Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A total of 55 previously untreated adults with acute lymphocytic leukemia (ALL), median age 38 years (range 15-73 years), were treated with MOAD (methotrexate, vincristine, L-asparaginase, and dexamethasone). This regimen includes five phases--induction, consolidation, cytoreduction, maintenance, and central nervous system (CNS) prophylaxis with parenteral high-dose methotrexate. Of the 55 evaluable patients, 42 achieved complete remission 76%), with a median CR duration of 12+ months (range 0.5-195+ months). The median survival in remission is 22+ months (range 1-198+ months), with 33% of remitters continuing in long-term remissions (> 5 years). Two out of four patients who developed CNS leukemia did so without marrow relapse, were successfully treated for that complication, and continue in total complete remission at 8+ and 16+ years. Another patient with extramedullary relapse (breast) was treated with radiation to that site and remains in total CR at 16+ years. Expected toxicities included myelosuppression during the induction phase of treatment, with 65% of patients requiring intravenous antibiotics. Mucositis was the next most frequent toxicity and required dose-reduction in seven patients. Minimal toxicity was seen during the post-remission phases of treatment. L-Asparaginase toxicity was more prominent during intravenous administration (24 patients) than when the intramuscular route of administration (30 patients) was used. The remission rate and long-term survivorship achieved with this regimen, without the use of an anthracycline, is comparable to that of other regimens for adult ALL. MOAD was well-tolerated by young and old adults with ALL. Aseptic necrosis of bone, successfully treated in each instance, occurred in four long-term disease-free survivors. The effect of this complication and its treatment on quality of life has been negligible.
Leukemia 1993 Aug
PMID:Long-term follow-up of treatment and potential cure of adult acute lymphocytic leukemia with MOAD: a non-anthracycline containing regimen. 835 Jun 24

L-Asparaginase treatment of leukemia patients causes hemostatic problems. To investigate whether L-asparaginase influences coagulation studies, 63 blood samples of 21 healthy male donors were incubated with L-asparaginase for 30 min at room temperature. After treatment with 100 IU/ml L-asparaginase plasma fibrinogen (P = 0.002), plasma antithrombin (P = 0.0002), plasma protein C (P = 0.0004), and plasma plasminogen (P = 0.0039) were decreased compared with controls. In contrast, a significant increase in plasma von Willebrand factor antigen (P = 0.08) and plasma thromboglobulin (P = 0.005) was observed. The decrease in plasma anti-thrombin (P = 0.001), plasma protein C (P = 0.0003), and plasma plasminogen (P = 0.0043) was also measurable after 0.05 IU/ml asparaginase treatment. The incubation with L-asparaginase was similar to the normal time from blood sampling to testing and hence the results suggest that L-asparaginase may directly attack proteins of the coagulation system during the interval between sampling and assay.
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PMID:Asparaginase decreases clotting factors in vitro: a possible pitfall? 856 77

L-Asparaginase derived from Erwinia chrysanthemi which is being investigated as an alternative to E. coli for the treatment of lymphoblastic leukaemia has been found in our laboratory to lose activity upon exposure to consecutive freeze-thaw cycles. An investigation was undertaken using several techniques to characterize fully the physicochemical changes L-Asparaginase is undergoing during freeze-thaw cycling leading to the loss of its activity. A total protein assay suggested that the loss of some enzyme activity was a result of protein precipitation. Circular dichroism (CD) studies showed a decrease of alpha-helical structure with a concomitant increase in beta sheet and random coil content, suggesting alterations in the secondary structure leading to unfolding, the first step of denaturation processes. The elution profiles obtained from size-exclusion chromatography (SEC) studies indicated the formation of several species during the process of freezing and thawing. Sodium dodecylsulphate-polyacrylamide gel electrophoresis (SDS-PAGE) studies showed bands corresponding to 1-3 kDa and 32 kDa, suggesting that some of the species are fragments and shortened monomers resulting from cleavage of monomers. The molecular weight distribution obtained using SEC-linked light scattering indicated a substantial fraction of polydispersed fragments ranging from 900 Da to 3 kDa and a small fraction of aggregates corresponding to 300 kDa. A scheme was proposed to explain the cascade of events leading to the loss of soluble protein and accompanying loss of enzyme activity. Tetramers of the enzyme dissociate into monomers some of which are cleaved into small fragments. The shortened monomers then aggregate and precipitate.
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PMID:Investigation of physicochemical changes to L-asparaginase during freeze-thaw cycling. 917 79

Thirty-nine consecutive patients with acute lymphoblastic leukemia were treated with an intensive chemotherapy protocol. There were 23 males and 16 females with a median age of 37 years (range: 15-65). Eighteen patients had common ALL, seven had pre-B ALL, three early-precursor B ALL, seven T-ALL and four had aberrant expression of myeloid antigens (c-ALL in three and pre-B ALL in one). The median initial leukocyte count was 11.8 x 10(9)/l (range: 0.65-295). Cytogenetic result of the marrow was available in 16 of 39 patients (41 per cent) and showed Philadelphia positivity in six, a normal result in six and one each of t(4,11), t(1,19), hyperdiploidy and del 12p. Hepatosplenomegaly was present in about 20 per cent of the patients. L-Asparaginase-related hepatic toxicity was the commonest toxicity (48.7 per cent) during phase I of induction. Prolonged pancytopenia and hypoplastic death were common during phase II. With the use of growth factors during the neutropenic period of phase II induction, the rate of hypoplastic death was reduced from 40 per cent to 3 per cent. Common causes of treatment failure included early hypoplastic death (27.8 per cent) and leukemia relapses (50 per cent) while primary refractory leukemia, hepatic failure and perforated peptic ulcer contributed to 11.1, 5.5 and 5.5 per cent of the other deaths. A high complete remission (CR) rate (87.4 per cent) was achieved after phase I induction. The median event-free survival (EFS) was 8 months and the 3-year event-free survival was 43 per cent. This result compared favourably to the other regimens previously employed in our institution. In conclusion, satisfactory survival can be achieved with this intensive regimen. Good supportive care was however, essential to minimize toxicities.
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PMID:Improved treatment outcome in adult acute lymphoblastic leukemia using the intensive German protocol, a preliminary report. 937 68

L-Asparaginase is an enzyme which hydrolyzes asparagine to produce aspartic acid and ammonia. It is an effective chemotherapeutic drug, especially in the treatment of acute lymphoblastic leukaemia in children. The enzyme from Escherichia coli was crystallized in a new crystal form with space group C2, unit-cell parameters a = 76.3 (0), b = 134.6 (2), c = 64.8 (7) A, beta = 110.5 (1) degrees and a dimer in the asymmetric unit. Synchrotron-radiation diffraction data have been collected to 1.95 A resolution.
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PMID:Preparation and preliminary X-ray diffraction studies of a new crystal form of L-asparaginase from Escherichia coli. 1048 65

L-Asparaginase is used for the treatment of acute leukemias, but is sometimes ineffective or associated with severe side-effects. We report here that the enzyme arginine deiminase is approximately 100-fold more potent than L-asparaginase in inhibiting the proliferation of cultured human lymphatic leukemia cell lines while it appears to be less effective in leukemia cells of myeloid origin. The inhibition of cell proliferation involves cell growth arrest in the G1- and/or S-phase and eventually apoptotic cell death. Our results suggest the possibility of a future use of arginine deiminase for the therapy of leukemia.
Leukemia 2000 May
PMID:Arginine deiminase inhibits proliferation of human leukemia cells more potently than asparaginase by inducing cell cycle arrest and apoptosis. 1080 13

The EORTC Children Leukemia Group (CLG) is part of the offspring of the EORTC Hemopathies Working Party which in 1978 split into a paediatric and to an 'adult' branch. At that time, the Berlin-Frankfurt-Munster (BFM) designed by H. Riehm for acute lymphoblastic leukaemia (ALL) appeared much more efficacious than all others and the CLG decided to adapt that treatment strategy for its own clinical trials. The main results of these may be summarised as follows:for standard risk patients, the deletion of cyclophosphamide from consolidation and reconsolidation courses does not jeopardise the patient's outcomefor medium- and high-risk patients receiving high-dose methotrexate (MTX), cranial radiotherapy is superfluouswith the dose scheduling of the BFM regimen, E-Coli L-Asparaginase is more efficacious than Erwinia L-Asparaginasethe addition of monthly intravenous (i.v.) 6-mercaptopurine to conventional maintenance chemotherapy is detrimentalthe assessment by quantitative polymerase chain reaction (PCR) of minimal residual disease at completion of induction is feasible in a cooperative setting and can be used as a powerful and independent prognostic factor. The CLG also conducted clinical studies of acute myeloblastic leukaemia. Since 1989, lymphoblastic non-Hodgkin's lymphomas have been treated within the ALL trials. The CLG collaborates with other Groups within the I-BFM Study Group and participants in the meta-analytic studies conducted by the Oxford team by the Oxford Children ALL Collaborative Group.
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PMID:The Children Leukemia Group: 30 years of research and achievements. 1185 64

L-Asparaginase is a standard component in chemotherapy of childhood acute lymphoblastic leukaemia (ALL). Leukaemic cells carrying TEL/AML1 fusion gene are more sensitive to treatment with L-asparaginase compared to other subtypes of ALL. We demonstrate in vitro the prolonged growth suppression of TEL/AML1[+] cells compared to TEL/AML1[-] leukaemic cells after L-asparaginase treatment simulating treatment protocol. Cell cycle analysis revealed TEL/AML1[+] cells to accumulate in G1/G0 phase (81-98%) compared to TEL/AML1[-] cells (47-60%). Quantitative analysis of asparagine synthetase (AsnS) expression showed the ability of TEL/AML1[+] cells to increase AsnS mRNA levels after L-asparaginase treatment to the same extent as TEL/AML1[-] leukaemic and nonleukaemic lymphoid cells. We hypothesise that TEL/AML1[+] cells are unable to progress into the S phase of cell cycle under nutrition stress caused by L-asparaginase, despite the ability of AsnS upregulation. Significantly higher expression of AsnS was found in untreated leukaemic cells from children with TEL/AML1[+] ALL (n=20) in comparison with the group of age-matched children with ALL bearing no known fusion gene (n=25; P=0.0043). Interestingly, none of the TEL/AML1[+] patients with high AsnS level relapsed, whereas 10/15 patients with AsnS below median relapsed (P=0.00028). Therefore, high AsnS levels in TEL/AML1[+] patients correlate with better prognosis, possibly reflecting the stretched metabolic demand of the lymphoblast.
Leukemia 2004 Mar
PMID:Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells. 1552 23

L-Asparaginase (isozyme II) from Escherichia coli is an important therapeutic enzyme used in the treatment of leukemia. Extracellular expression of recombinant asparaginase was obtained by fusing the gene coding for asparaginase to an efficient pelB leader sequence and an N-terminal 6x histidine tag cloned under the T7lac promoter. Media composition and the induction strategy had a major influence on the specificity and efficiency of secretion of recombinant asparaginase. Induction of the cells with 0.1 mM IPTG at late log phase of growth in TB media resulted in fourfold higher extracellular activity in comparison to growing the cells in LB media followed by induction during the mid log phase. Using an optimized expression strategy a yield of 20,950 UI/L of recombinant asparaginase was obtained from the extracellular medium. The recombinant protein was purified from the culture supernatant in a single step using Ni-NTA affinity chromatography which gave an overall yield of 95 mg/L of purified protein, with a recovery of 86%. This is approximately 8-fold higher to the previously reported data in literature. The fluorescence spectra, analytical size exclusion chromatography, and the specific activity of the purified protein were observed to be similar to the native protein which demonstrated that the protein had folded properly and was present in its active tetramer form in the culture supernatant.
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PMID:Extracellular expression and single step purification of recombinant Escherichia coli L-asparaginase II. 1547 79

L-Asparaginase is an effective antineoplastic agent, used in the acute lymphoblastic leukemia chemotherapy. It has been an integral part of combination chemotherapy protocols of pediatric acute lymphoblastic leukemia for almost 3 decades. The potential of L-asparaginase as a drug of leukemia has been a matter of discussion due to the high rate of allergic reactions exhibited by the patients receiving the medication of this enzyme drug. Frequent need of intramuscular injection has been another disadvantage associated with the native preparation. However, of late these clinical complications seem to have been addressed by modified versions of L-asparaginase. PEG-L-asparaginase proves to be most effective in this regard. It becomes important to discuss the efficacy of L-asparaginase as an antileukemic drug vis-a-vis these disadvantages. In this review, an attempt has been made to critically evaluate the pharmacological and clinical potential of various preparations of L-asparaginase as a drug. Advantages of PEG-L-asparaginase over native preparations and historical developments of therapy with l-asparaginase have also been outlined in the review below.
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PMID:Pharmacological and clinical evaluation of L-asparaginase in the treatment of leukemia. 1701 87


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