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Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
Recent developments in l-asparaginase discovery and its potential as anticancer agent Abhinav Shrivastava a,1 , Abdul Arif Khan a,b,∗,1 , Mohsin Khurshid b,c , Mohd Abul Kalam b , Sudhir K. Jain d , Pradeep K. Singhal e a College of Life Sciences, Cancer Hospital & Research Institute, Gwalior, MP 474009, India Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia College of Allied Health Professionals, Directorate of Medical Sciences, Government College University, Faisalabad, Pakistan d Department of Microbiology, Vikram University, Ujjain, MP, India e Department of Biological Sciences, Rani Durgavati University, Jabalpur, MP, India b
c
Accepted 5 January 2015
Contents 1. 2. 3.
4.
5.
6.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism of l-asparaginase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current asparaginase formulations: a comparative evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Current asparaginase formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Native E. coli asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Erwinia asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. PEG-asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems associated with clinical application of bacterial asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Hypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Coagulation disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Pancreatitis, hyperglycaemia, hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Resistance to l-asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Advancement in l-asparaginase discovery from alternative sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Algal asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Plants asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Fungal asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Actinomycetes asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Entrapment of l-asparaginase in erythrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and future direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract l-Asparaginase (EC3.5.1.1) is an enzyme, which is used for treatment of acute lymphoblastic leukaemia (ALL) and other related blood cancers from a long time. This enzyme selectively hydrolyzes the extracellular amino acid l-asparagine into l-aspartate and ammonia, leading to ∗ Corresponding author at: Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia. Tel.: +966 542854355. E-mail address:
[email protected] (A.A. Khan). 1 These authors have equal contribution.
http://dx.doi.org/10.1016/j.critrevonc.2015.01.002 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
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nutritional deficiencies, protein synthesis inhibition, and ultimately death of lymphoblastic cells by apoptosis. Currently, bacterial asparaginases are used for treatment purpose but offers scepticism due to a number of toxicities, including thrombosis, pancreatitis, hyperglycemia, and hepatotoxicity. Resistance towards bacterial asparaginase is another major disadvantage during cancer management. This situation attracted attention of researchers towards alternative sources of l-asparaginase, including plants and fungi. Present article discusses about potential of l-asparaginase as an anticancer agent, its mechanism of action, and adverse effects related to current asparaginase formulations. This article also provides an outlook for recent developments in l-asparaginase discovery from alternative sources and their potential as a less toxic alternative to current formulations. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: l-Asparaginase; Acute lymphoblastic leukaemia; Anticancer; l-Asparagine; Erwinase; Kidrolase; PEG-asparaginase
1. Introduction l-Asparaginase is an important chemotherapeutic agent for management of acute lymphoblastic leukaemia (ALL) and other hematopoietic malignancies. In the early fifties, Kidd identified that guinea pig serum has the ability to control the progression of murine lymphoma. The mice were transplanted with lymphoma cells during this experiment and repeated intraperitoneal injections of normal guinea pig serum were given to them. This treatment led to a regression of lymphoma and survival of treated mice while control mice grew lymphoma progressively and died within 20–30 days [1]. Much earlier the discovery of guinea pig serum anti-lymphoma activity, it was observed by Clementi (1922), that guinea pig serum is also a rich source of l-asparaginase [2]. In the early sixties, guinea pig serum susceptible lymphoma cells were grown in cell culture media devoid of the amino acid l-asparagine, this inadequacy declined cell population rapidly, but some cells survived and began to proliferate under l-aspargine limitation. These cells were found to have lost guinea pig serum susceptibility after transplantation in mice, while original lymphoma cells retained this susceptibility even after transplantation in mice. The lost susceptibility to guinea pig serum was restricted to l-asparagine limitation, while other amino acids, purines and pyrimidines were unable to complement this effect. Therefore, it was concluded that lasparaginase present in guinea pig serum is responsible for its antilymphoma activity [3]. These observations also attracted other researchers for the detection of anticancer potential of this enzyme, and it was found that the only guinea pig serum has anti-lymphoma activity, while sera from other animals, like horse serum and rabbit serum were not able to show comparable activity [1]. Furthermore, the same sera was tested against many cancer types and observed that it is effective against only some cancer but not all. Guinea pig serum was able to inhibit certain lymphoma cell lines in vivo, but the same activity was not possible with in vitro assays, provided that guinea pig serum is also a rich source of complement and proposed anticancer activity against cell lines may be due to complement mediated cytotoxicity. l-Asparaginase is an inhibitor of complement in whole guinea pig serum during in vitro assay [4]. Broome performed research to find out the relative contribution of complement and l-asparaginase
in anticancer activity, and concluded that l-asparaginase is a major anticancer agent in guinea pig serum [3,5]. The first clinical trial on l-asparaginase was performed in 1966 by Dolowy [6]. It is a major chemotherapeutic agent due to its ability for hydrolysis of l-asparagine into l-aspartic acid and ammonia. Current asparaginase formulations are used for management of acute lymphoblastic leukaemia from a long time, but these formulations are not free from adverse reaction. Therefore the search for alternative sources of this enzyme with reduced or no adverse reaction is an important goal for researchers. This article discusses the potential of l-asparaginase enzyme as anticancer agents, its mechanism of action, problems associated with bacterial asparaginases, future prospects in l-asparaginase discovery and their application as a less toxic alternative.
2. Mechanism of l-asparaginase activity Clinically used l-asparaginase enzyme from E. coli is active as a tetrameric protein with identical subunits, each with a molecular weight of 35.6 kDa according to x-ray crystallographic data [7]. The molecular formula for each subunit is C1377 H2208 N382 O442 S17. Chemically it is known as E. coli l-asparagine amidohydrolase. It is widely used for the treatment of haemopoietic diseases such as ALL in children that results from the monoclonal proliferation and expansion of lymphoid blasts in the bone marrows, blood, and other organs. ALL correspond to the most common childhood acute leukaemia contributing to approximately 80% of childhood leukaemias and 20% of adult leukaemias [8]. The antineoplastic activity results from depletion of the circulating pool of l-asparagine by l-asparaginase, which in turn inhibits the protein synthesis, causes cell cycle arrest in the G1-phase and ultimately apoptosis in susceptible leukemic cells [9,10]. Unlike normal cells, leukemic cells and other cancer cells have little or no asparagine synthetase and hence they are not able to carry out the de novo asparagine synthesis, resulting in inhibition of protein synthesis and subsequent death of the tumour cells [11] (Fig. 1). Normal cells are protected from asparagine requirement due to their ability to produce this amino acid [12]. Unlike conventional cancer therapy, l-asparaginase therapy is highly
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Fig. 1. General mechanism behind selective toxicity of l-asparaginase.
discriminatory. The main restrictions in using l-asparaginase as a remedial agent is its premature inactivation, more rapid plasma clearance and shorter duration of drug effect, thus frequent injections are required to maintain a therapeutic level, and a number of side effects like allergies, development of immune responses and finally anaphylactic shock, that might be serious and life-threatening [13–15]. The above-mentioned side effects of l-asparaginase may be due to several reasons, including its l-glutaminase activity. l-Glutaminase activity of enzyme results in some reduction of plasma l-glutamine level [16–18]. l-Asparaginase is enzymatically active against glutamine, but with a significantly lower affinity against glutamine than l-asparagine. As glutamine acts as an amino group donor for the enzyme l-asparagine synthetase for de novo biosynthesis of lasparagine, therefore, the decreased glutamine level because of l-asparaginase exposure also help in sustaining the asparagine level reduction and thus contributes the therapeutic effect of l-asparaginase [19] which can be explained as:
l-asparagine
l-asparaginase
−→
l-aspartic acid + NH3 ↑
l-glutamine
l-asparaginase
−→
l-glutamic acid + NH3 ↑
De novo biosynthesis: l-aspartic acid + NH3 (From glutamine) Asparagine Synthetase
−→
l-asparagine
Leukaemia cell after l-asparaginase: ↓↓ Asparagine → No l-asparagine → No Protein Synthesis → Cell Death The exact mechanism of l-asparaginase action is still not clear, although hydrolysis of l-asparagine is known to proceed in two steps via a -acyl-enzyme intermediate (Fig. 2). However, the l-glutaminase activity of asparaginases contributes to the associated side effects, but this activity is also related with cell growth inhibition in certain cancer treatments [20,21]. l-Asparaginase induced reduction of
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Fig. 2. Structural illustration of the of l-asparaginase reaction mechanism. During l-asparaginase reaction, covalent intermediate (-Acyl-Enzyme) is formed through nucleophilic attack by the enzyme. Green arrows indicate a nucleophilic attack. This intermediate later convert into l-aspartate and gives final reaction products as l-aspratate and ammonia.
asparagine and glutamine level is linked with mTOR pathway and its subsequent inhibition. This pathway includes an intracellular molecule mammalian target of rapamycin (known as mTOR). Inhibition of mTOR leads to inhibition of downstream events in its pathway including phosphorylation of the protein serine threonine kinase (p70S6 kinase or p70s6k) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) which suppresses synthesis of ribosomal proteins at mRNA translation level [22]. It has been found that inhibition of mTOR pathway by l-asparaginase greatly affect leukaemia cells and contributes to its antileukaemic activity. In a separate study on acute myeloid leukaemia, it has been found that l-asparaginase induces an autophagic process through inhibition of mTORC1 (mTOR has two structurally distinct complexes mTORC1 and mTORC2). mTORC1 is an important regulator of cell growth which activates protein translation and inhibit autophagy under amino acid abundance by regulating the autophagy related proteins Agt1/ULK and ATG13 [23]. Therefore l-asparaginase induced reduction of amino acid level is associated with cellular signalling which in turn leads to death of leukeamic cells. 3. Current asparaginase formulations: a comparative evaluation ALL and other lymphoid malignancies have been effectively treated with asparaginase for many years. The anti-leukemic activity of asparaginases depends upon the following factors. (i) The rate of hydrolysis, and the Km of the asparaginase. (ii) The pharmacological factors of serum clearance of the enzyme [24]. (iii) The development of asparaginase resistance in tumour cells [18]. (iv) Development of anti-asparaginase antibodies by the host immune system [25]. (v) The increased contribution of asparagine either from de novo biosynthesis of asparagine within the liver or the input from the nutrient intake [26]. The best possible formulation and dosage of asparaginases is still disputed, despite its use as a vital drug in all treatment protocols for ALL.
3.1. Current asparaginase formulations l-Asparaginases have been found not only in mammals, but also in birds, plants, bacteria (like Escherichia coli, Erwinia, Salmonella, Mycobacteria, Pseudomonas, and Acinetobacter species etc.), and fungi (Aspergillus, Fusarium spp. etc.) [27]. Bacillus licheniformis, a member of the Bacillus subtilis group has recently assessed for production of l-asparaginase with low glutaminase activity [28]. Similarly, moderate halophilic bacteria has recently showed production of l-asparaginase [29]. Although not all asparaginases possess anti-cancer activity and currently, the only preparations available for medical use are the E. coli, Erwinia chrysanthemi asparaginases, and their derivatives (Table 1). In the United States, three asparaginase formulations are widely used against ALL: native E. coli asparaginase (Elspar® ; Merck & Co., Inc., West Point, PA, USA), its Pegylated form (Oncaspar® ; Enzon, Inc., Bridgewater, NJ, USA) and Erwinase® , the product from cultures of Erwinia chrysanthemi (Ipsen-Speywood Pharmaceuticals Ltd, UK). The latter formulation is approved in UK as second line treatment for patients having hypersensitivity to the former two forms. These native asparaginase formulations are offered under different brand names; Medac® (Kyowa Hakko, Kogyo, Japan), Crasnitin® (Bayer AG, Leverkusen, Germany), Leunase® (Sanofi-Aventis, Paris, France) Paronal® , and Kidrolase® etc. in Europe and Asia. Table 1 Clinical pharmacology of asparaginases with frequently administered doses. Formulation
Elimination half life
Dosage
Native E. coli asparaginase PEG-asparaginase
26–30 h
Erwinia asparaginase
16 h
6000 IU/m2 three times/week 2000–2500 IU/m2 every 2 or 4 weeks 6000 IU/m2 daily × ten doses, then three doses weekly, or 30000 IU/m2 daily × ten doses in induction
5.5–7 days
Please cite this article in press as: Shrivastava A, et al. Recent developments in l-asparaginase discovery and its potential as anticancer agent. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.002
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First Line
Second Line
North America, UK, Australia, New Zealand Europe
E. coli-asparaginase or PEG-asparaginase
Erwinia asparaginase or PEG-asparaginase
E. coli-asparaginase or PEG-asparaginase E. coli-asparaginase
Erwinia asparaginase
Other countries
Erwinia asparaginase or PEG-asparaginase
However some of these are no longer available now and only referred in the literature [24,30] (Table 2). 3.1.1. Native E. coli asparaginase The asparaginase has improved event-free survival (EFS) for ALL from 80% in the past few years. In early 1990s, Crasnitin® (Bayer AG, Leverkusen, Germany) was not longer available. Therefore asparaginase formulation Medac® was included in Berlin, Frankfurt, Muenster-ALLnon-Hodgkin’s lymphoma (BFM-ALL-NHL) protocols, using the similar treatment regimen. However treatment with Medac® leads to more adverse reactions, especially coagulopathies like haemorrhagic and thrombotic events. In comparison of Medac versus Crasnitin, significant differences were described despite the fact that both enzymes were products of E. coli strains. Medac showed significantly higher biological activity so it was possible to decrease the dose to 25–50% of the dosage of Crasnitin in order to achieve sufficient asparagine depletion under careful pharmacokinetic and pharmacodynamic monitoring [31,32]. The former was more effective than crasnitin, not only in asparagine depletion but also in glutamine depletion. Complete asparagine depletion was attained in more than 90% of the children in treatment with Medac asparaginase. Large disparities exist between the various products and half life is particularly reliant on the preparation. Although there is no need to adjust the individual dose administered, alteration of the dosing interval is compulsory, resulting in variation to the number of dosages [33,34]. In a limited number of patients, the studies with reduced doses of asparaginase Medac were carried out because asparaginase activity higher than the therapeutic range may lead to increased toxicity. This is apparent from studies that complete asparagine depletion in serum and CSF was accomplished by reducing the induction dose from the common 10000 IU/m2 to 5000 IU/m2 and even to 2500 IU/m2 administered at 3-day intervals in order to reduce toxicity associated with highly active Medac asparaginase [31]. 3.1.2. Erwinia asparaginase Erwinia asparaginase (Erwinase) has been used to treat patients having allergy to E. coli asparaginases. Erwinase was licensed for use in patients in Europe and is now available in many countries [35]. Erwinia asparaginase is superior to the
5
E. coli preparations with reference to immunogenicity and less induction of coagulation disorders [36]. The efficacy of Erwinase has been doubted as the activity was significantly lower after the first exposure: a trough level of ≥100 U/L was achieved in 33% of patients as compared to 94.5% of patients treated with E. coli asparaginase. Moreover considerably lower i.e. 26% asparagine depletion has been found after a second exposure despite of equivalent dosages in contrast to the patients in E. coli group i.e. 92.6% [37,38]. In some similar studies with Erwinase complete asparagine depletion was achieved on day 3 of treatment in only 26% of patients, whereas in some patients no depletion was found [32]. Therefore, using Erwinia as replacements for non-pegylated E. coli asparaginases, a higher dose and increased frequency of treatment is the foremost step to be taken. A further necessary feature in the Erwinia asparaginase therapy is the route of administration. A slower increase of asparaginase activity is observed after intramuscular (IM) administration due to the depot effect while intravenous (IV) administration results in concomitant elevated peak plasma levels. Asparaginase activities below the desired level was less observed after Erwinia asparaginase administration through IM route as compared to intravenous administration [39]. On the other hand, no significant differences were found in mean enzyme activity or frequency of samples showing complete asparagine depletion after IV or IM administration of Erwinia asparaginase administered during the induction phase [37]. Likewise, in patients receiving more intense regimen through IM or IV route, analogous complete asparagine depletion was found in the induction phase [40]. With regards to the formation of asparaginase neutralizing antibody, no significant dissimilarities were found among the both routes of administration as a re-induction regimen [41]. In order to ensure maximum survival benefit in ALL patients, other asparaginase preparation should be employed in case of development of anti-asparaginase antibodies to a particular preparation. The assessment of silent inactivation cases and the degree of serum asparagine depletion is relatively based on asparaginase level investigation. In brief, depending upon regulatory factors, practice and availability, Erwinia asparaginase is a valid second or third-line therapy. Moreover the optimized use of Erwinia asparaginase necessitates further clinical and pharmacokinetic studies [30]. 3.1.3. PEG-asparaginase Nowadays, the most appropriate approach to enhance the plasma half-life and trim down the immunogenicity and antigenicity of many therapeutic agents is its covalent coupling with polyethylene-glycol (PEG) and the process is known as PEGylation [42–44]. PEG-asparaginase is the modified edition of l-asparaginase formed by the covalent conjugation of E. coli asparaginase to monomethoxypolyethylene glycol (PEG) resulted in significant pharmacokinetic variations in comparison with the native E. coli formulations [33,45,46]. PEGylation of proteins and enzymes results in
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Fig. 3. Regional PEG-asparaginase therapy in Naive and relapsed children
covering of few surface sites, thus increasing their molecular size and enhancing steric-hindrance. PEG-asparaginase has similar chemical properties like native E. coli l-asparaginase i.e. reaction temperature of 50 ◦ C, isoelectic point at pH 5.0 and optimum activity at pH 7.0 [47]. The currently available PEG-asparaginase formulation in most of the countries is the E. coli derived asparaginase, Oncaspar® [48]. Within the PEG-asparaginase products from different countries minor disparities may be found. PEG-asparaginase from the E. coli l-asparaginase obtained from Merck, Sharp and Dohme are manufactured by Enzon in US and marketed as Oncaspar® , while the product is derived from the Kyowa Hakko native asparaginase protein in Europe [49,50]. The elimination half life of PEG-asparaginase is five times longer than the native E. coli preparations and nine times longer than that of Erwinia i.e. around six days. This represents an imperative improvement in therapy through decreasing the number of injections needed to achieve therapeutic efficacy in naive patients [19]. In the USA, the formulation is being approved as first-line therapy whilst in Europe as a second-line treatment restricted to known patients allergic to native asparaginases (Fig. 3). In the cited study the absorption from the injection site was 1.7 days, whereas the asparaginase activity detectable for a longer period (elimination half-life; 5.5 days) whereas the peak enzymatic activity in plasma at 5 days after an intramuscular dose of PEGasparaginase [45]. The route of administration is the main factor, because maximum amino acid depletion and peak enzyme activity levels are attained within 5 days after intramuscular administration [18]. This step by step depletion of serum asparagine and glutamine may allow increased production of hepatic asparagine synthetase and asparagines, therefore diminishing cytotoxic effects exerted on the cancer cell. The intravenous
route of administration may become the route of choice because of extensive use and appraisal in adult and paediatric ALL patient trials. Intravenous route of PEG-asparaginase will not only deplete asparagine by achieving rapid peak levels, but also get rid of painful injections [51]. The dose-dependent reduction of CSF asparagine levels can be observed after l-asparaginase administration despite the fact that PEG-asparaginase penetrates poorly into the cerebro-spinal fluid (CSF) [18,52]. An IV dose of PEG-asparaginase 1000 IU/m2 was found insufficient for asparagine depletion in the CSF whereas significant exhaustion of asparagine in plasma (
