Download - ONCH_1928 - Recent Developments in L-Asparaginase Discovery and Its Potential as Anticancer Agent
-
Please citeagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 12
Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx
Recent developments in l-asparaginase discovery and its potential asanticancer 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, Indiab Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia
c College of Allied Health Professionals, Directorate of Medical Sciences, Government College University, Faisalabad, PakistanDepartment of Microbiology, Vikram University, Ujjain, MP, India
Contents
1. Introdu2. Mechan3. Curren
3.1. C
4. Problem4.1. H4.2. C4.3. P4.4. R
5. Advanc5.1. A5.2. P5.3. F5.4. A5.5. E
6. ConcluConflicReviewAcknowReferenBiograp
Abstractl-Asparag
cancers from
CorresponTel.: +966 54
E-mail ad1 These aut
http://dx.doi.o1040-8428/ this article in press as: Shrivastava A, et al. Recent developments in l-asparaginase discovery and its potential as anticancer Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.002
e Department of Biological Sciences, Rani Durgavati University, Jabalpur, MP, IndiaAccepted 5 January 2015
ction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ism of l-asparaginase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
t asparaginase formulations: a comparative evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00urrent asparaginase formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.1. Native E. coli asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1.2. Erwinia asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1.3. PEG-asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
s associated with clinical application of bacterial asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00oagulation disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ancreatitis, hyperglycaemia, hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00esistance to l-asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
ement in l-asparaginase discovery from alternative sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00lgal asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00lants asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ungal asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ctinomycetes asparaginase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ntrapment of l-asparaginase in erythrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
sion and future direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00t of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00ces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00hies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
inase (EC3.5.1.1) is an enzyme, which is used for treatment of acute lymphoblastic leukaemia (ALL) and other related blood a long time. This enzyme selectively hydrolyzes the extracellular amino acid l-asparagine into l-aspartate and ammonia, leading to
ding author at: Department of Pharmaceutics, College of Pharmacy, PO Box 2457, King Saud University, Riyadh 11451, Saudi Arabia.2854355.dress: [email protected] (A.A. Khan).hors have equal contribution.
rg/10.1016/j.critrevonc.2015.01.002 2015 Elsevier Ireland Ltd. All rights reserved.d
-
Please cite this article in press as: Shrivastava A, et al. Recent developments in l-asparaginase discovery and its potential as anticanceragent. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.01.002
ARTICLE IN PRESSONCH-1928; No. of Pages 122 A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx
nutritional deficiencies, protein synthesis inhibition, and ultimately death of lymphoblastic cells by apoptosis. Currently, bacterial asparaginasesare used for treatment purpose but offers scepticism due to a number of toxicities, including thrombosis, pancreatitis, hyperglycemia, andhepatotoxicity. Resistance towards bacterial asparaginase is another major disadvantage during cancer management. This situation attractedattention of researchers towards alternative sources of l-asparaginase, including plantl-asparagina ects realso provide fromalternative to 2015 Else
Keywords: l- Erwina
1. Introdu
l-Asparfor manageand other Kidd identtrol the protransplanteand repeateserum wer
sion of lymmice grew days [1]. Manti-lymphthat guinea[2]. In the phoma cellamino acidlation rapidunder l-asplost guineamice, whileity even aftto guinea pwhile otherto complemasparaginaantilymphoother reseathis enzymhas anti-lylike horse sparable actagainst maagainst only some cancer but not all. Guinea pig serum wasable to inhibit certain lymphoma cell lines in vivo, but thesame activity was not possible with in vitro assays, providedthat guinea pig serum is also a rich source of complementand proposed anticancer activity against cell lines may bedue to complement mediated cytotoxicity. l-Asparaginase isan inhibitor of complement in whole guinea pig serum dur-ing in vitro assay [4]. Broome performed research to find outthe relative contribution of complement and l-asparaginase
ticancjor antal triawy [6ility fmmo
anagetime, ion. Tme wifor rearagintion, pe prosn as a
echan
linicale as a
a mo
allogrnit is . coli e trea
ren thnsion ther o
acutehood eoplasool oits the
G1-phase and ultimately apoptosis in susceptible leukemiccells [9,10]. Unlike normal cells, leukemic cells and othercancer cells have little or no asparagine synthetase and hencethey are not able to carry out the de novo asparagine synthe-sis, resulting in inhibition of protein synthesis and subsequentdeath of the tumour cells [11] (Fig. 1).
Normal cells are protected from asparagine requirementdue to their ability to produce this amino acid [12]. Unlikeconventional cancer therapy, l-asparaginase therapy is highlyse as an anticancer agent, its mechanism of action, and adverse effs an outlook for recent developments in l-asparaginase discovery
current formulations.vier Ireland Ltd. All rights reserved.
Asparaginase; Acute lymphoblastic leukaemia; Anticancer; l-Asparagine;
ction
aginase is an important chemotherapeutic agentment of acute lymphoblastic leukaemia (ALL)
hematopoietic malignancies. In the early fifties,ified that guinea pig serum has the ability to con-gression of murine lymphoma. The mice were
d with lymphoma cells during this experimentd intraperitoneal injections of normal guinea pig
e given to them. This treatment led to a regres-phoma and survival of treated mice while controllymphoma progressively and died within 2030uch earlier the discovery of guinea pig serum
oma activity, it was observed by Clementi (1922), pig serum is also a rich source of l-asparaginaseearly sixties, guinea pig serum susceptible lym-s were grown in cell culture media devoid of the
l-asparagine, this inadequacy declined cell popu-ly, but some cells survived and began to proliferateargine limitation. These cells were found to have
pig serum susceptibility after transplantation in original lymphoma cells retained this susceptibil-er transplantation in mice. The lost susceptibilityig serum was restricted to l-asparagine limitation,
amino acids, purines and pyrimidines were unableent this effect. Therefore, it was concluded that l-
se present in guinea pig serum is responsible for itsma activity [3]. These observations also attractedrchers for the detection of anticancer potential ofe, and it was found that the only guinea pig serummphoma activity, while sera from other animals,erum and rabbit serum were not able to show com-ivity [1]. Furthermore, the same sera was testedny cancer types and observed that it is effective
in ana ma
clinicDoloits aband afor mlong reactenzygoal l-aspof acfuturcatio
2. M
Cactivwith crystsubuas Efor thchildexpaand ohoodchildantining pinhibs and fungi. Present article discusses about potential oflated to current asparaginase formulations. This article
alternative sources and their potential as a less toxic
se; Kidrolase; PEG-asparaginase
er activity, and concluded that l-asparaginase isicancer agent in guinea pig serum [3,5]. The firstl on l-asparaginase was performed in 1966 by]. It is a major chemotherapeutic agent due toor hydrolysis of l-asparagine into l-aspartic acidnia. Current asparaginase formulations are usedment of acute lymphoblastic leukaemia from abut these formulations are not free from adverseherefore the search for alternative sources of thisth reduced or no adverse reaction is an importantsearchers. This article discusses the potential ofase enzyme as anticancer agents, its mechanismroblems associated with bacterial asparaginases,pects in l-asparaginase discovery and their appli-less toxic alternative.
ism of l-asparaginase activity
ly used l-asparaginase enzyme from E. coli is tetrameric protein with identical subunits, eachlecular weight of 35.6 kDa according to x-rayaphic data [7]. The molecular formula for eachC1377H2208N382O442S17. Chemically it is knownl-asparagine amidohydrolase. It is widely usedtment of haemopoietic diseases such as ALL inat results from the monoclonal proliferation andof lymphoid blasts in the bone marrows, blood,rgans. ALL correspond to the most common child-
leukaemia contributing to approximately 80% ofleukaemias and 20% of adult leukaemias [8]. Thetic activity results from depletion of the circulat-
f l-asparagine by l-asparaginase, which in turn protein synthesis, causes cell cycle arrest in the
-
Please citeagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 12A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx 3
discriminatas a remedplasma cleaquent injecand a numimmune resbe serious
The abobe due to sel-Glutamintion of plais enzymaticantly lowAs glutamil-asparaginasparagineof l-asparasparaginetic effect o
l-asparagin this article in press as: Shrivastava A, et al. Recent developments in l-a Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
Fig. 1. General mechanism behind selective toxicity
ory. The main restrictions in using l-asparaginaseial agent is its premature inactivation, more rapidrance and shorter duration of drug effect, thus fre-tions are required to maintain a therapeutic level,ber of side effects like allergies, development ofponses and finally anaphylactic shock, that might
and life-threatening [1315].ve-mentioned side effects of l-asparaginase mayveral reasons, including its l-glutaminase activity.ase activity of enzyme results in some reduc-sma l-glutamine level [1618]. l-Asparaginaseically active against glutamine, but with a signif-er affinity against glutamine than l-asparagine.ne acts as an amino group donor for the enzymee synthetase for de novo biosynthesis of l-
, therefore, the decreased glutamine level becauseaginase exposure also help in sustaining the
level reduction and thus contributes the therapeu-f l-asparaginase [19] which can be explained as:
el-asparaginase l-aspartic acid + NH3
l-glutamin
De novo
l-aspartic aAsparagine
Leukaem
Aspara No P
The exanot clear, to proceed(Fig. 2). Hocontributesis also relacer treatmesparaginase discovery and its potential as anticancer1.002
of l-asparaginase.
el-asparaginase l-glutamic acid + NH3 biosynthesis:
cid + NH3 (From glutamine) Synthetase
l-asparagine
ia cell after l-asparaginase:gine No l-asparaginerotein Synthesis Cell Death
ct mechanism of l-asparaginase action is stillalthough hydrolysis of l-asparagine is known
in two steps via a -acyl-enzyme intermediatewever, the l-glutaminase activity of asparaginases
to the associated side effects, but this activityted with cell growth inhibition in certain can-nts [20,21]. l-Asparaginase induced reduction of
-
Please citeagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 124 A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx
Fig. 2. Struct raginase reaction, covalent intermediate (-Acyl-Enzyme) is formedthrough nucle his intermediate later convert into l-aspartate and gives final reactionproducts as l-
asparagineway and itan intracel(known as of downstrlation of thor p70s6k)tein 1 (4Eproteins atthat inhibitaffect leukactivity. Inhas been fprocess thstructurallymTORC1 ivates proteacid abundteins Agt1/induced redlular signacells.
3. Currena compara
ALL antively treaanti-leukemfollowing of the aspserum cleaof asparagiopment of system [25either fromliver or the ble formuladespite its ALL.
Curre
Asparlso innia, Setobac
spp. ellus suaraginrate h
of l-ass an
ns avaanthe
the idely
(ElspegylatJ, UwiniaUK). line trormers are
wa Hrkusence) Paural illustration of the of l-asparaginase reaction mechanism. During l-aspaophilic attack by the enzyme. Green arrows indicate a nucleophilic attack. Taspratate and ammonia.
and glutamine level is linked with mTOR path-s subsequent inhibition. This pathway includeslular molecule mammalian target of rapamycinmTOR). Inhibition of mTOR leads to inhibitioneam events in its pathway including phosphory-e protein serine threonine kinase (p70S6 kinase
and eukaryotic initiation factor 4E-binding pro--BP1) which suppresses synthesis of ribosomal
mRNA translation level [22]. It has been foundion of mTOR pathway by l-asparaginase greatlyaemia cells and contributes to its antileukaemic
a separate study on acute myeloid leukaemia, itound that l-asparaginase induces an autophagicrough inhibition of mTORC1 (mTOR has two
distinct complexes mTORC1 and mTORC2).s an important regulator of cell growth which acti-in translation and inhibit autophagy under aminoance by regulating the autophagy related pro-ULK and ATG13 [23]. Therefore l-asparaginaseuction of amino acid level is associated with cel-
lling which in turn leads to death of leukeamic
t asparaginase formulations:tive evaluation
d other lymphoid malignancies have been effec-
3.1.
l-but aErwiAcinriumBacil-aspmodetion posseratiochrys
Inare w
nase
its Pter, Nof ErLtd, ond the flation(KyoLeveFran this article in press as: Shrivastava A, et al. Recent developments in l-a Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
ted with asparaginase for many years. Theic activity of asparaginases depends upon the
factors. (i) The rate of hydrolysis, and the Kmaraginase. (ii) The pharmacological factors ofrance of the enzyme [24]. (iii) The developmentnase resistance in tumour cells [18]. (iv) Devel-anti-asparaginase antibodies by the host immune]. (v) The increased contribution of asparagine
de novo biosynthesis of asparagine within theinput from the nutrient intake [26]. The best possi-tion and dosage of asparaginases is still disputed,use as a vital drug in all treatment protocols for
Table 1Clinical pharm
Formulation
Native E. coliasparaginasePEG-asparagi
Erwinia asparnt asparaginase formulations
aginases have been found not only in mammals, birds, plants, bacteria (like Escherichia coli,almonella, Mycobacteria, Pseudomonas, andter species etc.), and fungi (Aspergillus, Fusa-tc.) [27]. Bacillus licheniformis, a member of thebtilis group has recently assessed for production ofase with low glutaminase activity [28]. Similarly,alophilic bacteria has recently showed produc-
sparaginase [29]. Although not all asparaginasesti-cancer activity and currently, the only prepa-ilable for medical use are the E. coli, Erwiniami asparaginases, and their derivatives (Table 1).United States, three asparaginase formulations
used against ALL: native E. coli asparagi-ar; Merck & Co., Inc., West Point, PA, USA),ed form (Oncaspar; Enzon, Inc., Bridgewa-SA) and Erwinase, the product from cultures
chrysanthemi (Ipsen-Speywood PharmaceuticalsThe latter formulation is approved in UK as sec-eatment for patients having hypersensitivity to
two forms. These native asparaginase formu- offered under different brand names; Medacakko, Kogyo, Japan), Crasnitin (Bayer AG,, Germany), Leunase (Sanofi-Aventis, Paris,
ronal, and Kidrolase etc. in Europe and Asia.sparaginase discovery and its potential as anticancer1.002
acology of asparaginases with frequently administered doses.
Elimination half life Dosage
2630 h 6000 IU/m2 threetimes/week
nase 5.57 days 20002500 IU/m2every 2 or 4 weeks
aginase 16 h 6000 IU/m2daily ten doses, thenthree doses weekly, or30000 IU/m2daily ten doses ininduction
saadHighlight
saadNoteErwinaze
saadHighlight
saadHighlight
saadNote(Jazz Pharmaceuticals, USA)
saadNoteThis asparaginase from Erwinia is registered in UK and other European countries as Erwinase.
-
Please citeagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 12A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx 5
Table 2Asparaginase formulations therapy in naive adult patients.
Region
North AmericAustralia, NZealand
Europe
Other countri
However soreferred in
3.1.1. NatiThe asp
for ALL fearly 1990was not lonMedac wnon-Hodgkusing the siMedac lelopathies li
In compferences wwere produhigher biothe dose tto achievepharmacokThe formeasparagineplete asparof the childdisparities particularlyneed to adjthe dosing number of the studiescarried out apeutic ranfrom studiand CSF wfrom the co2500 IU/mtoxicity as[31].
3.1.2. ErwErwinia
patients havlicensed fomany coun
E. coli preparations with reference to immunogenicity andless induction of coagulation disorders [36].
e efficacy of Erwinase has been doubted as the activ-as sig
of 1 to 94over ceen fosage
[37, asparaly 26%found on-peased f.
furthepy is aginanistratadmina leve
ess obgh IM
On thean en
lete awinia
[37].througtion w
formant disnistrat
ordents, otse of dular p
and ly basnding nia asover ts furth
. PEGowadaa halFirst Line Second Line
a, UK,ew
E. coli-asparaginaseor PEG-asparaginase
Erwinia asparaginaseor PEG-asparaginase
E. coli-asparaginaseor PEG-asparaginase
Erwinia asparaginase
es E. coli-asparaginase Erwinia asparaginaseor PEG-asparaginase
me of these are no longer available now and onlythe literature [24,30] (Table 2).
ve E. coli asparaginasearaginase has improved event-free survival (EFS)rom 80% in the past few years. Ins, Crasnitin (Bayer AG, Leverkusen, Germany)ger available. Therefore asparaginase formulationas included in Berlin, Frankfurt, Muenster-ALL-ins lymphoma (BFM-ALL-NHL) protocols,milar treatment regimen. However treatment withads to more adverse reactions, especially coagu-ke haemorrhagic and thrombotic events.arison of Medac versus Crasnitin, significant dif-ere described despite the fact that both enzymescts of E. coli strains. Medac showed significantlylogical activity so it was possible to decreaseo 2550% of the dosage of Crasnitin in order
sufficient asparagine depletion under carefulinetic and pharmacodynamic monitoring [31,32].r was more effective than crasnitin, not only in
depletion but also in glutamine depletion. Com-agine depletion was attained in more than 90%ren in treatment with Medac asparaginase. Largeexist between the various products and half life is
reliant on the preparation. Although there is noust the individual dose administered, alteration ofinterval is compulsory, resulting in variation to thedosages [33,34]. In a limited number of patients,
with reduced doses of asparaginase Medac werebecause asparaginase activity higher than the ther-ge may lead to increased toxicity. This is apparentes that complete asparagine depletion in serumas accomplished by reducing the induction dosemmon 10000 IU/m2 to 5000 IU/m2 and even to
2 administered at 3-day intervals in order to reduce
Thity wlevelparedMorehas blent d92.6%pletein onwas
for nincretaken
Atheraasparadmi(IV) plasmwas lthrou[39].in mcompof Erphasemen
depleto thenificaadmi
Inpatiein caparticcases
ativedepeErwiMoresitate
3.1.3N
plasm this article in press as: Shrivastava A, et al. Recent developments in l-a Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
sociated with highly active Medac asparaginase
inia asparaginase asparaginase (Erwinase) has been used to treating allergy to E. coli asparaginases. Erwinase was
r use in patients in Europe and is now available intries [35]. Erwinia asparaginase is superior to the
genicity ofwith polyeas PEGylaedition of tion of E. glycol (PEations in c[33,45,46].sparaginase discovery and its potential as anticancer
nificantly lower after the first exposure: a trough00 U/L was achieved in 33% of patients as com-.5% of patients treated with E. coli asparaginase.onsiderably lower i.e. 26% asparagine depletion
ound after a second exposure despite of equiva-s in contrast to the patients in E. coli group i.e.38]. In some similar studies with Erwinase com-gine depletion was achieved on day 3 of treatment
of patients, whereas in some patients no depletion[32]. Therefore, using Erwinia as replacements
gylated E. coli asparaginases, a higher dose andrequency of treatment is the foremost step to be
r necessary feature in the Erwinia asparaginasethe route of administration. A slower increase ofse activity is observed after intramuscular (IM)ion due to the depot effect while intravenousistration results in concomitant elevated peakls. Asparaginase activities below the desired levelserved after Erwinia asparaginase administration
route as compared to intravenous administratione other hand, no significant differences were foundzyme activity or frequency of samples showingsparagine depletion after IV or IM administration
asparaginase administered during the induction Likewise, in patients receiving more intense regi-h IM or IV route, analogous complete asparagineas found in the induction phase [40]. With regardstion of asparaginase neutralizing antibody, no sig-similarities were found among the both routes ofion as a re-induction regimen [41].r to ensure maximum survival benefit in ALLher asparaginase preparation should be employedevelopment of anti-asparaginase antibodies to areparation. The assessment of silent inactivation
the degree of serum asparagine depletion is rel-ed on asparaginase level investigation. In brief,upon regulatory factors, practice and availability,paraginase is a valid second or third-line therapy.he optimized use of Erwinia asparaginase neces-er clinical and pharmacokinetic studies [30].
-asparaginaseys, the most appropriate approach to enhance thef-life and trim down the immunogenicity and anti-
many therapeutic agents is its covalent couplingthylene-glycol (PEG) and the process is knowntion [4244]. PEG-asparaginase is the modifiedl-asparaginase formed by the covalent conjuga-coli asparaginase to monomethoxypolyethyleneG) resulted in significant pharmacokinetic vari-omparison with the native E. coli formulations
PEGylation of proteins and enzymes results in1.002
saadHighlight
saadNote(Erwinaze, USA, Erwinase UK)
-
Please citeagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 126 A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx
aive a
covering ofsize and ensimilar chei.e. reactionand optimuPEG-asparthe E. coli PEG-aspardisparities l-asparaginmanufacturwhile the pasparagina
The elitimes longtimes longrepresents decreasingapeutic effiformulationEurope as aallergic to nabsorption asparagination half-liin plasma asparagina
The roumaximum levels are atration [18]and glutamasparaginecytotoxic e
of ause of
patienot ons, but e dosan be
ite thethe ce-asparaginef aspa
dose ens af
IntravFig. 3. Regional PEG-asparaginase therapy in N
few surface sites, thus increasing their molecularhancing steric-hindrance. PEG-asparaginase hasmical properties like native E. coli l-asparaginase
temperature of 50 C, isoelectic point at pH 5.0m activity at pH 7.0 [47]. The currently availableaginase formulation in most of the countries isderived asparaginase, Oncaspar [48]. Within theaginase products from different countries minormay be found. PEG-asparaginase from the E. coliase obtained from Merck, Sharp and Dohme areed by Enzon in US and marketed as Oncaspar,roduct is derived from the Kyowa Hakko native
se protein in Europe [49,50].mination half life of PEG-asparaginase is fiveer than the native E. coli preparations and nine
routebecaALLwill level
Thels cdespinto PEGaspartion osame
happ[53]. this article in press as: Shrivastava A, et al. Recent developments in l-a Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
er than that of Erwinia i.e. around six days. Thisan imperative improvement in therapy through
the number of injections needed to achieve ther-cacy in naive patients [19]. In the USA, the
is being approved as first-line therapy whilst in second-line treatment restricted to known patientsative asparaginases (Fig. 3). In the cited study thefrom the injection site was 1.7 days, whereas these activity detectable for a longer period (elimina-fe; 5.5 days) whereas the peak enzymatic activityat 5 days after an intramuscular dose of PEG-se [45].te of administration is the main factor, becauseamino acid depletion and peak enzyme activityttained within 5 days after intramuscular adminis-. This step by step depletion of serum asparagineine may allow increased production of hepatic
synthetase and asparagines, therefore diminishingffects exerted on the cancer cell. The intravenous
sufficient topared to
-
Please cite in l-aagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 12A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx 7
important and the best possible method should be defined forthe use of l-asparaginase in ALL therapy. The productionof neutralizing anti-asparaginase antibodies may be avoidedby the alte(Native E.asparaginaFurthermorlevels shousilent hypeof asparagi
4. Problembacterial a
Despiteopment, cuMajor advasparaginasubsequentuse of aspa
Allergicantibody itoxicity dutions exagproper imwith steroidreduction asparaginanase in comof hyperseQuinckes oThe inciden(IM) administration. Greactions aasparaginamany reasoing remissiproper immtion and susymptoms during induhypersensithere is rapsensitivity suboptimal
Productfor resistanhigh level tion reducecases [60,6preparationof allergic immune su
that belong to immunologic sensitization to a foreign proteinand another related to the protein synthesis inhibition [62].
Hyper
s disc reac
rash ass, antion o
fromess, iria, rema, aginadysfucidosin synulopathas b
g fromaraginaginaring a
Coagu
sparagd abn
n (inhde an
are alaring.14%bin a
as facth formolyticthat coed by
ity andisternd sideotein inoge
partient c
ately eedingnts alpy.
Pancr
lthougell d this article in press as: Shrivastava A, et al. Recent developments
rnate use of various asparaginase formulations coli asparaginase PEG-asparaginase, Erwiniase) during the different phases of ALL therapy.e, anti-asparaginase antibodies and asparagineld be monitored strictly to facilitate detection ofrsensitivity. In that case, the change in formulationnase may be able to improve its activity [45].
s associated with clinical application ofsparaginase
significant advancement in l-asparaginase devel-rrent formulations are not free from limitations.erse events are related to immune reaction tose protein. Furthermore asparagine depletion and
protein synthesis inhibition also aid in restrictingraginase.
reactions are primarily due to anti-asparaginasen circulation and lead to major reason fore to l-asparaginase [18,25]. Such complica-gerate when asparaginase was given withoutmune-suppressive therapy. Immunosuppression
reduces the chances of hypersensitivity throughof high titre antibodies. Production of antise antibody was higher with native asparagi-
paring to PEG-asparaginase. Clinical symptomsnsitivity include anaphylaxis, pain, oedema,edema, urticaria, erythema, rash and pruritis [25].ce of skin reactions was high with intramuscularistration compared with intravenous (IV) admin-enerally, it has been observed that hypersensitivityre found during post-induction phase when l-se is not provided for week or months. There arens for the low frequency of allergic reactions dur-on induction, like there is a delay for generation ofune response due to delay in complement activa-bsequent production of antibodies [26]. Allergicmight hide by intensive corticosteroids therapyction phase [26]. About 30% patients show silent
tivity or silent inactivation. During this conditionid inactivation of asparaginase instead of hyper-reaction which leads to asparagine depletion at a
level [25,58,59].ion of anti-asparaginase antibody is responsiblece in asparaginase therapy and also causes the
of asparagines in blood plasma [50]. This condi-s the therapeutic efficacy of asparaginase in some1]. All these conditions demand the alternative
of asaparaginase for removal or low frequencyreactions [59]. The toxicities of l-asparaginaseppression may divide into two types; firstly those
4.1.
Alogicand distresentarangesicknurticaerythasparliver ketoaprotecoag
It ferinl-aspasparrequi
4.2.
Arelateserpiinclutionscompand 1thromwell whicprotefied inducactivER cciateon prplasmvatedtreatmultimof blpatiethera
4.3.
Anot w Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
sparaginase discovery and its potential as anticancer
sensitivity
ussed earlier, bacterial proteins induce immuno-tions leading to localized, transient erythemat the site of injection to urticaria, respiratoryd acute life-threatening anaphylaxis. Clinical pre-f asparaginase hypersensitivity reactions may, allergic reactions, anaphylaxis (rare), serumtching and swelling of extremities, oedema,ash and broncospasm, localized or generalizedand other clinically related reactions. Moreover,ses treatment can also lead to organ toxicities,nction, pancreatitis and related hyperglycemia,is, glucosuria, cerebral dysfunction, decreasedthesis, hypofibrinonemia, hypercoagulable state-hies, hypoalbuminemia [26].een observed that about 60% patients were suf-
hypersensitivity reactions during therapy ofase from E. coli. Even E. coli derived PEG
se also shows hypersensitivity reactions, thus shift to another form of asparaginase [63].
lation disorder
inase therapy can also lead to several coagulationormalities due to severe acquired deficiency ofibitor of serine protease) proteins. These proteinstithrombin and 1 antitrypsin. Such complica-so higher with native forms of l-asparaginase in
to PEG asparaginase with the risk of 2.115% respectively [55,64]. Physiological inhibition of
nd other coagulation factor like IXa, Xa, XIa asor VII is majorly regulated through antithrombin,s an irreversible link with enzyme leading to its
activity inhibition [65]. Researchers have identi-nformational changes in antithrombin molecule
l-asparaginase are responsible for the loss of its formation of protein aggregates accumulated in
s [66]. Furthermore, coagulation disorders asso- effects are produced due to the effect of drugsynthesis, reduction in antithrombin, fibrinogen,n, and factors IX and X with prolongation of acti-al thromboplastin time [67,68]. l-Asparaginasean also lead to protein C and S deficiency, whichincreases thrombin level and increase the risk
and thrombosis [69,70]. Generally, 1565% ofso show hypofibrinogenemia after asparaginase
eatitis, hyperglycaemia, hepatotoxicity
h, the reason behind such adverse reaction isefined but it has been reported to occur due to1.002
-
Please cite in l-aagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 128 A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx
defects in protein synthesis. Asparaginase treatment asso-ciated liver toxicity includes oxidative stress, glutaminedeficiency, decreased hepatic protein synthesis, and lateron impairmPatients wiment rarelymicrovesic
Furthermpancreatic enzymes isasparaginepancreas [diabetes inthrough affexocrine (d
In addsymptoms asparaginain level ofsues is resof l-asparinclude halalso reportposterior re
4.4. Resist
The measparaginal-asparaginl-asparagindepletion causes l-l-asparaginactivity, resduration ofpatients ha
Resistanbecause of lar expresshence protesynthetase and the hytheir increaversely, inover expreinated and in TEL/AMthat cellulashown to bALL with thomolog lefusion gene
Resistanexpressioncells after e
of asparagine synthetase by the mesenchymal cells of thebone marrow which constitute the marrow microenvironmentfor leukaemia cells where the leukemic cells mature [78,79].
ultureytotoxeffect
regults of metase
ested marro
entratient [7tical in
and inimaanismagina53-depe meciated kiri an
dvancnative
orderformu
been i, yeas
effecrity ofcationrganispeutic
Algal
Aspared tomined
m we
purifieays int 55 C
abilitarcomnti-tumysiolome by
rate o87]. Aed maginaith th this article in press as: Shrivastava A, et al. Recent developments
ent of beta-oxidation in mitochondria [7173].th liver abnormalities through asparaginase treat-
show its histological presentation but macro- andular liver steatosis have been described [71,74].
ore, l-asparaginase treatment can also increaseamylase and lipase. Synthesis inhibition of these
regulated by l-asparagine. In the absence of l-, these enzymes create severe complications in65,75]. l-Asparaginase therapy can also induce
some patients due to decreased insulin synthesisecting both the endocrine (insulin-secreting) andigestive enzyme-secreting) cells of the pancreas.ition to above complications, CNS relatedare another adverse events associated with l-
se therapy. It has been proposed that a reduction l-asparagine and l-glutamine in cerebral tis-ponsible for these adverse reactions. Symptomsaginase associated CNS related adverse eventslucination, drowsiness, and amentia [76]. It hased that l-asparaginase therapy is associated withversible encephalopathy syndrome (PRES) [77].
ance to l-asparaginase
chanisms behind the failure and resistance to l-se treatment is still doubtful [78,79]. Activity ofase is dependent on the development of anti-ase antibodies, leading to failure of asparagine
after re-administration of l-asparaginase, andasparaginase resistance [25,51]. These anti-ase antibodies neutralize the l-asparaginaseulting in more rapid plasma clearance and shorter
drug effect. Antibody development may occur inving clinical allergy symptoms [24,25,32].ce to l-asparaginase therapy may also be assumedthe high level of l-asparaginase synthetase cellu-ion, that allows the production of asparagine andin synthesis. Expression of cellular l-asparagineis found low in B-lineage ALL with TEL/AML1per-diploid subtype and may be an indication ofsed sensitivity to l-asparaginase [78,80]. Con-
some new studies of TEL/AML1 ALL cells,ssion of asparagine synthetase mRNA was orig-did not correlate with resistance to l-asparagineL1 [81]. In other words, it can be summarizedr asparaginase synthetase over expression was
e higher in T-lineage ALL and lower in B-lineageranslocation-erythroblastosis virus E26 oncogeneukaemia-acute myeloid leukaemia 1 TEL-AML1
[78].ce to l-asparaginase also arise from the increased
of asparagine synthetase stimulated by the tumourxposure to l-asparaginase and from the expression
Co-cthe cding downeffecsynthsuggboneconc
ronm
is cricellsof mmechasparare pby thassoc
Hara
5. Aalter
Innase
havefungmour
majoapplieral othera
5.1.
l-purifideterand KThe 24 dity alittlephosfor aat phenzyslowKm [satisfiasparies w Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
sparaginase discovery and its potential as anticancer
with mesenchymal cells protected ALL cells fromicity caused by l-asparaginase, and this shiel-
correlated with asparagine synthetase levels, i.e.ation by RNA interference decreased the shieldingesenchymal cells, whereas enforced asparagine
expression give enhanced protection. The authorsthat mesenchymal cells-mediated niches in thew form a safe haven for ALL blasts by increasingons of asparagine in the leukemic cell microenvi-8]. It is yet to be decided whether this association
vivo or if the relationship between the leukemicmesenchymal cells contributes to developmentl residual disease in ALL patients [79]. Others regulating sensitivity of leukemic cells to l-
se are still doubtful and unstated. l-Asparaginasesendent therapeutic agents that cause cytotoxicityhanism of apoptosis. Other key apoptotic geneswith l-asparaginase resistance are BCL2L13,d TNF [45,82].
ement in l-asparaginase discovery from sources
to overcome the limitations of current asparagi-lations, modified preparations of l-asparaginaseproposed [83]. Occurrence of l-asparaginases ints, bacteria and animal cells, and their antitu-
ts were reviewed in many articles [84,85], but the l-asparaginases cannot be translated for humans. Despite this, discovery of l-asparaginase in sev-ms raises optimism about the development of this
agent with less adverse reactions.
asparaginase
aginase from a Chlamydomonas species has been near homogeneity (78 units/mg of protein) as
by disc-gel electrophoresis. Its molecular weightre about 275Kd and 1.34 104 M respectively.d enzyme was stable at room temperature for
sterile solution and showed the greatest activ-. The Chlamydomonas l-asparaginase possess
y to inhibit the growth of the Gardners lym-a in C3H mice [86]. As an important requirement
our activity, this enzyme showed good activitygical pH and temperature, no inhibition of the
reaction end products, no cofactor requirement,f clearance from the serum and relatively lowlthough, the Chlamydomonas asparaginase has
any of these requirements, it Km is higher thanses employed in chemotherapy [85]. Kinetic stud-is enzyme indicate that the relatively high Km1.002
-
Please cite in l-aagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 12A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx 9
value may have limited its antitumour activity, although otherfactors such as serum survival were not investigated [88].
5.2. Plants
In comphave been the major nare utilizedsues. Aspaof nitrogenother legum
There ardependent The plant aany signific23% identiinase [89].
Withanivarious foin vitro cywas observthe fruits oinhibitory [3-(4,5-dimmide] (MTresearch waasparaginahas less tox
5.3. Funga
A long activity inasparagina& Mothesasparaginagrowth of et al. (1971from myceinability oflymphosarcthe extracemicro-orgaby several [96]. l-Asshows anti[97].
Recentlwith l-aspaeffect agaiAsparaginashow no cyanti-prolifeHL60 [100
5.4. Actinomycetes asparaginase
l-Asparaginase with antineoplastic activity is also foundtinomht 140.0. l-eas th
huma
Entra
ythrod byansferum. lsible fficien
e is nrocytespara
neutrasing rpy prend theas a n
degrarom sw fre
atients additn glyctial oonia taminraginabacterity [10
onclu
sparagent o
due tchemo
mild hts of a
to thition,
majoactionl-condvantnzymenic c
has b this article in press as: Shrivastava A, et al. Recent developments
asparaginase
arison to the bacterial enzymes, the plant enzymesstudied less thoroughly. In plants, l-asparagine isitrogen storage and transport compounds, those
in protein synthesis in the actively growing tis-ragine is the major nitrogen assimilatory product
fixation and nitrate reduction in Lupinus and manyes [89].e two groups of such proteins, called potassium-and potassium-independent asparaginases [90].sparaginase amino acid sequences did not haveant similarity with microbial asparaginase but wascal and 66% similar to a human glycosylasparag-
a somnifera L. has been traditionally used inlklores as a sedative and hypnotic. Recently,totoxicity of l-asparaginase from W. somniferaed in a study where enzyme was purified fromf W. somnifera L. The antitumour and growth
effect of the l-asparaginase was assessed usingethyl-thiazol-2yl)-2,5-diphenyl-tetrazolium bro-T) calorimetric dye reduction method. Thiss proposed as first report of the plant containing l-
se with antitumour activity. W. somnifera enzymeicity compared to bacterial l-asparaginase [91].
l asparaginase
time ago, researchers found the l-asparaginase Penicillium camemberti [92]. In 1930, l-se of Aspergillus niger was studied by Schmalfuss
[93]. De-Angeli et al. (1970) reported l-se isolated from A. terreus, which suppressed theWalker 256 ascites sarcoma in rats [94]. Scheetz) studied the properties of l-asparaginase purifiedlia of Fusarium tricinctum, and pointed out the
the enzyme to suppress the growth of GC3HEDoma in mice [95]. Arima et al. (1972) examined
llular formation of l-asparaginase by a variety ofnisms and indicated that the enzyme was producedspecies of Penicillium, Aspergillus, and Nectriaparaginase from Cladosporium cladosporiodies-tumour activity against Erlichs ascites in mice
y, Shrivastava et al. (2010) found several fungiraginase activity. Few of them show the cytotoxic
nst various human cancer cell lines [98,99]. l-se from Aspergillus niger was also obtained whichtotoxicity against normal human cells, but showrative effect against leukemic cell line RS4; and].
in acweigpH 8wherK562
5.5.
Ertigatebe trmedirever
and eThererythto l-amay
Utheralife acells rapidism fthe lofor p
Inhumapotenamm
l-glulaspawith activ
6. C
Atreatmariseas a
fromeffectionsdeplein thegic reglycoical aThe eantigfore, Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
sparaginase discovery and its potential as anticancer
ycetes. Partially purified enzyme with molecularKd, optimum stability at temperature 60 C and
Asparaginase showed a cytostatic effect in 24 h,e cytotoxic effect in 48 h against JURKAT andn cancer cell line [101].
pment of l-asparaginase in erythrocytes
cytes can be used as a microbioreacter. As inves- Ataullakhanov et al. (1985), asparagine canred into human erythrocytes from the external-Asparaginase can enter in the erythrocytes byosmotic lysis [102]. The enzyme remains activet in the erythrocytes during the circulation flow.
o significant alteration of half life of transfuseds. The erythrocyte membrane provides protectionginase from anti-l-asparaginase antibodies whichlize or significantly reduce enzyme activity.ed blood cells as a micro-bioreactor for enzymesents many advantages, especially increased half-
reduction in hypersensitivity. Therefore, using redew entrapped form would protect enzymes from adation in the blood and provide the safety organ-
ide effects. Due to prolonged one month half-life,quency of injections would be more comfortable
with this preparation [103].ion to the above mentioned alternative sources,osylasparaginase is also investigated due to theirf l-asparagine hydrolysis into l-aspartate andsimilar to bacterial asparaginases without anyase activity. It is suggested that human glycosy-ses can be used to reduce side effects associatedial asparaginases due to absence of glutaminase4].
sion and future direction
inase therapy is an important component in thef children with ALL. However complications mayo certain side effects of the enzyme when usedtherapeutic agent. The complications may rangeypersensitivity to anaphylactic shocks. The toxic
sparaginase are related primarily to immune reac-s bacterial protein and to the effects of asparagineand its subsequent inhibition of protein synthesisr glands such as the liver and pancreas. The aller-s are the most prominent toxicities. Polyethylene
jugated asparaginase has significant pharmacolog-ages over native Escherichia coli asparaginase.e derived from Erwinia carotovora does not shareross-reactivity with the E. coli enzyme and, there-een used when patients develop hypersensitivity1.002
-
Please cite in l-aagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 1210 A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx
to the E. coli enzyme. This condition attracted scientist fordiscovering this activity in many other organisms. In fact theresearch gathers optimism about prospects of l-asparaginaseobtained frmanagemehaps, futurealternative posed by c
Conict of
Authorsinterest rel
Reviewers
Xu ZheMetabolic Houston, T
Dr ZakiInstitute of
Acknowled
The authand Researversity, Riy
Reference
[1] Kidd Jmeans
of varioor rabb
[2] ClemenLes DLogiqu1922;1
[3] Broomis respocells cceptibi1963;1
[4] Delage1971;2
[5] Patil Sphobla2011;3
[6] DolowStudy ochild w
[7] Swain an enz
1993;9[8] Fullme
phobla
[9] Lee SM, et al. L-asparaginase from Erwinia carotovora. An improvedrecovery and purification process using affinity chromatography. ApplBiocheKeatingpast, 1537.Killandduring leukemKotzia asparag2007;4Mashbasparag1964;1Moola ping an1994;3SoaresicochemPharm Distasigenes: 1982;3Villa P,and lowToxicoAvramEschergated astandarGroup ZeidanBiol ThWu MCnoma tWise apeutic42733Iiboshisignali5349.JacquescienceAvramrelationand r2005;4Panosyin childrens 2004;2AvramASNasNanomVerma Crit ReMahajaBacilluscale u2012;1Ebrahihalophbiol 20Pietersphobla2010;1 this article in press as: Shrivastava A, et al. Recent developments
om alternative sources as therapeutic agents fornt of ALL and other related malignancies. Per-
research can usher in the development of suitableof l-asparaginase which can pass all limitationsurrent asparaginase formulations.
interest
do not have any personal or financial conflict ofated to this work.
n, Institute of Molecular Medicine, Center forand Degenerative Diseases, 1825 Pressler Street,X 77030, United States.r Khan, Department of Biotechnology, Madhav
Technology and Science, Gwalior, India.
gement
ors are grateful to Deanship of Scientific Researchch Center, College of Pharmacy, King Saud Uni-adh, Saudi Arabia
s
G. Regression of transplanted lymphomas induced in vivo byof normal guinea pig serum. I. Course of transplanted cancersus kinds in mice and rats given guinea pig serum, horse serum,it serum. J Exp Med 1953;98(6):56582.ti A. La Dsamidation Enzymatique De Lasparagine Chez
iffrentes Espces Animales Et La Signification Physioe De Sa Presence Dans Lorganisme. Arch Physiol Biochem9(4):36998.e JD. Evidence that the L-asparaginase of guinea pig serumnsible for its antilymphoma effects. II. Lymphoma 6C3HED
ultured in a medium devoid of L-asparagine lose their sus-lity to the effects of guinea pig serum in vivo. J Exp Med18:12148.
JM, et al. l-Asparaginase and complement. Nature33:4856., et al. Asparaginase in the management of adult acute lym-stic leukaemia: is it used appropriately? Cancer Treat Rev7(3):2027.y WC, et al. Toxic and antineoplastic effects of L-asparaginase.f mice with lymphoma and normal monkeys and report on aith leukemia. Cancer 1966;19(12):18139.
AL, et al. Crystal structure of Escherichia coli L-asparaginase,yme used in cancer therapy. Proc Natl Acad Sci U S A0(4):14748.r A, et al. Emerging therapy for the treatment of acute lym-stic leukemia. Expert Opin Emerg Drugs 2010;15(1):111.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30] Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
sparaginase discovery and its potential as anticancer
m Biotechnol 1989;22(1):111. MJ, et al. L-asparaginase and PEG asparaginase
present, and future. Leuk Lymphoma 1993;10(Suppl):
er D, et al. Hypersensitive reactions and antibody formationL-asparaginase treatment of children and adults with acuteia. Cancer 1976;37(1):2208.GA, et al. Tailoring structure-function properties of L-inase: engineering resistance to trypsin cleavage. Biochem J
04(2):33743.urn LT, Wriston Jr JC. Tumor inhibitory effect of L-inase from Escherichia coli. Arch Biochem Biophys
05:4502.ZB, et al. Erwinia chrysanthemi L-asparaginase: epitope map-d production of antigenically modified enzymes. Biochem J
02(Pt 3):9217. AL, et al. Effects of polyethylene glycol attachment on phys-
ical and biological stability of E. coli L-asparaginase. Int J2002;237(1-2):16370.o JA, et al. Glutaminase-free asparaginase from vibrio succino-an antilymphoma enzyme lacking hepatotoxicity. Int J Cancer0(3):3437.
et al. L-asparaginase effects on inhibition of protein synthesisering of the glutamine content in cultured rat hepatocytes.
l Lett 1986;32(3):23541.is VI, et al. A randomized comparison of nativeichia coli asparaginase and polyethylene glycol conju-sparaginase for treatment of children with newly diagnosedd-risk acute lymphoblastic leukemia: a Childrens Cancerstudy. Blood 2002;99(6):198694.
A, et al. Pegasparaginase: where do we stand? Expert Opiner 2009;9(1):1119., et al. Mechanism of sensitivity of cultured pancreatic carci-
o asparaginase. Int J Cancer 1978;22(6):72833.DR, Thompson CB. glutamine addiction: a new ther-
target in cancer. Trends Biochem Sci 2010;35(8):.
Y, et al. L-asparaginase inhibits the rapamycin-targetedng pathway. Biochem Biophys Res Commun 1999;260(2):
N, Bouscary D. Targeting glutamine uptake in AML. Onco- 2014;1(1):12.is VI, Panosyan EH. Pharmacokinetic/pharmacodynamicships of asparaginase formulations: the past, the present
ecommendations for the future. Clin Pharmacokinet4(4):36793.an EH, et al. Asparaginase antibody and asparaginase activitydren with higher-risk acute lymphoblastic leukemia: Chil-Cancer Group Study CCG-1961. J Pediatr Hematol Oncol6(4):21726.is VI, Tiwari PN. Asparaginase (native ASNase or pegylatede) in the treatment of acute lymphoblastic leukemia. Int Jedicine 2006;1(3):24154.N, et al. L-asparaginase: a promising chemotherapeutic agent.v Biotechnol 2007;27(1):4562.n RV, et al. Efficient production of L-asparaginase froms licheniformis with low-glutaminse activity: Optimization,p and acrylamide degradation studies. Bioresour Technol25C:116.minezhad A, et al. L-asparaginase production by moderateilic bacteria isolated from Maharloo Salt Lake. Indian J Micro-12;51(3):30711.
R, et al. L-asparaginase treatment in acute lym-stic leukemia: a focus on Erwinia asparaginase. Cancer17(2):23849.1.002
-
Please cite in l-aagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 12A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx 11
[31] Ahlke E, et al. Dose reduction of asparaginase under pharma-cokinetic and pharmacodynamic control during induction therapyin children with acute lymphoblastic leukaemia. Br J Haematol1997;9
[32] Boos J,els in c1996;3
[33] Asselinasparag
[34] MullerOncol
[35] Salzer leukem
[36] AlbertsintravePharma
[37] Rizzariin childErwini2000;1
[38] Gentilifluid oquent e72530
[39] SchreyALL-BCancer
[40] Albertsin chil2001;5
[41] Albertsintramu2002;3
[42] Veroneand sol
[43] Veronedeliver
[44] Harris Rev Dr
[45] Fu CH,2007;8
[46] Vieira asparagtic leuk
[47] Wada asparag
[48] Berg 2010;5
[49] Vieira Pconcen
sion otreated2006;4
[50] Hak LJamongLeukem
[51] Douer pargaseyounge2007;1
[52] Appel Iafter oninitial d
[53] Riccardlevels iRes 19
[54] Miller HK, et al. Amino acid levels following L-asparagine amido-hydrolase (EC.3.5.1.1) therapy. Cancer Res 1969;29(1):1837.
[55] Holle LM. Pegaspargase: an alternative? Ann Pharmacother1997;3Armstraffects patientGrahamDeliv RAsselinogy an1999;4WenneIU/m(2leukemLarsonimpactleukemWoo MasparaglymphoWang BparaginlymphoPietersphobla2011;1NowaklymphomethasPiatkowphoblaGroup.Hernantype I Pathol Mitchein childOncol MinierphoblascheduNowakdren wEscherRes 20Athale tic leuklymphoRes 20BodmelymphoDigestiFromenoxidati1995;6FromenmicrovcytokinSahoo inducedRaja RHaemaChabneB, Lonand pra this article in press as: Shrivastava A, et al. Recent developments
6(4):67581. et al. Monitoring of asparaginase activity and asparagine lev-hildren on different asparaginase preparations. Eur J Cancer2A(9):154450.
BL, et al. Comparative pharmacokinetic studies of threeinase preparations. J Clin Oncol 1993;11(9):17806.
HJ, Boos J. Use of L-asparaginase in childhood ALL. Crit RevHematol 1998;28(2):97113.W, et al. Erwinia asparaginase in pediatric acute lymphoblasticia. Expert Opin Biol Ther 2012;12(10):140714.en BK, et al. Pharmacokinetics of Erwinia asparaginase afternous and intramuscular administration. Cancer Chemothercol 2001;48(1):7782.
C, et al. L-asparagine depletion and L-asparaginase activityren with acute lymphoblastic leukemia receiving i.m. or i.v.
a C. or E. coli L-asparaginase as first exposure. Ann Oncol1(2):18993.
D, et al. L-asparagine depletion in plasma and cerebro-spinalf children with acute lymphoblastic leukemia during subse-xposures to Erwinia L-asparaginase. Ann Oncol 1996;7(7):.
D, et al. Therapeutic drug monitoring of asparaginase in theFM 2000 protocol between 2000 and 2007. Pediatr Blood
2010;54(7):9528.en BK, et al. Monitoring of Erwinia asparaginase therapydhood ALL in the Nordic countries. Br J Clin Pharmacol2(4):4337.en BK, et al. Antibody formation during intravenous andscular therapy with Erwinia asparaginase. Med Pediatr Oncol
8(5):3106.se FM. Peptide and protein PEGylation: a review of problemsutions. Biomaterials 2001;22(5):40517.se FM, Pasut G. PEGylation, successful approach to drugy. Drug Discov Today 2005;10(21):14518.JM, Chess RB. Effect of pegylation on pharmaceuticals. Natug Discov 2003;2(3):21421.
Sakamoto KM. PEG-asparaginase. Expert Opin Pharmacother(12):197784.Pinheiro JP, et al. Drug monitoring of low-dose PEG-inase (Oncaspar) in children with relapsed acute lymphoblas-aemia. Br J Haematol 2001;113(1):1159.H, et al. Antitumor enzyme: polyethylene glycol-modifiedinase. Ann N Y Acad Sci 1990;613:95108.HVD. Asparaginase revisited. Leuk Lymphoma
2(2):16878.inheiro JP, et al. Serum asparaginase activities and asparagine
trations in the cerebrospinal fluid after a single infu-f 2,500 IU/m(2) PEG asparaginase in children with ALL
according to protocol COALL-06-97. Pediatr Blood Cancer6(1):1825., et al. Asparaginase pharmacodynamics differ by formulation
children with newly diagnosed acute lymphoblastic leukemia.ia 2004;18(6):10727.
D, et al. Pharmacodynamics and safety of intravenous pegas- during remission induction in adults aged 55 years orr with newly diagnosed acute lymphoblastic leukemia. Blood09(7):274450.M, et al. Lack of asparagine depletion in the cerebrospinal fluide intravenous dose of PEG-asparaginase: a window study atiagnosis of childhood ALL. Leukemia 2003;17(11):22546.i R, et al. L-asparaginase pharmacokinetics and asparagine
n cerebrospinal fluid of rhesus monkeys and humans. Cancer81;41(11 Pt 1):45548.
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76] Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
sparaginase discovery and its potential as anticancer
1(5):61624.ong JK, et al. Antibody against poly(ethylene glycol) adverselyPEG-asparaginase therapy in acute lymphoblastic leukemia
s. Cancer 2007;110(1):10311. ML. Pegaspargase: a review of clinical studies. Adv Drugev 2003;55(10):1293302.
BL. The three asparaginases. Comparative pharmacol-d optimal use in childhood leukemia. Adv Exp Med Biol57:6219.r KA, et al. asparagine concentration in plasma after 2,500) PEG-asparaginase i.v. in children with acute lymphoblasticia. Klin Padiatr 2005;217(6):3216.
RA, et al. Hypersensitivity reactions to L-asparaginase do not on the remission duration of adults with acute lymphoblasticia. Leukemia 1998;12(5):6605.H, et al. Hypersensitivity or development of antibodies toinase does not impact treatment outcome of childhood acuteblastic leukemia. J Clin Oncol 2000;18(7):152532., et al. Evaluation of immunologic crossreaction of antias-
ase antibodies in acute lymphoblastic leukemia (ALL) andma patients. Leukemia 2003;17(8):15838.
R, et al. L-asparaginase treatment in acute lym-stic leukemia: a focus on Erwinia asparaginase. Cancer17(2):23849.-Gottl U, et al. Thromboembolic events in children with acuteblastic leukemia (BFM protocols): prednisone versus dexa-one administration. Blood 2003;101(7):252933.ska-Jakubas B, et al. Use of L-asparaginase in acute lym-
stic leukemia: recommendations of the Polish Adult Leukemia Pol Arch Med Wewn 2008;118(11):6649.dez-Espinosa D, et al. L-asparaginase-induced antithrombindeficiency: implications for conformational diseases. Am J2006;169(1):14253.ll LG, et al. Effect of disease and chemotherapy on hemostasisren with acute lymphoid leukemia. Am J Pediatr Hematol
1994;16(2):1206.o R, et al. Hemostatic changes in children with acute lym-stic leukemia treated according to two different L-asparaginaseles. Am J Pediatr Hematol Oncol 1986;8(2):11620.-Gottl U, et al. Thrombotic events revisited in chil-ith acute lymphoblastic leukemia: impact of concomitantichia coli asparaginase/prednisone administration. Thromb01;103(3):16572.UH, Chan AK. Thrombosis in children with acute lymphoblas-emia. Part II. Pathogenesis of thrombosis in children with acuteblastic leukemia: effects of the disease and therapy. Thromb
03;111(45):199212.r M, et al. Fatal liver failure in an adult patient with acuteblastic leukemia following treatment with L-asparaginase.on 2006;74(1):2832.ty B, Pessayre D. Inhibition of mitochondrial beta-
on as a mechanism of hepatotoxicity. Pharmacol Ther7(1):10154.ty B, Pessayre D. Impaired mitochondrial function in
esicular steatosis. Effects of drugs, ethanol, hormones andes. J Hepatol 1997;26(Suppl 2):4353.S, Hart J. Histopathological features of L-asparaginase-
liver disease. Semin Liver Dis 2003;23(3):2959.A, et al. Asparaginase-associated pancreatitis in children. Br Jtol 2012;159(1):1827.r BA, Loo TL. Enzyme therapy: L-asparaginase. In: Chabner
go DL, editors. Cancer chemotherapy and biotherapy, principlectice (Vol. 2). Lippincott-Raven Pub; 1996.1.002
-
Please cite in l-aagent. Crit
ARTICLE IN PRESSONCH-1928; No. of Pages 1212 A. Shrivastava et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxxxxx
[77] Thachil J. L-Asparaginase, nitric oxide and posterior reversibleencephalopathy syndrome. Ann Hematol 2012.
[78] Iwamoto S, et al. Mesenchymal cells regulate the response ofacute l2007;1
[79] WilliamJ Med
[80] Kasperacute lantime1995;8
[81] Stams with LTEL-A2005;1
[82] Hollemto lineachildho
[83] Thomain the t2010;9
[84] Adamsties of Rep 19
[85] WristoRelat A
[86] Paul JHasparag
[87] Holcenglutam1976;2
[88] Broomagent.
[89] Lough arbore
[90] Sodek Asparaother p
[91] Oza VPfrom WAppl B
[92] Dox AWin Peni
[93] Schmadurch 13453
[94] Carta dterreus54950
[95] Scheetasparag1971;1
[96] Arima microo
[97] Ali SS,rium cl
[98] Shrivasanti-neasparag
[99] Shrivaslium di
[100] Loureinative reus an
2012;2
[101] Dhevagi P, Poorani E. Isolation and characterization of L-asparaginase from marine actinomycetes. Ind J Biotechnol 2006;5:51420.Ataullakhanov FI, et al. Permeability of human erythrocytes toasparagines. Biokhimiya 1985;50(10):17337.Godfrin Y, Bertand Y. Oncology news 2006;1(1):103.Kelo Eleukem2009;2
raphi
r. Abhr in Carch Iest incative
tion. H plants
r. Abdarmacurren
tions lopmeancer
r. Moical S, Pakge of ia. Hisis, anthe pogeme
r. Mohcs) inlty of
Novt Dep
Saudest incl drug
r. Sudpartm. His vel drbolite
r. Pra of Bpur, Inchnoloding L this article in press as: Shrivastava A, et al. Recent developments
ymphoblastic leukemia cells to asparaginase. J Clin Invest17(4):104957.s DA. A new mechanism of leukemia drug resistance? N Engl
2007;357(1):778.s GJ, et al. Favorable prognosis of hyperdiploid commonymphoblastic leukemia may be explained by sensitivity totabolites and other drugs: results of an in vitro study. Blood5(3):7516.WA, et al. Asparagine synthetase expression is linked-asparaginase resistance in TEL-AML1-negative but notML1-positive pediatric acute lymphoblastic leukemia. Blood05(11):42235.an A, et al. The expression of 70 apoptosis genes in relationge, genetic subtype, cellular drug resistance, and outcome inod acute lymphoblastic leukemia. Blood 2006;107(2):76976.s X, et al. Therapeutic alternatives to native L-asparaginasereatment of adult acute lymphoblastic leukemia. Bull Cancer7(9):110517.on RH, Fabro S. Antitumor activity and other biologic proper-L-asparaginase (NSC-109229) a review. Cancer Chemother68;52(6):61726.n Jr JC, Yellin TO. L-asparaginase: a review. Adv Enzymolreas Mol Biol 1973;39:185248.. Isolation and characterization of a Chlamydomonas L-
inase. Biochem J 1982;203(1):10915.berg JS, Teller DC. Physical properties of antitumorinase-asparaginase from Pseudomonas 7A. J Biol Chem51(17):537580.e JD. L-asparaginase: the evolution of a new tumor inhibitoryTrans N Y Acad Sci 1968;30(5):690704.TJ, et al. L-asparaginase from developing seeds of Lupinusus. Phytochemistry 1992;31(5):151927.L. Distribution and properties of a potassium-dependentginase isolated from developing seeds of Pisum sativum andlants. Plant Physiol 1980;65(1):226., et al. Anticancer properties of highly purified L-asparaginaseithania somnifera L. against acute lymphoblastic leukemia.iochem Biotechnol 2010;160(6):183340.
. The intracellular enzymes of lower fungi, especially thosecillium camemberti. J Biol Chem 1909;6:4617.lfuss K, Mothes K. Uber die fermentative DesamidierungAspergillus niger. Bio- chemische Zeitschrift 1930;221:.e-Angeli L, et al. Effect of L-asparaginase from Aspergillus
on ascites sarcoma in the rat. Nature 1970;225(5232):.
z RW, et al. Purification and properties of an L-inase from Fusarium tricinctum. Arch Biochem Biophys
42(1):1849.K, et al. Production of extracellular L-asparaginases by
rganisms. Agri Biol Chem 1972;36:35661. et al. Antineoplastic activity in L-asparaginase of Cladospo-adosporiodies. Ind J Clin Biochem 1993;8(1):6870.tava A, et al. Biotechnological advancement in isolation ofoplastic compounds from natural origin: a novel source of L-inase. Acta Biomed 2010;81(2):1048.tava A, et al. Kinetic studies of L-asparaginase from Penicil-gitatum. Prep Biochem Biotech 2012;42(6):57481.ro CB, et al. Purification and biochemical characterization ofand pegylated form of L-asparaginase from Aspergillus ter-d evaluation of Its ant proliferative activity. Adv Microbiol:13845.
[102]
[103] [104]
Biog
DfessoReseinteralternmulafrom
Dof PhHis cinfecdeveand c
MMedlabadColleArabgeneand mana
DceutiFacuSincesor a
Kinginternove
Din DeIndiaof nometa
DmentJabalbioteinclu Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.0
sparaginase discovery and its potential as anticancer
, et al. Depletion of L-asparagine supply and apoptosis ofia cells induced by human glycosylasparaginase. Leukemia3(6):116771.
es
inav Shrivastava is working as Assistant Pro-ollege of Life Sciences, Cancer Hospital and
nstitute, Gwalior, India. His primary researchludes the development of L-asparaginase fromsources in order to develop less toxic enzyme for-e is involved in the isolation of L-asparaginase
, animals, and microorganisms.
ul Arif Khan is an Assistant Professor in Collegey, King Saud University, Riyadh, Saudi Arabia.
t research focus is on cancer associated bacterialand their role in cancer aetiology and diagnosis,nt of anticancer substances from microbial origin,
system biology.
hsin Khurshid is a Lecturer at Directorate ofciences, Government College University, Faisa-istan. Previously he has served as Lecturer inPharmacy, King Saud University, Riyadh, Saudis research interest includes the bacterial Patho-tibiotic resistance mechanisms among bacteriatential role of bacteria in cancer diagnosis andnt.
d Abul Kalam has completed his PhD (Pharma- June 2011 from Department of Pharmaceutics,
Pharmacy, Jamia Hamdard, New Delhi, India.ember 2011, he is working as Assistant Profes-artment of Pharmaceutics, College of Pharmacy,
University, Riyadh, Saudi Arabia. His researchludes the development of nanoformulations as a
delivery system.
hir K Jain is working as Associate Professorent of Microbiology. Vikram University, Ujjain,research activities are focused on identificationug targets for new drug development, secondaryproduction from Keratinophilic and soil fungi.
deep K Singhal is a Professor in Depart-iological Science, Rani Durgavati University,dia. His research interest includes environmentalgy and development of anticancer formulations-asparaginase.1.002
Recent developments in l-asparaginase discovery and its potential as anticancer agent1 Introduction2 Mechanism of l-asparaginase activity3 Current asparaginase formulations: a comparative evaluation3.1 Current asparaginase formulations3.1.1 Native E. coli asparaginase3.1.2 Erwinia asparaginase3.1.3 PEG-asparaginase
4 Problems associated with clinical application of bacterial asparaginase4.1 Hypersensitivity4.2 Coagulation disorder4.3 Pancreatitis, hyperglycaemia, hepatotoxicity4.4 Resistance to l-asparaginase
5 Advancement in l-asparaginase discovery from alternative sources5.1 Algal asparaginase5.2 Plants asparaginase5.3 Fungal asparaginase5.4 Actinomycetes asparaginase5.5 Entrapment of l-asparaginase in erythrocytes
6 Conclusion and future directionConflict of interestReviewersAcknowledgementReferences
Biographies