L-asparaginase

Question 1

L-asparagine is a nonessential amino acid synthesized by what process?

Where does the amine group come from?

Answer 1

transamination of l-aspartic acid

reaction catalyzed by l-asparagine synthetase

amine group from glutamine

Question 2

What two things make cells sensitive to Lspar?

Answer 2

1. Sensitive cells require asparagine as a constituent of protein
2. Sensitive cells depend on asparagine as a NH2 donor group for glycine synthesis

Question 3

MOA of Lspar?

Answer 3

Rapid/complete depletion of L-asparagine leads to inhibition of protein synthesis

Question 4

What is the effect of Lspar on methotrexate?

Answer 4

L-asparaginase blocks methotrexate action, “rescues” from methotrexate toxicity

(inhibition of PS, prevention of entry into S phase)

Question 5

Resistance to Lspar due to what? This is associated with what effect on the gene?

Answer 5

Upregulation of asparagine synthase causes resistance. Associated w HYPOMETHYLATION of asparagine synthetase gene

Question 6

Name toxicities associated w Lspar

Answer 6

Decreased PS.
Pancreatitis
Hyperglycemia dt decreased insulin synthesis
Decreased procoagulant and anticoag clotting factors (2,5,7,9,10,AT3)
Serum sickness
HS reactions (patients usually have IgE and IgG abys to l-asp in serum…but lots patients have these w/o HS)
Cerebral dysfunction (hyperammonemia?)

Question 7

Why should vinc be given before Lspar?

How much before?

Answer 7

L-asparaginase may reduce hepatic clearance of vincas (esp VCR), which may result in increased toxicity•

Give VCR 12-24h before L-spar

Question 8

What is the effect of Lspar on methotrexate?

How does this relate to the cell cycle?

Answer 8

Asparaginase blocks methotrexate action, “rescues” from methotrexate toxicity
♣ Inhibition of PS, prevention of entry into S phase of cell cycle