Abstract
The discovery of the tumour-inhibitory properties of asparaginase began 50 years ago with the observation that guinea-pig serum-treated lymphoma-bearing mice underwent rapid and often complete regression. Soon afterwards, the asparaginase of bacterial origin was isolated. The asparaginases of bacterial origin induce anti-asparaginase neutralising antibodies in a large proportion of patients (44–60%), thus negating the specific enzymatic activity and resulting in failure of the target amino acid deamination in serum. There is immunological cross-reaction between the antibodies against various formulations of native Escherichia coli-asparaginase and polyethylene glycol (PEG)-asparaginases, but not to Erwinia asparaginase, as suggested by laboratory preclinical findings. This evidence was strongly inferred from the interim analyses in the Children’s Cancer Group (CCG)-1961 study. Thus, anti-E. coli or PEG-asparaginase antibodies seropositive patients may benefit from the Erwinia asparaginase.
The inter-relationships between asparaginase activity, asparagine (ASN) and glutamine deamination remain largely unexplored in patients. Studies have shown that ASN depletion is insufficient to induce apoptosis in T lymphoblasts in vitro and that the inhibitory concentration of CEM T-cell line is correlated with the asparaginase concentration responsible for 50% glutamine deamination. The optimal catalysis of ASN and glutamine deamination in serum by asparaginase induces apoptosis of leukaemic lymphoblasts. The percentage of ASN and glutamine deamination was predicted by asparaginase activity. Asparaginase activity of 0.1 IU/mL provided insufficient depletion of both amino acids in high-risk acute lymphoblastic leukaemia (ALL) patients. With increasing glutamine deamination, mean asparaginase activities and percentages of post-treatment samples with effective ASN depletion (s<3 µmol/L) increase. Both glutamine and ASN deamination are predicted by asparaginase activity. Further population analyses resulted in identification of sigmoid relationships between asparaginase levels and post-treatment glutamine and ASN deamination.
Furthermore, pharmacodynamic analyses strongly suggested that ≥90% deamination of glutamine must occur before optimal ASN deamination takes place, due to the de novo ASN biosynthesis by the liver. These pharmacodynamic results from the best-fit population pharmacokinetic/pharmacodynamic model obtained from nonlinear mixed effects model pharmacodynamic analyses for standard-risk ALL patients are similar. These analyses produced the following results: (i) asparaginase activity <-0.4 IU/mL provided insufficient deamination of ASN, whereas >0.4–0.7 IU/mL was required for optimal (90%) ASN and glutamine deamination; and (ii) deamination of glutamine is dependent on asparaginase activity and it correlates with enhanced serum ASN deamination. Thus, glutamine deamination enhances asparaginase efficacy in ALL patients. Deamination of ASN >90% of control or ASN concentration <3 µmol/L may be associated with improved survival in this subset of patients. Our findings support the pharmacodynamic mechanism of PEG-asparaginase for disease control in ALL patients. These results taken together strongly support new experimental approaches for application of population pharmacokinetic/pharmacodynamic analyses to further enhance survival of leukaemia patients.
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References
Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med 1998 Aug 27; 339(9): 605–15
Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 2003 Aug 14; 349(7): 640–9
Kidd JG. Regression of transplanted lymphomas induced in vivo by means of normal guinea-pig serum: I. Course of transplanted cancers of various kinds in mice and rats given guinea-pig serum, horse serum or rabbit serum. J Exp Med 1953; 98: 565–82
Broome JD. Evidence that the L-asparaginase activity of guinea-pig serum is responsible for its antilymphoma effects. Nature 1961; 191: 1114–5
Broome JD. Evidence that the L-asparaginase activity of guinea-pig serum is responsible for its antilymphoma effects: I. Properties of the L-asparaginase of guinea-pig serum in relation to those of the antilymphoma substance. J Exp Med 1963; 118: 99–120
Sobin LH, Kidd JG. The incorporation of l-asparagine-14C by lymphoma 6C3HED cells: its inhibition by guinea-pig serum. Cancer Res 1966 Feb; 26(2): 208–11
Sobin LH, Kidd JG. Alterations in protein and nucleic acid metabolism of lymphoma 6C3HED-og cells in mice given guinea-pig serum. J Exp Med 1966 Jan 1; 123(1): 55–74
Yellin TO, Wriston JC. Purification and properties of guinea-pig serum asparaginase. Biochemistry 1966; 5: 1605–12
Mashburn LT, Wriston JC. Tumor inhibitory effect of L-as-paraginase from Escherichia coli. Arch Biochem Biophys 1964; 105: 451–2
Broome JD. Antilymphoma activity of L-asparaginase in vivo: clearance rate of enzyme preparations from guinea-pig serum and yeast in relation to their effects on tumor growth. J Natl Cancer Inst 1965; 35: 967–74
Schwartz JH, Reeves JY, Broome JD. Two L-asparaginases from E. coli and their action against tumors. Proc Natl Acad Sci U S A 1966; 56: 1516–9
Wade HE, Elsworth R, Herbert D, et al. A new L-asparaginase with anti-tumor activity. Lancet 1968; II: 776–7
Oettgen HF, Old LJ, Boyse HA, et al. Inhibition of leukaemias in man by L-asparaginase. Cancer Res 1967; 27: 2619–31
Sobin LH, Kidd JG. A metabolic difference between two lines of lymphoma 6C3HED cells in relation to asparagine. Proc Soc Exp Biol Med 1965; 119: 325–7
Broome JD. L-Asparaginase: discovery and development as a tumor-inhibitory agent. Cancer Treat Rep 1981; 65: 111–4
Burchenal JH, Karnofsky DA. Clinical evaluation of L-asparaginase. Cancer 1970 Feb; 25(2): 241–3
Goody HE, Ellem KA. Nutritional effects on precursor uptake and compartmentalization of intracellular pools in relation to RNA synthesis. Biochim Biophys Acta 1975 Feb 24; 383(1): 30–9
Holcenberg JS, Teller DC. Physical properties of antitumor glutaminase-asparaginase from Pseudomonas 7A. J Biol Chem 1976; 251(17): 5375–80
Holcenberg JS, Roberts J. Enzymes as drugs. Annu Rev Pharmacol Toxicol 1977; 17: 97–116
Khan A, Hill JM. Atopic hypersensitivity to L-asparaginase: resistance to immunosuppression. Int Arch Allergy Appl Immunol 1971; 40(3): 463–9
Ertel IJ, Nesbit ME, Hammond D, et al. Effective dose of L-asparaginase for induction of remission in previously treated children with acute lymphocytic leukemia: a report from Childrens Cancer Study Group. Cancer Res 1979; 39(10): 3893–6
Pui C-H. Childhood leukemias. N Engl J Med 1995; 332: 1618–30
Gaynon PS. Acute leukemia in children. Curr Opin Hematol 1995; 2(4): 240–6
Chabner BA, Loo TL. Enzyme therapy: L-asparaginase. In: Chabner BA, Longo DL, editors. Cancer chemotherapy and biotherapy: principles and practice. 2nd ed. Philadelphia (PA): Lippincott-Raven Publishers, 1996: 485–92
Hustu HO, Aur RJ, Verzosa MS, et al. Prevention of central nervous system leukemia by irradiation. Cancer 1973; 32(3): 585–97
Pinkel D, Woo S. Prevention and treatment of meningeal leukemia in children. Blood 1994; 84(2): 355–66
Pinkel D. Five-year follow-up of “total therapy” of childhood lymphocytic leukemia. JAMA 1971; 216(4): 648–52
Aur RJ, Simone JV, Verzosa MS, et al. Childhood acute lymphocytic leukemia: study VIII. Cancer 1978; 42(5): 2123–34
Henze G, Langermann HJ, Ritter J, et al. Treatment strategy for different risk groups in childhood acute lymphoblastic leukemia: a report from the BFM Study Group. Hematol Blood Transfus 1981; 26: 87–93
Gaynon PS, Steinherz PG, Bleyer WA, et al. Intensive therapy for children with acute lymphoblastic leukaemia and unfavourable presenting features: early conclusions of study CCG-106 by the Childrens Cancer Study Group. Lancet 1988; II(8617): 921–4
Henze G, Fengler R, Hartmann R, et al. BFM group treatment results in relapsed childhood acute lymphoblastic leukemia. Hematol Blood Transfus 1990; 33: 619–26
Nachman JB, Sather HN, Sensel MG, et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 1998; 338(23): 1663–71
Perel Y, Auvrignon A, Leblanc T, et al. Impact of addition of maintenance therapy to intensive induction and consolidation chemotherapy for childhood acute myeloblastic leukemia: results of a prospective randomized trial, LAME 89/91. Leucamie Aique Myeloide Enfant. J Clin Oncol 2002 Jun 15; 20(12): 2774–82
Simone JV, Lyons J. The evolution of cancer care for children and adults. J Clin Oncol 1998; 16(9): 2904–5
Sallan SE, Hitchcock-Bryan S, Gelber R, et al. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia. Cancer Res 1983; 43(11): 5601–7
Clavell LA, Gelber RD, Cohen HJ, et al. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 1986; 315(11): 657–63
Schorin MA, Blattner S, Gelber RD, et al. Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children’s Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85–01. J Clin Oncol 1994; 12(4): 740–7
Amylon MD, Shuster J, Pullen J, et al. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia 1999; 13(3): 335–42
Otten J, Philippe N, Suciu S, et al. The Children’s Leukaemia Group: 30 years of research and achievements. Eur J Cancer 2002; 38 Suppl. 4: S44–9
Albertsen BK, Schroder H, Ingerslev J, et al. Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system. Br J Haematol 2001 Dec; 115(4): 983–90
Abshire TC, Pollock BH, Billett AL, et al. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood 2000; 96(5): 1709–15
Riccardi R, Holcenberg JS, Glaubiger DL, et al. L-Asparaginase pharmaeokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans. Cancer Res 1981; 41(11 Pt 1): 4554–8
Ettinger LJ. Asparaginases: where do we go from here? J Pediatr Hematol Oncol 1999; 21(1): 3–5
Broome JD. Studies on the mechanism of tumor inhibition by L-asparaginase: effects of the enzyme on asparagine levels in the blood, normal tissues, and 6C3HED lymphomas of mice: differences in asparagine formation and utilization in asparaginase-sensitive and -resistant lymphoma cells. J Exp Med 1968 Jun 1; 127(6): 1055–72
Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood 1997; 89(6): 1845–53
Avramis VI, Kwock R, Avramis IA, et al. Synergistic antiviral effect of PEG-Asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma. In Vivo 2001; 15: 1–10
Fu CH, Martin-Aragon S, Weinberg KI, et al. Reversal of cytosine arabinoside (ara-C) resistance by the synergistic combination of 6-thioguanine plus ara-C plus PEG-asparaginase (TGAP) in human leukemia lines lacking or expressing p53 protein. Cancer Chemother Pharmacol 2001; 48(2): 123–33
Jolivet J, Cole DE, Holcenberg JS, et al. Prevention of methotrexate cytotoxicity by asparaginase inhibition of methotrexate polyglutamate formation. Cancer Res 1985; 45(1): 217–20
Sur P, Fernandes DJ, Kute TE, et al. L-asparaginase-induced modulation of methotrexate polyglutamylation in murine leukemia L5178Y. Cancer Res 1987; 47(5): 1313–8
Boos J, Werber G, Ahlke E, et al. Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations. Eur J Cancer 1996; 32A(9): 1544–50
Boos J. Pharmacokinetics and drug monitoring of L-asparaginase treatment. Int J Clin Pharmacol Ther 1997; 35(3): 96–8
Ettinger LJ, Kurtzberg J, Voute PA, et al. An open-label, multicenter study of polyethylene glycol-L-asparaginase for the treatment of acute lymphoblastic leukemia. Cancer 1995 Mar 1; 75(5): 1176–81
Cheung NK, Chau IY, Coccia PF. Antibody response to Escherichia coli L-asparaginase: prognostic significance and clinical utility of antibody measurement. Am J Pediatr Hematol Oncol 1986; 8(2): 99–104
Kurtzberg J, Asselin B, Poplack D, et al. Antibodies to asparaginase alter pharmacokinetics and decrease enzyme activity in patients on asparaginase therapy [abstract]. Proc Annu Meet Am Assoc Cancer Res 1993; 34: A1807
Woo MH, Hak LJ, Storm MC, et al. Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia. Leukemia 1998 Oct; 12(10): 1527–33
Woo MH, Hak LJ, Storm MC, et al. Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 2000 Apr; 18(7): 1525–32
Avramis VI, Sencer S, Periclou AP, et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 2002; 99(6): 1986–94
Panosyan EH, Scibel NL, Gaynon PS, et al. Asparaginase antibody and asparaginase activity in children with higher risk acute lymphoblastic leukemia: Children’s Cancer Group Study CCG-1961. J Pediatr Hematol Oncol 2004 Apr; 26(4): 217–26
Gaynon PS, Harris RE, Stram SO, et al. Asparagine (ASN) depletion and treatment response in childhood acute lymphoblastic leukemia (ALL) after an early marrow relapse: a Children’s Cancer Group trial (CCG-1941) [abstract]. Blood 1999; 94(10 Suppl. 1): 682a
Hawkins DS, Park JR, Thomson BG, et al. Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia. Clin Cancer Res 2004 Aug 15; 10(16): 5335–41
Hak LJ, Relling MV, Cheng C, et al. Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia. Leukemia 2004 Jun; 18(6): 1072–7
Fernandes AI, Gregoriadis G. The effect of polysialylation on the immunogenicity and antigenicity of asparaginase: implication in its pharmacokinetics. Int J Pharm 2001; 217(1–2): 215–24
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 Jul–Aug; 6(4): 230–4
Asselin BL, Whitin JC, Coppola DJ, et al. Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 1993; 11(9): 1780–6
Majlessipour F, Kwock R, Martin-Aragon S, et al. Development of a double-resistant human leukemia model to cytosine arabinoside and L-asparaginase: evaluation of cross-resistance to other treatment modalities. Anticancer Res 2001; 21: 11–22
Douer D, Cohen LJ, Periclou AP, et al. PEG-Asparaginase (PEG-ASP) in a remission induction regimen for newly diagnosed acute lymphoblastic leukemia (ALL) adults [abstract]. Blood 1998; 92(10 Suppl. 1): 400A
Ronghe M, Burke GA, Lowis SP, et al. Remission induction therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines. Cancer Treat Rev 2001; 27(6): 327–37
Grenzebach J, Schrappe M, Ludwig WD, et al. Favorable outcome for children and adolescents with T-cell lymphoblastic lymphoma with an intensive ALL-type therapy without local radiotherapy. Ann Hematol 2001; 80 Suppl. 3: B73–6
Tzortzatou-Stathopoulou F, Papadopoulou AL, Moschovi M, et al. Low relapse rate in children with acute lymphoblastic leukemia after risk-directed therapy. J Pediatr Hematol Oncol 2001; 23(9): 591–7
Albertsen BK, Jakobsen P, Schroder H, et al. Pharmacokinetics of Erwinia asparaginase after intravenous and intramuscular administration. Cancer Chemother Pharmacol 2001; 48(1): 77–82
Albertsen BK, Schroder H, Jakobsen P, et al. Monitoring of Erwinia asparaginase therapy in childhood ALL in the Nordic countries. Br J Clin Pharmacol 2001; 52: 433–7
Panosyan E, Avramis IA, Scibel NL, et al. Glutamine (Gln) deamination by asparaginases (ASNases) in children with higher risk acute lymphoblastic leukemia (HR ALL), (CCG-1961 study) [abstract]. Blood 2002; 100: 759A
Capizzi RL. Asparaginase revisited. Leuk Lymphoma 1993; 10 Suppl.: 147–50
Silverman LB, Gelber RD, Dalton VK, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91–01. Blood 2001 Mar 1; 97(5): 1211–8
Albertsen BK, Schroder H, Jakobsen P, et al. Antibody formation during intravenous and intramuscular therapy with Erwinia asparaginase. Med Pediatr Oncol 2002; 38(5): 310–6
Klug-Albertsen B, Schmiegelow K, Schroder H, et al. Anti-Erwinia asparaginase antibodies during treatment of childhood acute lymphoblastic leukemia and their relationship to outcome: a case-control study. Cancer Chemother Pharmacol 2002; 50(2): 117–20
Ahlke E, Nowak-Göttl U, Schulze-Westhoff P, et al. Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia. Br J Hematol 1997; 96: 675–81
Vieira Pinheiro JP, Ahlke E, Nowak-Göttl U, et al. Pharmacokinetic dose adjustment of Erwinia asparaginase in protocol II of the paediatric ALL/NHL-BFM treatment protocols. Br J Haematol 1999; 104: 313–20
Müller HJ, Löning L, Horn A, et al. Pegylated asparaginase (Oncaspar™) in children with ALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols. Br J Haematol 2000; 110: 379–84
Müller HJ, Beier R, Löning L, et al. Pharmacokinetics of native E. coli asparaginase (Asparaginase Medac™) and hypersensitivity reactions in ALL-BFM 95 re-induction treatment. Br J Haematol 2001; 114(4): 794–9
Vieira Pinheiro JP, Müller HJ, Schwabe D, et al. Drug monitoring of low dose PEG-asparaginase (Oncaspar™) in children with relapsed acute lymphoblastic leukaemia (ALL). Br J Haematol 2001; 113(1): 115–9
Müller HJ, Beier R, da Palma JC, et al. PEG-asparaginase (Oncaspar™) 2,500 U/m2 BSA in re-induction and relapse treatment of the ALL/NHL-BFM protocols. Cancer Chemother Pharmacol 2002; 49: 149–54
Duval M, Suciu S, Ferster A, et al. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children’s Leukemia Group phase 3 trial. Blood 2002; 99(8): 2734–9
Avramis VI, Panosyan EH, Fu CH, et al. Pharmacodynamic (PD) analyses of asparagine (Asn) deamination and Asn input (Imax) in serum of pediatric patients with standard risk acute lymphoblastic leukemia (SR ALL) receiving native or pegylated E. coli asparaginases (ASNase) (CCG-1962) [abstract no. 2082]. Blood 2004; 104(11): 573A
Fine BM, Kaspers GJ, Ho M, et al. A genome-wide view of the in vitro response to 1-asparaginase in acute lymphoblastic leukemia. Cancer Res 2005 Jan 1; 65(1): 291–9
Grigoryan RS, Panosyan EH, Avramis IA, et al. Correlation of 3 essential and 4 non-essential amino acid levels with asparaginase concentrations in serum of higher risk acute lymphoblastic leukemia pediatric patients after chemotherapy (CCG-1961) [abstract]. 39th Annual Meeting of the American Society of Clinical Oncology; 2003 May 31–Jun 3; Chicago
Holland JF, Ohnuma T. Asparaginase and amino acids in cancer therapeutics. Cancer Treat Rep 1981; 65 Suppl. 4: 123–30
Wang B, Relling MV, Storm MC, et al. Evaluation of immunological crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients. Leukemia 2003; 17(8): 1583–8
Acknowledgements
We would like to thank all the paediatric oncologists involved for their contribution and especially Dr Hans-Joachim Müller for his support and help in the preparation of this manuscript.
These studies have been funded in part by CCG, by the TJ Martell Foundation for Leukemia, Cancer, and AIDS Research, (New York, NY, USA), and by a Grant In Aid from Rhone-Poulenc Rorer (RPR). The authors have no conflicts of interest directly relevant to the content of this review. These studies were undertaken for the betterment of our understanding for the optimal use of asparaginase against ALL patients.
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Avramis, V.I., Panosyan, E.H. Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations. Clin Pharmacokinet 44, 367–393 (2005). https://doi.org/10.2165/00003088-200544040-00003
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DOI: https://doi.org/10.2165/00003088-200544040-00003