5-Fluoropyrimidines Flashcards
Which of the following drugs may decrease the clearance of 5-FU?
a. Ranitidine
b. Cimetidine
c. Ondansetron
d. Omeprazole
b.
Cimetidine (but not ranitidine) may decrease the clearance of 5-FU
Which of the following are the 2 primary mechanisms of action of 5-FU?
a. Inhibition of thymidylate synthase and incorporation into RNA, which may result in alterations in RNA processing and function
b. Induces cytotoxic effects by covalently binding to purine DNA bases and disrupting the normal functions of cellular DNA
c. Inhibition of dihydrofolate reductase leads to partial depletion of reduced folates and polyglutamates inhibit purine and thymidylate biosynthesis
d. Inhibits DNA polymerase α, is incorporated into DNA, and terminates DNA chain elongation
a.
FdUMP (deoxyfluorodeoxyuridine diphosphate) binds tightly to TS (thymidylate synthase) and prevents formation of thymidylate (thymidine 5-monophosphate, dTMP), the essential precursor of thymidine 5-triphosphate (dTTP), which is required for DNA synthesis and repair.
5-FU is extensively incorporated into nuclear and cytoplasmic RNA fractions, which may result in alterations in RNA processing and function, such as inhibiting the processing of intitial pre-RNA transcripts to the cytoplasmic rRNA species in a dose and time dependent manner.
Answer B is the mechanism of action of cisplatin (platinum analogue) Chabner Ch. 15
Answer C is the mechanism of action of methotrexate Chabner Ch. 8
Answer D is the mechanism of action of cytosine arabinoside (cytidine analogue) Chabner Ch. 10
Choose the most appropriate answer in regards to elimination of 5-FU from the body if it is administered as a bolus.
a. 75% is eliminated by the liver and 25% by the kidneys
b. 60% is eliminated by metabolism and 40% by the kidneys
c. 80% is eliminated by the liver and 20% by metabolism
d. 90% is eliminated by metabolism and 10% by the kidneys
d.
After bolus dosing of 5-FU, about 90% is eliminated by metabolism (catabolism»_space; anabolism) and less than 10% is excreted in the urine. With CI of 5-FU 2.3 g/m2, less than 2% of F-FU was excreted in the urine.
What is the mechanism for synergy between leucovorin and 5-FU?
A. Promotes inhibition of thymidylate synthase.
B. Enhances the incorporation of fluorouridine triphosphate into RNA.
C. Leucovorin is antiangiogenic
D. Dual inhibition of orotic acid phosphoribosyl transferase (OPRTase)
a.
Leucovorin is readily converted reduced folic acid derivatives. A reduced folate cofactor is required for tight binding of FdUMP to thymidylate synthase. Inhibition of TS → decreased formation of thymidylate (dTMP) → decreased thymidine triphosphate (dTTP). dTTP is required for DNA synthesis and repair.
What is the initial rate limiting step in 5-FU metabolism?
A. Phosphorylation of C5 position via orotic acid phosphoribosyl transferase
B. Polyglutamation via folypolyglutamyl synthase
C. Reduction of pyrimidine ring by dihydropyrimidine dehydrogenase
D. Catabolism via hepatic P450 isoenzymes
c.
DPD works to reduce the pyrimidine ring of 5-FU. Fluorine atom is positioned at C5 position on pyrimidine ring in place of hydrogen (see figure 9-1). In the presence of NADPH, DPD converts 5-FU to dihydropyrimidine (dihydrofluorouacil; DHFU). DPD is widely distributed throughout body, but due to size the liver has the highest total content of DPD and is the major site of catabolism. Clinically, rarely need to decrease the dosage of 5-FU in the presence of hepatic dysfunction.
5-FU has several mechanisms for inducing cytotoxicity. Which of the following cytotoxic mechanisms is thought to predominate during prolonged duration of exposure to 5-FU?
A. Incorporation of FdUTP into DNA
B. Incorporation of FUTP into RNA
C. Inhibition of DNA synthesis and repair secondary to thymidylate synthase binding
D. Depletion of reduced folates leading to intracellular purine and pyrimidine deficiency
b.
Withrow pg 145 – section Relative Importance of RNA- Versus DNA-Directed Effects
- 5-FU concentration and duration of exposure play pivotal roles in determining the basis of cytotoxicity
- In some models, RNA-directed effects have been predominant, particularly with prolonged duration of exposure
- DNA-directed effects have been important during short term exposure of cells in S phase
Which of the following medications may potentiate 5-FU toxicity if administered concurrently?
a. Omeprazole
b. Cimetidine
c. Hydralazine
d. L-asparaginase
e. Enalapril
b.
Cimetidine interferes with the ability of dihydropyrimidine dehydrogenase (DPD) to catabolize 5-FU. On a related note, other research has shown that patients with DPD deficiency are more likely to experience excessive toxicity from 5-FU.
Which of the following is the dose-limiting toxicity when 5-FU is administered as a CRI?
a. Neutropenia
b. Thrombocytopenia
c. Mucositis
d. Diarrhea
e. Vomiting
c.
Side effects of 5-FU administration include mucositis, hand-foot syndrome, diarrhea, and neutropenia. Mucositis is the dose-limiting toxicity when the drug is administered as a CRI. Myelosuppression is more commonly seen with bolus dosing. Thrombocytopenia can occur as well, though it is uncommon.
The antineoplastic effects of 5-FU occur through several mechanisms of action. Identify the correct mechanism below that has also been correlated to clinical response.
a. Oxidative cleavage of DNA by hydrogen abstraction
b. Incorporation of fluorouridine into DNA
c. Incorporation of FUTP into RNA
d. Thymidylate synthase inhibition
e. Upregulation of dihydropyrimidine dehydrogenase
d.
Both b, c and d are mechanisms of action for 5-FU. TS inhibition, however, has been correlated with clinical response while DNA/RNA effects have not. Additionally, high TS expression has been correlated with decreased survival. Answer “a” is the MOA for bleomycin. Answer “e” is also wrong – DPD is responsible for breaking down 5-FU, and increased levels would decrease [5-FU].
Which of the following could cause resistance in cells treated with 5-fluorouracil?
i. mutation of p53
ii. overexpression of bcl-2
iii. appropriate response to Fas-associated apoptosis
iv. loss of MutSα and MutLβ
v. loss of DNA polymerase-β
a. I, ii, iii
b. ii, iii, iv
c. iii, iv, v
d. I, ii, iv, v
e. ii, iii, iv, v
d.
I and II) Factors operating downstream from TS clearly influence the cellular response to genotoxic stress, such as overexpression of the cellular oncoproteins bcl-2 and mutant p53. III) Thymineless death may be mediated by Fas and Fas-ligand interactions; therefore, increases in Fas Those cells insensitive to Fas-mediated apoptosis are insensitive to 5-FU. IV) In vitro studies suggest that MMR-proficient cells are more sensitive to 5-FU or FdUrd than MMR-deficient cells. V) BER is also essential in removing the incorporated 5-FU which DNA polymerase-beta.
Which of the following schedule of 5FU would be MOST associated with myelotoxicity?
a. 500mg/m2 IV once as a 15 minute bolus b. 750mg/m2 PO once c. 150mg/m2 IV over 8 hours for four days d. 350mg/m2 IV over 12 hours for 2 days e. 250mg/m2 PO q24 h for four days
a.
Serious myelosuppresion is more common with intravenous bolus schedules of 5-FU and FdUrd.
Which of the following is true regarding metabolic activation of 5-FU in normal tissues?
a. The orotic acid phosphoribosyl transferase (OPRTase) pathway plays a greater role in normal tissues
b. The uridine (Urd) phosphorylase pathway plays a greater role in normal tissues
c. The OPRTase and Urd phosphorylase pathways play equal roles in normal tissues
d. Inhibition of the Urd phosphorylase pathway by allopurinol is protective to normal tissues.
a.
Inhibition of this pathway is protective to the bone marrow and GI tract. B and C are wrong. An allopurinol metabolite can inhibit OPRTase (not Urd phosphorylase) to protect BM and GIT.
Which of the following would increase a cell’s sensitivity to 5FU?
a. decreased activity of DNA mismatch repair
b. decreased FAS-mediated apoptosis
c. high thymidylate synthase expression
d. increased OPRTase activity
d.
Answers A, B, and C all increase a cell’s ability to decrease or survive 5FU-mediated damage. OPRTase is one of the pathways for activation the drug.
Which of the following has been documented to increase the risk of bleeding when used together with 5FU?
a. Enoxaparin
b. Coumadin
c. Clopidogrel
d. Aspirin
b.
Concurrent use of coumadin, or warfarin, has been shown to increase INR in 1/3 of patients, with bleeding complications observed in 8%.
