<scp>l</scp>-asparaginase: an effective agent in the treatment of acute lymphoblastic leukemia

Kumar, Kuldeep; Kaur, Jagjeet; Walia, Shefali; Pathak, T; Aggarwal, Diwakar

doi:10.3109/10428194.2013.803224

Cited by 44 publications

(28 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, the enzymatic inhibition caused by metal ions and the presence of 10 cysteines in ScASNase1 (Fig. 3A) suggest that certain vicinal sulfhydryl groups are important for protein stabilization, a property described for other L-ASNases3233. It is noteworthy to cite that the incubation of EcASNase2 with human serum did not affect the activity, while ScASNase1 presented a significant augment of specific activity (Fig.…”

Section: Discussionmentioning

confidence: 78%

Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Costa

Schultz

Pedra

et al. 2016

Sci Rep

View full text Add to dashboard Cite

L-asparaginase (L-ASNase) (EC 3.5.1.1) is an important enzyme for the treatment of acute lymphoblastic leukaemia. Currently, the enzyme is obtained from bacteria, Escherichia coli and Erwinia chrysanthemi. The bacterial enzymes family is subdivided in type I and type II; nevertheless, only type II have been employed in therapeutic proceedings. However, bacterial enzymes are susceptible to induce immune responses, leading to a high incidence of adverse effects compromising the effectiveness of the treatment. Therefore, alternative sources of L-ASNase may be useful to reduce toxicity and enhance efficacy. The yeast Saccharomyces cerevisiae has the ASP1 gene responsible for encoding L-asparaginase 1 (ScASNase1), an enzyme predicted as type II, like bacterial therapeutic isoforms, but it has been poorly studied. Here we characterised ScASNase1 using a recombinant enzyme purified by affinity chromatography. ScASNase1 has specific activity of 196.2 U/mg and allosteric behaviour, like type I enzymes, but with a low K0.5 = 75 μM like therapeutic type II. We showed through site-directed mutagenesis that the T64-Y78-T141-K215 residues are involved in catalysis. Furthermore, ScASNase1 showed cytotoxicity for the MOLT-4 leukemic cell lineage. Our data show that ScASNase1 has characteristics described for the two subfamilies of l-asparaginase, types I and II, and may have promising antineoplastic properties.

show abstract

Section: Discussionmentioning

confidence: 78%

Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Costa

Schultz

Pedra

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…1 Nevertheless, ASNS has already been known as a resistant marker in acute lymphoblastic leukemia (ALL). 2 For curing certain ALL that lacks ASNS, L-asparaginase is a successful chemotherapy drug by removing L-asparagine outside leukemia cells to avoid exo-L-asparagine entering the cancer cell for further protein synthesis and cell survival. However, some resistant ALL cells begin to express ASNS because of gene mutation.…”

Section: Introductionmentioning

confidence: 99%

Role of asparagine synthetase in doxorubicin-induced resistance

Lin

Chou

2013

Biomarkers and Genomic Medicine

View full text Add to dashboard Cite

Research has shown drug resistance as the major cause of failure of cancer chemotherapy. In this study, doxorubicin-sensitive human uterine cancer cell (hUCC) MES/SA, as well as doxorubicin-resistant hUCC MES/SA-DxR 2mM and MES/SA-DxR 8mM were used. Subsequently, asparagine synthetase (ASNS), a protein that had previously been proposed to be a putative cancer drug target in our laboratory, was silenced by siRNA knockdown to study the mechanism of doxorubicin-induced resistance further. After potent knockdown of ASNS, cell viability in two doxorubicin-resistant cell lines MES/SA-DxR 2mM and MES/SA-DxR 8mM was decreased, as indicated by an MTT cell proliferation assay. By coupling two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, proteins that play a vital role in ASNS signaling network and development of doxorubicininduced resistance were identified. Among all the proteins that we have identified, GRP78 and AKR1C1 appear to be involved in drug resistance, replication factor C appears to participate in DNA repairing, and PP6C is proposed to play a role in cell cycle arrest.

show abstract

“…PEG-ASP preserves the enzymatic function of native L-ASP, but decreases the immunogenicity of the protein, thus potentially reducing the risk of hypersensitivity reactions. Another advantage of PEG-ASP is its prolonged half-life compared with native L-ASP; a single injection of PEG-ASP can be given instead of inconveniently administering multiple doses of native L-ASP (6,8). Comparative studies between L-ASP and PEG-ASP treatments in pediatric and adult ALL patients suggest that patients treated with PEG-ASP had faster clearance of tumor cells and more prolonged activity.…”

Section: Introductionmentioning

confidence: 99%

PEG-asparaginase in BFM-90 regimen improves outcomes in adults with newly diagnosed lymphoblastic lymphoma

Zheng

Ren

et al. 2017

Chinese Journal of Cancer Research

View full text Add to dashboard Cite

ObjectiveAlthough L-asparaginase (L-ASP) is a standard treatment for lymphoblastic lymphoma (LBL), hypersensitivity reactions by some patients limit its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and is a standard treatment in all pediatric acute lymphoblastic leukemia (ALL). In this study, we investigated the efficacy and toxicity of PEG-ASP instead of L-ASP as used in the BFM-90 regimen (PEG-ASP-BFM-90) for adult LBL.MethodsBetween June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEG-ASP-BFM-90 in a prospective, multicenter and single-arm clinical study at 5 participating institutions in China.ResultsAll the 30 patients, including 19 males and 11 females with a median age of 30 (range: 18–62) years, completed 128 times of the PEG-ASP, with the median of 4 (range: 2–6) times. Patients did not receive radiotherapy at this time. The overall response rate was 86.7% (26/30), with 50.0% (15/30) complete response and 36.7% (11/30) partial response. The 3-year overall survival was 46.0% [95% confidence interval (95% CI), 28.2%–64.8%], and the 3-year progression-free survival was 43.0% (95% CI, 25.7%–62.0%). Major adverse events were myelosuppression, reduced fibrinogen, liver dysfunction and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded.ConclusionsOur clinical data and observed outcomes indicate that 1 dose of PEG-ASP can replace multiple doses of native L-ASP in BFM-90, with predominantly grade 3–4 neutropenia for adult LBL, and no therapy-related deaths. The effect is similar to previous reports of PEG-ASP-containing regimens for adult ALL. Major advantages include less serious allergic reactions, 2–3 weeks of action duration, and convenience for patients and physicians.

show abstract

l-asparaginase: an effective agent in the treatment of acute lymphoblastic leukemia

Cited by 44 publications

References 54 publications

Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: an allosteric enzyme with antineoplastic activity

Role of asparagine synthetase in doxorubicin-induced resistance

PEG-asparaginase in BFM-90 regimen improves outcomes in adults with newly diagnosed lymphoblastic lymphoma

Contact Info

Product

Resources

About