ライフサイエンスコーパス: asparaginase

1 ntensification 3 (high-dose cytarabine and l-asparaginase).

2 ent of macrophagelike cells in the uptake of asparaginase.

3 e of asparaginase-associated pancreatitis to asparaginase.

4 side, but not to a non-DNA damaging agent, l-asparaginase.

5 ent ER stress during amino acid depletion by asparaginase.

6 was retained in Atf4 (-/-) mice treated with asparaginase.

7 regimen of vincristine, dexamethasone, and l-asparaginase.

8 se who received intramuscular native E colil-asparaginase.

9 effect of treating arabica coffee beans with asparaginase.

10 undly sensitized drug-resistant leukemias to asparaginase.

11 ignaling to improve the therapeutic index of asparaginase.

12 mplementary roles in the hepatic response to asparaginase.

13 e and mediating GCN2-mTORC1 signaling during asparaginase.

14 required for downregulation of mTORC1 during asparaginase.

15 ment rather than a ping-pong mechanism for l-asparaginases.

16 uld be beneficial to replace them with human asparaginases.

17 Because gpASNase1 and human L-asparaginase 1 (hASNase1) share 70% amino-acid identity,

18 n a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m(2) every 2 weeks) or

19 with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial gro

20 luded an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dos

21 ent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given

22 P2 evaluated whether substitution of Erwinia asparaginase 25000 IU/m(2) for 6 doses given intramuscul

23 Following allergy to pegaspargase, Erwinia asparaginase 25000 IU/m(2) x 6 intramuscularly M/W/F can

24 ochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginas

25 nts were started with 20,000 IU/m(2) Erwinia asparaginase 3 times per week, and l-asparagine was meas

26 tients were randomly assigned to receive PEG-asparaginase 3,500 U/m(2) versus the conventional 2,500

27 ery 2 weeks) or intramuscular native E colil-asparaginase (30 doses of 25 000 IU/m(2) weekly), beginn

28 The antileukemic drug asparaginase, a key component in the treatment of acute

29 Asparaginase, a widely used chemotherapeutic agent, arre

30 The anti-leukemic agent asparaginase activates the integrated stress response (I

31 Asparaginase activates the integrated stress response (I

32 The proportion of patients with plasma asparaginase activity >/= 100 mIU/mL and >/= 400 mIU/mL

33 spargase would provide a 48-hour nadir serum asparaginase activity (NSAA) >/= 0.10 IU/mL.

34 adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations.

35 00 achieves a significantly longer period of asparaginase activity above defined thresholds and aspar

36 asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucl

37 ng identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase

38 The mean half-life of plasma asparaginase activity for both SC-PEG doses was approxim

39 on of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine d

40 However, the effect of reduced asparaginase activity levels on toxicity is limited.

41 ubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hyp

42 nd 6%, respectively, and not associated with asparaginase activity levels.

43 The median nadir serum asparaginase activity was significantly higher in patien

44 endpoints were disease-free survival, serum asparaginase activity, and quality of life during therap

45 rameters were estimated by fitting the serum asparaginase activity-time course for all 6 doses given

46 than WoA-P121, yet both showed comparable L-asparaginase activity.

47 cleavage reaction, all are essential for the asparaginase activity.

48 Erwinia asparaginase administered with this schedule achieved th

49 Metabolic complications due to asparaginase affect liver function in humans.

50 regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a

51 The strongest risk factors for asparaginase allergy are variants within genes regulatin

52 Current FDA-approved l-asparaginases also possess significant l-glutaminase act

53 Resistance to asparaginase, an antileukemic enzyme that depletes aspar

54 94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intra

55 Regimens containing l-asparaginase and drugs unaffected by P-glycoprotein are

56 We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrath

57 The mutant shows completely preserved asparaginase and glutaminase activities, long-term stora

58 orly understood, in part because of its dual asparaginase and glutaminase activities.

59 ation courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus ofatumumab on courses 6

60 ive toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparagina

61 However, the asparaginase and intravenous methotrexate used in the au

62 otherapeutic agents including doxorubicin, l-asparaginase, and dexamethasone.

63 b with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity.

64 o chemotherapy, especially dexamethasone and asparaginase, and have increased risk of extramedullary

65 Older age, higher exposure to asparaginase, and higher Native American ancestry were i

66 ith dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months.

67 igher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01

68 The presence of asparaginase antibodies was related to allergies and sil

69 examethasone is higher in patients with anti-asparaginase antibodies.

70 Since currently approved L-asparaginases are of bacterial origin, immunogenicity is

71 Bacterial asparaginases are used in cancer chemotherapy to deplete

72 Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the da

73 ling factor was shown to be an enzyme with L-asparaginase (ASNase) activity.

74 l-asparaginase (ASNase) is a first-line therapy for ALL th

75 Asparaginase (ASNase) is an important component of acute

76 Asparaginase (ASNase) is an important drug for the treat

77 L-Asparaginases (ASNases) have been used as first line dru

78 ng periplasmic enzymes glutaminase (Ggt) and asparaginase (AsnB).

79 ed that therapeutic drug monitoring (TDM) of asparaginase (ASP) activity levels in plasma may be an i

80 Occurrence of asparaginase-associated hypersensitivity, pancreatitis,

81 Asparaginase-associated pancreatitis (AAP) is common in

82 to asparaginase, including 59 after a severe asparaginase-associated pancreatitis (abdominal pain or

83 as not associated with severity of the first asparaginase-associated pancreatitis and a second aspara

84 ned as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-expo

85 dominal pain after having had two versus one asparaginase-associated pancreatitis did not differ (thr

86 aginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an

87 ations and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18

88 exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase.

89 Asparaginase-associated pancreatitis was defined by at l

90 Risk of a second asparaginase-associated pancreatitis was not associated

91 INTERPRETATION: Since the risk of a second asparaginase-associated pancreatitis was not associated

92 44 (46%) patients developed a second asparaginase-associated pancreatitis, 22 (52%) of 43 bei

93 1 year after diagnosis of asparaginase-associated pancreatitis, 31 (11%) of 275 pa

94 Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 wit

95 sparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertens

96 Within 8 years of asparaginase-associated pancreatitis, risk of abdominal

97 n 50 days of asparaginase exposure developed asparaginase-associated pancreatitis.

98 severe toxic effects of treatment, including asparaginase-associated pancreatitis.

99 Several asparaginase-associated toxicities were studied.

100 The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity [n =

101 The efficacy of TDM and its effect on asparaginase-associated toxicity are reported.

102 Asparaginase-associated toxicity reduction was confirmed

103 iation factor 2 phosphorylation responses to asparaginase at all ages.

104 ginase) is the only Escherichia coli-derived asparaginase available in the United States.

105 hages as a rate-limiting factor in degrading asparaginase both in vitro and in vivo.

106 or liver toxicity by the anti-leukemic agent asparaginase, but the mechanism is unknown.

107 of rapamycin (mTOR) and show that the enzyme asparaginase can be used to target this dependence.

108 Asparaginases catalyze the hydrolysis of the amino acid

109 To examine how the liver response to asparaginase changes during maturity to adulthood, here

110 n current treatment of ALL using different l-asparaginase delivery and encapsulation methods as well

111 r treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamat

112 Higher doses of PEG-asparaginase did not affect treatment outcome.

113 structural and functional integrity of the L-asparaginase domain and provide a direct comparison of s

114 Cumulative asparaginase dose >/=120,000 IU/m(2) was associated with

115 a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents wit

116 blished previously for complexes of type I L-asparaginase (EcAI) from E. coli.

117 levels may also be inversely correlated with asparaginase efficacy in certain solid tumors as well.

118 ek, and l-asparagine was measured to monitor asparaginase efficacy.

119 , possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein.

120 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reac

121 the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics p

122 bed structures of the Erwinia chrysanthemi l-asparaginase (ErA) to inform the design of mutants with

123 the tetrameric enzyme Erwinia chrysanthemil-asparaginase (ErA), in which case electrophoresis-compat

124 Asparaginase-exposed adults also had a serine/glycine/on

125 ed steatosis and iron accumulation following asparaginase exposure along with a hepatic gene signatur

126 erapy intensification (including 30 weeks of asparaginase exposure and dexamethasone/vincristine puls

127 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated

128 echanisms of liver protection during chronic asparaginase exposure in mice.

129 aginase, suggesting mTORC1 inhibition during asparaginase exposure is not driven via eIF2-ATF4-Sestri

130 ic risk factors identifying patients in whom asparaginase exposure should be restricted is needed.

131 of mTORC1 and maintenance of ApoB100 during asparaginase exposure.

132 n, obesity promotes a maladaptive ISR during asparaginase exposure.

133 sensitivity reactions can lead to suboptimal asparaginase exposure.

134 iver transcriptome and hepatic function upon asparaginase exposure.

135 Higher doses of PEG-asparaginase failed to improve outcome, but additional i

136 an evolutionary conserved motif among this L-asparaginase family.

137 etermined mainly by the anticipated need for asparaginase for antileukaemic efficacy.

138 nism of hydrolysis of L-Asn by the type II L-asparaginase from E. coli (EcAII), but that work was lim

139 mechanism of catalysis by the L-glutaminase-asparaginase from Pseudomonas 7A (PGA) was investigated

140 port, we postulate that all homotetrameric L-asparaginases from mesophilic bacteria utilize a common

141 We are exploring the guinea pig L-asparaginase (gpASNase1) as a potential replacement of t

142 recently identified the low KM guinea pig L-asparaginase (gpASNase1).

143 nt-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparagin

144 ions (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the in

145 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the in

146 of 231 patients in the intramuscular E colil-asparaginase group) and asparaginase-related allergic re

147 patients in the intramuscular native E colil-asparaginase group, p=0.60), or in the individual freque

148 paraginase group than in the intravenous PEG-asparaginase group.

149 Administering asparaginase has always been problematic in adults becau

150 Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially

151 ur long-term goal is the design of a human l-asparaginase (hASNase3) variant, suitable for use in can

152 use, we determined the structure of human l-asparaginase (hASNase3).

153 Many side effects of current FDA-approved L-asparaginases have been related to their secondary L-glu

154 However, all human L-asparaginases have millimolar KM for asparagine.

155 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparagina

156 de approach to identify loci associated with asparaginase hypersensitivity in children with ALL enrol

157 l of infection, S Typhimurium lacking both l-asparaginase I and II genes competes poorly with wild-ty

158 ly to the periplasm and acts together with l-asparaginase I to provide S Typhimurium the ability to c

159 -asparaginase structural homology isozymes L-asparaginases I (AnsA) and II (AnsB), which are shown vi

160 trate anion to the active sites of E. coli L-asparaginases I and II, even in the presence of the nati

161 we have studied the catalytic mechanism of L-asparaginase II computationally.

162 S. Typhimurium lacking the L-Asparaginase II gene (STM3106) are unable to inhibit T c

163 L-Asparaginase II is necessary and sufficient to suppress

164 Furthermore, we report that l-asparaginase II localizes primarily to the periplasm and

165 agine deprivation such as that mediated by l-asparaginase II of S Typhimurium causes suppression of a

166 We previously showed that l-asparaginase II produced by Salmonella enterica serovar

167 dsbA) of Escherichia coli, is required for l-asparaginase II stability and function.

168 L-Asparaginase-II from Escherichia coli (EcA) is a central

169 Asparaginase immune complexes induce Fc-gammaRIII-depend

170 teraction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme

171 sparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymp

172 not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase.

173 Use of native E coli asparaginase in induction leads to high hypersensitivity

174 ntensification after receiving native E coli asparaginase in induction.

175 ution studies showed a rapid accumulation of asparaginase in macrophage-rich tissues such as the live

176 iew collates research on the use of enzymes, asparaginase in particular, to mitigate acrylamide forma

177 i asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (

178 ls markedly prolonged the serum half-life of asparaginase in vivo and decreased drug uptake in these

179 cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cel

180 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-a

181 e is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human

182 sm is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previousl

183 To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort o

184 e CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

185 ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in

186 es that have driven these advances including asparaginase intensification, the use of induction dexam

187 pancreatitis is one of the common causes of asparaginase intolerance.

188 L-asparaginase is a chemotherapy drug used to treat acute

189 Asparaginase is a critical agent used to treat acute lym

190 Asparaginase is a powerful tool for the food industry an

191 Asparaginase is a therapeutic enzyme used to treat leuke

192 l-asparaginase is a universal component of treatment for c

193 Furthermore, asparaginase is almost exclusively used in acute lymphob

194 Asparaginase is an amino acid-depleting agent used to tr

195 Asparaginase is an essential drug in childhood acute lym

196 tration of the asparagine depletion enzyme l-asparaginase is an important therapy option.

197 This asparaginase is an N-terminal nucleophile (Ntn) family m

198 regimens, but the optimal implementation of asparaginase is not well studied, considering its potent

199 We showed that asparaginase is rapidly cleared from the serum by liver-

200 Asparaginase is used to treat acute lymphoblastic leukem

201 main prerequisite for clinical efficacy of L-asparaginases is micromolar KM for asparagine to allow f

202 e depletion of blood asparagine by bacterial asparaginases is their low micromolar KM value.

203 l-asparaginase (l-ase) is an anticancer agent also harbori

204 has largely replaced native Escherichia coli asparaginase (L-ASP) in the treatment of acute lymphobla

205 L-Asparaginase (L-ASP) is a key component of therapy for a

206 r thrombosis, caused in part by the use of l-asparaginase (L-ASP).

207 Type II bacterial L-asparaginases (L-ASP) have played an important therapeut

208 Switching to Erwinia asparaginase leads to effective asparaginase levels in m

209 % and 67% of the PEGasparaginase and Erwinia asparaginase levels > 100 IU/L, respectively.

210 , which is similar to ALL-11 but with higher asparaginase levels during intensification.

211 g to Erwinia asparaginase leads to effective asparaginase levels in most patients.

212 cus and identify the p.G178R mutation in the asparaginase like-1 gene (ASRGL1), segregating with the

213 lysis time of 2 h, water content of 90%, and asparaginase load of 5000 ASNU/kg.

214 we also show that these highly human-like L-asparaginases maintain their in vitro ALL killing potent

215 donors, the authors support the notion that asparaginase may offer a therapeutic benefit in AML-not

216 establish the ISR as a conserved response to asparaginase-mediated amino acid deprivation and provide

217 s, including corticosteroids, vincristine, L-asparaginase, methotrexate, and 6-mercaptopurine.

218 gned to receive intramuscular native E colil-asparaginase (n=231) or intravenous PEG-asparaginase (n=

219 olil-asparaginase (n=231) or intravenous PEG-asparaginase (n=232).

220 layed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alter

221 After one dose of pegylated asparaginase on induction day 4, plasma asparagine was u

222 Unbiased exploration of the effect of asparaginase on the liver transcriptome revealed that th

223 l-asparaginase, one of the primary drugs used in treatment

224 after backward elimination and no effect of asparaginase or azoles were found.

225 after backwards elimination and no effect of asparaginase or azoles were found.

226 Gcn2 (-/-), and Atf4 (-/-) mice treated with asparaginase or excipient and further explored selected

227 lutaminase activity of these highly active l-asparaginases, our engineered ErA variants hold promise

228 ge (P < .001), and higher cumulative dose of asparaginase (P < .001).

229 ose assigned to intramuscular native E colil-asparaginase (p=0.58).

230 to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there wo

231 Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life a

232 longed courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase

233 yethylene glycol-conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase

234 ellular and molecular components controlling asparaginase pharmacokinetics.

235 Bacterial L-asparaginases play an important role in the treatment of

236 ginase, supporting its use as the front-line asparaginase preparation in children with newly diagnose

237 that the reaction catalyzed by L-glutaminase-asparaginases proceeds through formation of a covalent i

238 dyl succinate (SS) linker, is the first-line asparaginase product used in Children's Oncology Group (

239 biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided w

240 both in relation to first-time AAP and after asparaginase re-exposure have not been explored.

241 Asparaginase re-exposure should be considered only for p

242 involve an increased risk of complications, asparaginase re-exposure should be determined mainly by

243 the key regions that govern cleavage and the asparaginase reaction, which may inform the design of va

244 ) for the enzyme-activating autocleavage and asparaginase reactions, we prepared the T168S, T186V and

245 Fifteen of 34 asparaginase-rechallenged patients developed a second AA

246 Asparaginase reduced body growth and liver mass in juven

247 ntramuscular E colil-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3

248 treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6.7%] in th

249 roup vs two [0.8%] in the standard group and asparaginase-related pancreatitis in eight [3.0%] vs one

250 er significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patient

251 ised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pan

252 The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbiliru

253 Asparaginase-related toxicities were monitored after 173

254 There was no difference in asparaginase-related toxicity by EC-Asnase dosing method

255 = .04), but did not reduce the frequency of asparaginase-related toxicity.

256 This bacterial-type cytoplasmic L-asparaginase resides in the N-terminal subdomain of an o

257 hemotherapy (dexamethasone, vincristine, PEG-asparaginase) resulted in significantly improved surviva

258 TDM of asparaginase results in a significant reduction of the P

259 Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant

260 characterization of water dynamics on the L-asparaginase structural homology isozymes L-asparaginase

261 the first N-terminal nucleophile plant-type asparaginase structure in the covalent intermediate stat

262 y-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none

263 trin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during aspara

264 y compared with intramuscular native E colil-asparaginase, supporting its use as the front-line aspar

265 d on the characterization of another human L-asparaginase, termed hASNase1.

266 her in patients who received intravenous PEG-asparaginase than in those who received intramuscular na

267 nderstanding of the catalytic mechanism of L-asparaginases that is in agreement with the available ex

268 However, unlike the bacterial asparaginases, the human enzymes have a millimolar K(m)

269 munized mice and ALL patients who were given asparaginase therapy for several weeks recognized the K2

270 expression is associated with resistance to asparaginase therapy in childhood acute lymphoblastic le

271 f these variants could significantly advance asparaginase therapy of leukemia in the future.

272 dded to our ALL-11 protocol to individualize asparaginase therapy.

273 es subsets of gastric and hepatic cancers to asparaginase therapy.

274 The use of asparaginase to convert asparagine to aspartic acid may

275 The exact mechanism used by L-asparaginases to catalyze the hydrolysis of asparagine i

276 In contrast, asparaginase-treated adult mice displayed greater variab

277 ASNS expression can counterbalance l-asparaginase treatment by mitigating nutrient stress.

278 xplain why ALL cells are most sensitive to l-asparaginase treatment compared with other cancers.

279 The asparaginase treatment did not influence the major bioac

280 studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of r

281 Asparaginase treatment is standard in all pediatric acut

282 i asparaginase (PEGasparaginase) and Erwinia asparaginase treatment of pediatric acute lymphoblastic

283 However, the potential adverse effects of asparaginase treatment on sensory properties of cooked f

284 ed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased ri

285 ith a hepatic gene signature indicating that asparaginase uniquely affects lipid, cholesterol, and ir

286 the in vivo biodistribution of radiolabeled asparaginase, using a combination of imaging and biochem

287 Sensitization to asparaginase was mediated by Wnt-dependent stabilization

288 Intravenous PEG-asparaginase was not more toxic than, was similarly effi

289 lization of (111)In-labeled Escherichia coli asparaginase was performed in C57BL/6 mice by both small

290 Asparaginase was truncated in 17/21 patients with AAP wh

291 two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group.

292 ult of this observation, several bacterial L-asparaginases were developed and are currently approved

293 otable examples of a therapeutic enzyme is L-asparaginase, which has been established as an antileuke

294 PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker,

295 c and non-specific interactions of protected asparaginase with biological media while prolong the dru

296 ur engineered ErA variants hold promise as l-asparaginases with fewer side effects.

297 Therefore, l-asparaginases with reduced l-glutaminase activity are pr

298 vorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue.

299 The Wolinella succinogenes L-asparaginase (WoA) has been reported to be L-glutaminase

300 Gcn2 intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR g