Anti-metabolites Flashcards
What is the active metabolite of the prodrug 5-FU?
5 F-dump
What is the normal function of thymidylate synthase?
converts dUMP to dTMP by breaking C5-H bond
How does 5 FdUMP inhibit thymidylate synthase?
C5-F bond cannot be broken by TS
What is the MOA of 5-FU?
irreversible, covalent inhibition of thymidylate synthase
Why is Leucovorin given with 5-FU?
increases clinical efficacy by helping 5 F-dUMP bind stronger to thymidylate synthase; precursor to folate
How long before 5-FU should Leucovorin be given?
60 min
What is needed for 5-FdUMP to inhibit thymidylate synthase?
folate
Why is Capecitabine a top 200 drug compared to other antimetabolites?
- oral
- more selective toxicity for cancer cells
How does Capecitabine have greater selectivity for cancer cells?
thymidylate phosphorylase needed for activation of the Capecitabine prodrug has a higher concentration in cancer cells
What enzyme is responsible for carrying out the natural detoxifying metabolism of fluoropyrimidines?
DPD (dihydropyrimidine dehydrogenase)
How can genetic variations in the DPYD gene affect DPD enzyme?
- decreased activity of DPD
- complete lack of DPD
What are patients with partial or complete DPD deficiency at an increased risk for?
5 F- dUMP mediated myelosuppression
What is the purpose of folic acid in the body?
used as cofactors for enzymes that catalyze one-carbon transfer reactions
What enzyme do anti-folates inhibit?
DHFR (dihydrofolate reductase)
What part of the cell cycle do anti-folates act?
s phase
What type of cells do anti-folates tend to have a greater effect on?
have a greater cytotoxic effect on rapidly dividing cancer cells; rate theory
What reactions do anti-folates inhibit?
protein/ enzyme synthesis
DNA/ RNA synthesis and repair
What drug is used to inhibit folate metabolism?
Methotrexate
What is the difference between MTX and natural substrates for DHFR?
MTX binds to DHFR 1000 times stronger than natural substrates
When MTX inhibits DHFR, what products are not being made?
- dTMP
- purines (A,G) and pyrimidines (C, T, U)
- amino acids
What usually follows high-dose MTX?
Leucovorin rescue
Does Leucovorin show selectivity in its “rescue” properties?
no; rescues normal and cancer cells
What is another name for Leucovorin?
folinic acid
How is Levoleucovorin dosed differently then racemic leucovorin?
use 1/2 the dose of racemic leucovorin
What type of MTX must be used if administered intrathecally?
preservative-free
What side effects is MTX known for?
nephrotoxicity
crystalluria
What metabolizes anti-metabolites?
kidneys
What is given with high dose MTX to reduce nephrotoxicity and crystalluria?
hydration and IV sodium bicarbonate
Is the ionized form or unionized form of MTX more likely to cause crystalluria?
unionized
What enzyme is used as the MTX antidote of last resort?
Glucarpidase VOROXAZE
How does VOROXAZE work to reverse MTX toxicity?
converts extracellular MTX to less toxic metabolites that are handled by the liver and not the kidneys
What are other ways to reverse MTX overdose?
- Leucovorin
- alkalinize the urine
What drugs interact with high-dose MTX?
- high dose salicylate NSAIDs
- PPIs
- sulfonamide ABX
- beta-lactam ABX
- Probenecid
Why do these drugs interact with MTX?
compete with MTX in the kidneys for organic transporter proteins that facilitate renal elimination of MTX; leading to increased nephrotoxicity
What structure does Pemetrexed mimic?
folic acid
What 3 enzymes needed for purine and pyrimidine synthesis are inhibited by pemetrexed?
- TS
- DHFR
- GARFTase
What is supplemented to reduce the frequency of adverse events with pemetrexed?
vitamin B12 and folic acid
What is given to prevent skin rashes with pemetrexed infusion?
dexamethasone
