Purine Antimetabolites

Question 1

Which of the following known side effects of 6-mercaptopurine is seen only with high-dose protocols? (Assume the patient has no metabolic deficiencies affecting 6-MP metabolism.)

a. Thrombocytopenia
b. Hematuria
c. Pancreatitis
d. GI mucositis

Answer 1

b.

Precipitation of the drug can occur in the renal tubules when dose is >1000 mg/m2.

Question 2

What is the primary mechanism by which allopurinol may be helpful in treating tumor lysis syndrome?

a. It decreases de novo purine synthesis
b. It protects against uric acid nephropathy
c. It helps counteract hypocalcemia
d. It enables greater purine excretion.

Answer 2

d.
Tx with allopurinol divides the purine excretion load among multiple different products , allowing more of each of them to be excreted. In patients with tumor lysis, be cautious of xanthine precipitation/xanthine nephropathy. (a) is also an effect of the drug but less relevant in tx of ATLS (where existing purines are the problem), and (b) and (c) are just plain made up.

Question 3

Which of the following converts azathioprine to 6-mercaptopurine non-enzymatically?

a. glutathione
b. water
c. guanine
d. allopurinol
e. 6-thioguanine

Answer 3

a.

Question 4

Which of the following would be used to mimic the action of urate oxidase?

a. xanthine oxidase
b. allopurinol
c. rasburicase
d. l-asparaginase
e. pyruvate kinase

Answer 4

c.

Also used in ATLS.

Question 5

What mechanism allows azathioprine to inhibit lymphocyte activity?

a. Upregulation of the CCR1 receptor
b. Inhibition of JAK2
c. Upregulation of STAT3
d. Inhibition of Rac1
e. Downregulation of ICAM-1

Answer 5

d.
Azathioprine inhibits T-lymphocyte activity (and B lymphocytes, to a lesser extent) by inhibition of Rac1. Rac1 is a GTP-binding protein involved in T-cell development, differentiation and proliferation.

Question 6

Which of the following compounds can increase 6-mercaptopurine cytotoxicity?

i. Hydroxyuracil
ii. Allopurinol
iii. Cytosine arabinoside
iv. Methotrexate

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

Answer 6

c.

Both allopurinol and methotrexate can increase bioavailability of 6-MP through inhibition of xanthine oxidase.

Question 7

When should precautionary measures in dosing of the guanine analogs be taken into consideration?

a. In a patient with a genetic deficiency of 6-thioinosine monophosphate
b. In a patient with a genetic deficiency of thiopurine methyltransferase
c. In a patient with a genetic deficiency of hypoxanthine-guanine phosphoribosyl transferase
d. In a patient with a genetic deficiency of 6-thioguanylic acid

Answer 7

b.
Patients with low TPMT activity are susceptible to 6-MP and 6-TG induced myelosuppression. Genetic testing using PCR-based methods can now identify TMPT deficient and heterozygous patients. In 2004, the FDA suggested TMPT testing for patients developing myelosuppression with standard dose of 6-MP with subsequent dosage modification for TPMT deficient patients.

Question 8

Incorporation of thioguanine nucleotides into DNA triggers programmed cell death through what mechanism?

a. DNA crosslinking
b. Double DNA strand break
c. Mismatch repair system
d. Caspase activation

Answer 8

c.
Following 6-TG incorporation into DNA there is recognition of the abnormal base pairs by proteins of the postreplicative mismatch repair system triggers apoptosis.

Question 9

Which of the following could increase toxicity of guanine analogues through alterations in thiopurine methyltransferase (TPMT)?

a. Allopurinol
b. Sulfasalazine
c. Cimetidine
d. Cephalosporin

Answer 9

b.
Olsalazine, mesalazine, and sulfasalazine are inhibitors of TPMT and can increase the toxicity of mercaptopurine and azathioprine. TPMT is responsible for creating the inactive metabolite, methyl mercaptopine, from 6-MP. Inhibition of TPMT will NOT increase toxicity of 6-thioguanine.