Asparaginase (L-asparaginase)

L-asparaginase is a bacterial enzyme isolated from Escherichia coli and Erwinia carotovora. The enzyme from this latter has some advantages (less risk of causing allergic reactions) and some disadvantages (reduced activity and often difficult to obtain). There is also a pegylated form (PEG-asparaginase), which is the enzyme extracted from E. coli stabilised by polyethylene glycol. PEG-asparaginase has a longer half-life and, therefore, greater antitumour activity; it also has a lower potential to cause allergic reactions.

PHARMACOKINETIC PROPERTIES

After administration, the plasma half-life of L-asparaginase is about 30 hours. The enzyme is distributed mainly in the intravascular compartment. L-asparaginase does not enter the cerebrospinal fluid and does not cross the blood-brain barrier. L-asparaginase has never been detected in the urine and it is thought that it is destroyed in the body through immunochemical mechanisms.

MECHANISM OF ACTION

Among the numerous chemotherapeutic drugs, L-asparaginase is considered to have a unique mechanism of action. It catalyses the hydrolysis of asparagine to aspartic acid and ammonia. The sensitive neoplastic cells have low levels of asparagine synthetase and, therefore, require an exogenous source of asparagine. L-asparaginase breaks down the stores of asparagine (both endogenous and exogenous), inhibiting the synthesis of proteins and enzymes essential for the proliferation of neoplastic cells. In contrast, normal cells, which are able to synthesise asparginase, are spared. L-asparaginase is a phase-specific agent, acting on the G1 phase of the cell cycle.

MECHANISM OF RESISTANCE

Resistance is secondary to increased activity of asparagine synthetase in neoplastic cells. Since L-asparaginase is a foreign compound, antibodies which inactivate the drug can be formed, contributing to the development of resistance.

CLINICAL INDICATIONS AND DOSAGE

L-asparaginase is used in polychemotherapy regimens in the treatment of lymphomas (Fig. 1 and 2) and acute leukaemias[3], both in the dog and in the cat. It is administered at a dose of 400 UI/kg (the total dose should not exceed 10,000 UI) by the subcutaneous or intramuscular route.

 
    Fig. 1                                                 Fig. 2

TOXICITY

The side effects of L-asparaginases include:

• urticarial or anaphylactic-type allergic reactions: caused by the formation of antibodies to L-asparaginase. The risk of allergic side effects increases in subjects that have received L-asparaginase in early stages of treatment;
• acute pancreatitis, which can evolve into haemorrhagic pancreatitis;
• decreased liver function, with exacerbation of toxicity induced by contemporaneously administered chemotherapeutic agents (e.g. vinca alkaloids);
• alterations of blood coagulation because of decreased synthesis of clotting factors V, VIII and IX.

Suggested reading

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3. LeBlanc AK, Cox SK, Kirk CA et al: Effects of L-asparaginase on plasma amino acid profiles and tumor burden in cats with lymphoma. J Vet Intern Med. 2007; 21: 760-3.
4. MacDonald VS, Thamm DH, Kurzman ID et al: Does L-asparaginase influence efficacy or toxicity when added to a standard CHOP protocol for dogs with lymphoma? J Vet Intern Med. 2005; 19: 732-6.
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6. MacEwen EG, Rosenthal RC, Fox LE et al: Evaluation of L-asparaginase: polyethylene glycol conjugate versus native L-asparaginase combined with chemotherapy. A randomized double-blind study in canine lymphoma. J Vet Intern Med. 1992; 6: 230-4.
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9. Rogers KS. L-asparaginase for treatment of lymphoid neoplasia in dogs. J Am Vet Med Assoc. 1989; 194: 1626-30.
10. Rogers KS, Barton CL, Benson PA, Green RA: Effects of single-dose L-asparaginase on coagulation values in healthy dogs and dogs with lymphoma. Am J Vet Res. 1992; 53: 580-4.
11. Teske E, Rutteman GR, van Heerde P, Misdorp W: Polyethylene glycol-L-asparaginase versus native L-asparaginase in canine non-Hodgkin's lymphoma. Eur J Cancer. 1990; 26: 891-5.
12. Valerius KD, Ogilvie GK, Fettman MJ et al: Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin. J Am Vet Med Assoc. 1999; 214: 353-6.
13. Wright Z, Steiner J, Suchodolski J et al: A pilot study evaluating changes in pancreatic lipase immunoreactivity concentrations in canines treated with L-asparaginase (ASNase), vincristine, or both for lymphoma. Can J Vet Res. 2009; 73: 103-10.