Hydroxyurea

Question 1

At what phase of the cell cycle is the M2 component of the ribonucleotide reductase system at its highest point?

Answer 1

M2 levels are highest in S phase.

Question 2

Which of the following patients would need a reduction in the dose of hydroxyurea?

a. 14-year-old, spayed female, mixed breed dog with concurrent congestive heart failure
b. 1-year-old, intact male, domestic shorthair with FeLV
c. 12-year-old, intact female, domestic shorthair with stage IV chronic kidney insufficiency, proteinuric, hypertensive
d. 13-year-old, neutered male, Doberman Pinscher undergoing antiepileptic therapy with levetiracetam
e. 9-year-old, neutered male, domestic shorthair with FIV

Answer 2

c.

Question 3

Which of the following is true regarding administration of hydroxyurea (HU)?

a. HU is only administered orally, as intravenous dosing is associated with severe side effects.
b. HU is largely excreted unchanged by the kidneys.
c. High levels of its metabolite, hydroxylamine, can cause renal tubular dysfunction.
d. HU does not penetrate the blood-brain barrier.

Answer 3

b.
The bioavailability and side effect profile of PO and IV dosing is similar. 40-80% of HU is excreted unchanged in the urine. Although hydroxylamine is its metabolite, this has not been identified in humans. Lastly, HU penetrates the CSF, breast milk, and third-space accumulations of fluid.

Question 4

What is the principal mechanism by which cells achieve resistance to hydroxyurea?

a. Elevation in cellular ribonucleotide reductase activity
b. Generation of nitroxyl radicals
c. Acceleration of the loss of extrachromosomally amplified genes
d. Inactivation of the tyrosol free radical on the M-2 subunit

Answer 4

a.

a. The primary site of cytotoxic action for HU in inhibition of the ribonucleotide reductase (RR) enzyme system.
b. HU may be transformed in vivo to nitric oxide, which is also a RR inhibitor
c. A potentially important HU action is accelearation of the loss of extrachromosomally amplified genes that are present in double minute chromosomes. Exposure to HU at clinically achievable concentrations leads to enhanced loss of both amplified oncogenes and drug resistance genes.
d. The inhibition of the RR occurs as a result of the drug’s chelation of iron and its inactivation of the tyrosyl free radical on the M-2 subunit, with disruption of the enzyme’s iron-building center.

Question 5

Which of the following drugs has been reported to have synergistic effects when given in combination with HU for the treatment of solid tumors in experimental tumor models?

a. Prednisone
b. Carboplatin
c. Toceranib phosphate
d. 5-Fluorouracil

Answer 5

d.
The major clinical interest in HU in the treatment of solid tumors has been in combination with 5-FU. Synergy has been demonstrated in experimental tumor models, presumably based on the ability of HU to lower cellular pools of deoxyuridine monophosphate, the competitive substrate for inhibition of thmidylate synthase by 5-fluorodeoxyuridylate.

Question 6

Which of the following induce radiosensitization via inhibition of ribonucleotide reductase, thus depleting the deoxynucleotide pools?

i. Carboplatin
ii. Gemcitabine
iii. Hydroxyurea
iv. Doxorubicin

a. i
b. ii, iii
c. i, iv
d. ii, iii, iv
e. i, ii

Answer 6

b

Question 7

At what phase of the cell cycle is the M1 component of the ribonucleotide reductase system at its lowest point?

Answer 7

M1 levels are lowest in G0