Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Miscellaneous Anticancer Drugs: 

  • L-Asparaginase (Elspar) :

    • Asparaginase¹⁹

      Attribution: Elder J All About Asparaginase https://www.youtube.com/watch?v=Kb6y-gP7KgI (9/2018) Hematology/Oncology Pharmacy Assocation (HOPA) Youtube Channel:  https://www.youtube.com/channel/UCNtip5ccofKuBNr8x67lCqw

    • Overview:

      • Numerous metabolic differences have been described when comparing malignant to normal cells.¹² 

        • Some differences are related to metabolic dependencies on certain enzyme systems.

        • For example, in lymphoid cells (ALL) a dependence on an exogenous amino acid, asparagine resulted in development of L-asparaginase (L-ASPA) for use in treating childhood acute lymphoblastic leukemia (ALL)

        • L-asparagine is formed by transamination of L-aspartic acid.¹² 

          • Asparagine Biosynthesis¹⁵

            Attribution: Hbf878: Biosynthesis of asparagine.15  L-aspartate is formed from oxaloacetate. Subsequently, aspartate is converted to asparagine with an amine group donated by glutamine and the reaction catalyzed by asparagine synthase. https://commons.wikimedia.org/wiki/File:Asn_biosynthesis.svg

        • Although the enzyme L-asparagine synthetase (L-ASPS) is typically found in tissues, in the case of human lymphocytic malignancies the ability to synthesize asparagine is not present.

          • Accordingly, L-asparagine would have to be obtained from other sources, such as blood.

          • At all events, the enzyme asparaginase (L-ASPA, L-asparagine aminohydrolase) hydrolyzes asparagine to aspartic acid (and ammonia) and this enzyme has become an important agent in managing childhood and adult acute lymphoblastic leukemia (ALL).¹²

            • Asparaginase tetramer + 4 Asp; E. Coli¹⁶

              Attribution: Astrojan Asparaginase tetramer + 4 Asp, E. Coli https://www.rcsb.org/structure/3eca; Swain A Jaskolski M Housset D Rao J Wlodawer A Crystal structure of Escherichia coli L-asparaginase, an enzyme used in cancer therapy Proc Natl Acad Sci USA 90:  1474-1478 (1993). https://www.ncbi.nlm.nih.gov/pubmed/?term=8434007 https://commons.wikimedia.org/wiki/File:3eca.jpg16

    • Mechanism of Action:

      • Normal tissues usually synthesize L-asparagine.¹ 

        • However, lymphocytic leukemia exhibits reduced levels of the synthetic enzyme, asparagine synthase, to meet cellular requirements.

          • Therefore these malignant cells must obtain sufficient asparagine from blood or other sources.

        • Asparaginase reduces available extracellular L-asparagine by catalyzing hydrolysis of asparagine to aspartic acid and ammonia.

          • As a result, malignant cells are unable to obtain adequate asparagine levels and cell death ensues.¹

        • Also, asparaginase may also exhibit antineoplastic activity by depleting essential glutamines stores (a glutaminase effect) that results in DNA biosynthesis inhibition.¹⁰ 

          • Glutaminase activity may be associated with side effects including:

            • Pancreatitis

            • Homeostatic abnormalities

            • Thrombotic complications

            • Neurologic complications.¹⁰

          • "Schematic representation of action of L-asparaginase"¹³

            Attribution:  Narta U Kanwar S Azmi W Pharmacological and clinical evaluation of L-asparaginase in the treatment of leukemia. Critical Reviews in Oncology/Hematology 61:  208-221. 2007. Figure 1, reference 13 https://www.ncbi.nlm.nih.gov/pubmed/17011787

          •  

            "Antineoplastic action of L-asparaginase"^13,14

            Attribution:  Cachumba J Antunes F Peres G Brumano L Dos Santos J Da Silva Current applications and different approaches for microbial L-asparaginase production Braz. J. Microbiol 47 v7 supl.1. Dec 2016; Figure 2, reference 14

     

    • Absorption, Distribution, Biotransformation, Excretion:

      • The route of administration of asparaginase is intravenous (IV) or intramuscular (IM).¹

        • E. coli-derived asparaginase exhibits a plasma clearance rate of about 0.035 ml/min/kg and a volume of distribution (Vd) approximately equivalent to human plasma volume.¹ 

          • Blood plasma represents about 55% of total blood volume.¹⁷ 

            • In males, blood plasma volume approximates 39 mL/kg of body weight.

            • In females, plasma volume is about 40mL/kg.¹⁷

        • The plasma half-life of asparaginase (t_1/2) is about 24-30 hours (following IV administration).^1,12 

          • The plasma elimination half-life of asparaginase (t_1/2) increases to about 35-50 hours following intramuscular administration.⁹

        • Time to peak plasma levels for asparaginase derived from E. coli and after intramuscular administration is about 20 hours.

        • A substantially longer plasma half-life (t_1/2) is associated with a pegylated form of asparaginase, Pegaspargase which involves conjugation of asparaginase to 5000 Dalton (Da) units of monomethoxy polyethylene glycol.

          • With pegaspargase, plasma half-life is extended to about 6-7 days with intramuscular administration every two weeks.

            • Pegaspargase is especially useful in patients who exhibit hypersensitivity to asparaginase because pegaspargase is not immunogenic in most patients (70%).

            • For patients who exhibit hypersensitivity reactions to the E. coli-based L asparaginase preparations an alternative is the Erwinia (from Erwinia chrysanthemi) enzyme.

              • Erwinia chrysanthemi¹⁸

                Attribution: Wick R Erwinia chrysanthemi University of Massachusetter Amherst The Center for Agriculture, Food and the Environment https://ag.umass.edu/greenhouse-floriculture/photos/sedum-erwinia-chrysanthemi

          • Pegaspargase administration is associated with rapid and near-complete plasma in tumor cell asparagine depletion for about three weeks in most patients.¹

    • Clinical Uses:

      • Asparaginase is frequently used in combination with other agents for treatment of acute lymphoblastic (lymphocytic) leukemia and high-grade lymphomas.

        • Resistance to asparagine appears to be associated with induction of the enzyme asparagine synthetase in the cancer cell.¹

      • Adults diagnosed with acute lymphoblastic leukemia undergo induction therapy using a combination of:

        • Vincristine

        • Prednisone

        • an Anthracycline

        • Asparaginase

        • Cyclophosphamide (on occasion).²⁰

      • In adults, consolidation treatment following remission is intensive with some protocols using

        • Methotrexate (high-dose)

        • Cytarabine

        • Asparaginase.²⁰

      • In the pediatric patient diagnosed with acute lymphoblastic leukemia, remission induction protocols typically involve:²¹ 

        • Glucocorticoid (prednisone, dexamethosone, prednisolone)

        • Vincristine

        • Asparaginase +/- Daunorubicin.

      • Pediatric Remission induction protocols typically include asparaginase.

        • Different forms of asparaginase exhibit differing pharmacocokinetics as well as differences in efficacy and toxicity.

        • For example, compared with E. coli asparaginase, Erwinia asparaginase may exhibit poorer antileukemic responses.²¹

    • Adverse Effects/Toxicities¹²

      • Two major toxicity groups are associated with L asparaginase administration.^1,12 

        • (1) Toxicities secondary to asparagine depletion and reduced protein synthesis and

        • (2) Toxicities stemming from immunologic reactions to the foreign protein, asparaginase.

      • Hypersensitivity responses to asparaginase are both common and associated with asparaginase inactivation.

        • These reactions may be fatal.

        • When asparaginase is used in monotherapy, hypersensitivity reactions are more likely.

          • In this single-agent treatment setting, sensitization may be noted in up to 40% of patients receiving the drug.

            • In combination protocols involving asparaginase, the concurrent presence of corticosteroids, 6-mercaptopurine as well as other antileukemic drugs is likely responsible four reduced hypersensitivity incidents (<20%).¹²

      • In those patients susceptible to asparaginase hypersensitivity responses, an effective and safe alternative is offered by pegaspargase.

      • Hypersensitivity reactions may be "silent" in that antibody-mediated asparaginase inactivation may happen in patients not exhibiting clinically observable hypersensitivity. In this case adverse clinical outcome may occur, notably in ALL high-risk individuals.¹

      • Hypersensitivity to asparaginase is associated with various clinical responses.¹²  

        • About 2/3 of hypersensitivity reactions (reported) involve urticaria (itching).

        • Other reactions include dyspnea along with major anaphylactic responses ("hypotension, laryngospasm, and cardiac arrest").

        • Notably, the occurrence of hypersensitivity reactions represents an indication of asparaginase inactivation which likely predisposes to an adverse clinical result.

        • Fatal reactions to E. coli asparaginase are infrequent (<1%).

        • However, an indication of hypersensitivity should be sufficient to change from E. coli asparaginase to Erwinia asparaginase.

        • Allergic reactions to Erwinia asparaginase may also occur in patients not previously treated with the E. coli enzyme.¹² 

      • Toxicities resulting from protein synthesis inhibition due to inadequate asparagine levels as a result of asparaginase activity include:¹

        • Hyperglycemia secondary to insulin deficiency

        • Clotting abnormalities as a result of inadequate clotting factors

          • The effect on clotting may in the extreme present as intracranial hemorrhage soon after asparaginase treatment initiation.

            • Fortunately, this adverse effect is classified as "infrequent".

        • Hypertriglyceridemia as a result of aberrant lipoprotein production

        • Hypoalbuminemia.¹