Shields 5FU

Question 1

What are the 3 ways 5FU works to interfere??

Answer 1

1. interferes with thymidine synth via thymidylate synthase
2. RNA fxn via incorporation to RNA
3. DNA synthesis via incorporation into DNA

Question 2

What role does Leucovorin play in the MOA of 5FU?

Answer 2

Leucovorin acts as a methyl group donor.

FdUMP and leuc form a tertiary complex with TS, blocking conversion of dUMP to thymidine.

Question 3

What is a toxicity unique to 5FU administered continuously?

Answer 3

Hand-Foot Syndrome (palmar-plantar erythrodysesthesia) effects about 23%!!

Question 4

What are some mechanisms of resistance to 5FU?

Answer 4

Deletion of activation enzymes
increased catabolism
deficiency of folate cofactor
decreased incorporation RNA+DNA
increases or alterations inTS

Question 5

Examples of 5FU drug interactions that are schedule dependent?

Answer 5

Thymidine! decreased toxicity if given right after but increases if given simultaneously (COMPETES!)

Methotrexate! decrease efficacy if MTX first
Increase efficacy if MTX second

Question 6

In general, leucovorin interacts with 5FU by..

Answer 6

increased efficacy and toxicity

Question 7

What enzyme is responsible for pyrimidine catabolism?

Answer 7

DPD! Dihydropyrimidine dehydrogenase
highest activity in liver.
presence interferes with intestinal absorption of 5FU… genetic deficiency may explain extremes in toxicity

Question 8

How does uridine triacetate work for overexposure?

Answer 8

8x more active than uridine. Competes with 5FU for RNA incorporation but less orally available.

Question 9

What drug intentionally makes a patient DPD deficient?

Answer 9

Ethynyluracil! Inhibits DPD activity! prolongs 5FU half life through inhibition of catabolism.

so you can use 1/10 the dose!

Question 10

What metabolic difference arises if DPD is irreversibly inactivated by ethynyluracil?

Answer 10

Now more of it is excreted renally! (previously all by catabolism)

Question 11

Capecitabine gets around the oral problem by…?

Answer 11

It is a prepro drug! it is inactive without enzymatic alteration.

Question 12

Tegafur is…

Answer 12

another prodrug digested to 5FU! competitive DPD inhibitor… minimizes activity in GI tract it is inhibited by Uracil

Question 13

S-1 Mechanism has 3 drugs in 1… how???

Answer 13

• 5FU prodrug Tegafur
• Competitive DPD inhibitor
• Inhib of 5FU phosphorylation in the GI tract

Question 14

5FU efficacy and toxicity are…

Answer 14

dose and schedule dependent