and repair

Question 18

What drug is used to inhibit folate metabolism?

Answer 18

Methotrexate

Question 19

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

Answer 19

MTX binds to DHFR 1000 times stronger than natural substrates

Question 20

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

Answer 20

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

Question 21

What usually follows high-dose MTX?

Answer 21

Leucovorin rescue

Question 22

Does Leucovorin show selectivity in its “rescue” properties?

Answer 22

no; rescues normal and cancer cells

Question 23

What is another name for Leucovorin?

Answer 23

folinic acid

Question 24

How is Levoleucovorin dosed differently then racemic leucovorin?

Answer 24

use 1/2 the dose of racemic leucovorin

Question 25

What type of MTX must be used if administered intrathecally?

Answer 25

preservative-free

Question 26

What side effects is MTX known for?

Answer 26

nephrotoxicity crystalluria

Question 27

What metabolizes anti-metabolites?

Answer 27

kidneys

Question 28

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

Answer 28

hydration and IV sodium bicarbonate

Question 29

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

Answer 29

unionized

Question 30

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

Answer 30

Glucarpidase VOROXAZE

Question 31

How does VOROXAZE work to reverse MTX toxicity?

Answer 31

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

Question 32

What are other ways to reverse MTX overdose?

Answer 32

1. Leucovorin 2. alkalinize the urine

Question 33

What drugs interact with high-dose MTX?

Answer 33

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

Question 34

Why do these drugs interact with MTX?

Answer 34

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

Question 35

What structure does Pemetrexed mimic?

Answer 35

folic acid

Question 36

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

Answer 36

1. TS 2. DHFR 3. GARFTase

Question 37

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

Answer 37

vitamin B12 and folic acid

Question 38

What is given to prevent skin rashes with pemetrexed infusion?

Answer 38

dexamethasone