Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.1.1 (asparaginase)
2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seventy-six patients with advanced acute leukemia refractory to conventional chemotherapy were treated with a sequential combination of methotrexate (MTX) and L-asparaginase (L-ASP), based on the reported schedule-dependent synergism between the two drugs in human leukemic cells in vitro. On Day 1, patients received 60 mg/m2 of MTX iv, followed 24 hours later by L-ASP at a dose of 10,000 IU/m2 iv. This sequence was repeated weekly with 50% escalations in the dose of MTX with each course. Overall, 31 of 76 patients (40.7%) achieved complete remission after a median of three courses; the response rate was 35.5% in patients with acute nonlymphocytic leukemia (21 of 59 patients) and 58.8% in patients with acute lymphocytic leukemia (ten of 17). Increasing the starting dose of MTX to 200 mg/m2 did not improve the response rate. Maintenance therapy with the same combination given every 2 weeks produced a median complete remission of 10 weeks. Toxicity was manifested by: acute hypersensitivity reactions to L-ASP (five patients), stomatitis (36 patients), and mild liver abnormalities (five patients). MTX in doses up to 200 mg/m2 caused minimal myelosuppression. We conclude that the MTX-L-ASP combination is a well-tolerated, highly effective induction regimen for refractory acute leukemia.
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PMID:Sequential combination of methotrexate and L-asparaginase in the treatment of refractory acute leukemia. 693 51

In the ongoing trial ALL-BFM 90 for the treatment of childhood non-B cell acute lymphoblastic leukemia (ALL) 1468 unselected patients (pts) were enrolled from 84 centers in Germany and Switzerland from 4/90 to 12/93. Based on the results of the previous trial ALL/NHL-BFM 86 this treatment program focused especially on therapy modifications for average (MRG) and high risk (HRG) pts, on the evaluation of therapy response for prognosis, and on the identification of high risk pts by molecular genetics. For average risk pts consolidation therapy was intensified by the addition of L-asparaginase (L-ASP) on a randomized basis. In HRG induction and consolidation therapy was modified by introduction of early intensification elements that had proved to be effective in relapsed pts. This patient group was randomized for the evaluation of the effects of G-CSF administered in the intervals between the intensification elements. Distribution of the 1376 eligible pts into the three treatment arms SRG (standard risk), MRG, and HRG was as expected (17 pts not yet assigned): 385 pts (28.0%), 834 pts (60.6%), and 140 pts (10.2%), respectively. Treatment consisted of the 8-drug induction (Protocol I), consolidation (Protocol M), reinduction (Protocol II), and maintenance therapy (total therapy duration 24 months). The drug doses and combinations were only slightly modified compared to the previous study ALL-BFM 86 with the exception of the randomized L-ASP containing arm MRG-2 (Protocol M-A) and group HRG. Preventive cranial irradiation was reduced to 12 Gy and applied to MRG and HRG pts only. As in study ALL-BFM 86, the initial response to a 7-day exposure to prednisone and to the first intrathecal injection of MTX at diagnosis was evaluated at day 8 of treatment with regard to blast count in peripheral blood (PB). In addition, pts were now investigated for the presence of blasts in the bone marrow (BM) at day 15 of treatment to compare the prognostic power of both response parameters. Identification of translocation t(9; 22) and/or BCR-ABL rearrangement characterized a small subgroup of pts that were not detected by poor initial therapy response. These pts were enrolled in HRG for more intensive treatment including allogeneic bone marrow transplantation (BMT). After a median observation time of 22 months, the overall probability for event-free survival (p-EFS) is 82 +/- 2%. 11 pts (0.8%) died before complete remission (CR) was achieved, 15 pts (1.1%) died while in CR for reasons other than relapse.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Concept and interim result of the ALL-BFM 90 therapy study in treatment of acute lymphoblastic leukemia in children and adolescents: the significance of initial therapy response in blood and bone marrow]. 752 27

In a boy with non-Hodgkin's lymphoma (NHL), two different complications developed concurrently associated with L-asparaginase (L-ASP) therapy. A non-ketotic hyperglycemic state was observed simultaneously with bilateral acute parotitis after the patient was subjected to L-ASP. The hyperglycemia with normal insulin levels and the absence of plasma and urine ketones was controlled with insulin therapy and no residual impairment of glucose tolerance was demonstrated later. Bilateral acute parotitis, which is a rare complication associated with L-ASP, resolved spontaneously within a week after cessation of L-ASP. The rarely observed toxic effects of L-ASP, such as parotitis, should be recognized as promptly as the better-known complications, e.g., hyperglycemia, to avoid the continuation of this antineoplastic agent.
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PMID:Hyperglycemia and acute parotitis related to L-asparaginase therapy. 900 80

We have compared the antileukemic activity of the investigational biotherapeutic agent B43-PAP to the antileukemic activities of the standard chemotherapeutic drugs vincristine (VCR), methylprednisolone (PDN), L-asparaginase (L-ASP) as single agents as well as in a 3-drug combination regimen ("VPL") using a SCID mouse model of human B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). When mice (N = 95) were challenged with 1 x 10(6) NALM-6 leukemia cells, all of them died of disseminated leukemia with a median event-free survival (EFS) of 47 +/- 6 days. B43-PAP was more active than VCR, PDN, or L-ASP and the two-drug combinations VCR + B43-PAP, PDN + B43-PAP, or L-ASP + B43-PAP were not significantly more active than B43-PAP. The 120 days EFS outcome results were 46 +/- 13% for B43-PAP (Median EFS = 92 +/- 22 days), 0 +/- 0% for VCR (Median EFS = 49 +/- 1 days), 40 +/- 22% for PDN (Median EFS = 100 +/- 20 days), 0 +/- 0% for L-ASP (Median EFS = 41 +/- 1 days), 60 +/- 22% for VCR + B43-PAP (Median EFS = >120 days), 60 +/- 22% for PDN + B43-PAP (Median EFS = >120 days), and 50 +/- 25% for L-ASP + B43-PAP (Median EFS = 93 +/- 27 days), When mice (N = 61) were challenged with 5 x 10(6) NALM-6 cells, all of them rapidly died of disseminated leukemia with a median EFS of 37 +/- 3 days. The 3-drug combination "VPL" (Median EFS = 75 +/- 23 days) was slightly less active than B43-PAP (Median EFS = 84 +/- 19 days) (P = 0.09). Notably, the combination of "VPL" with B43-PAP (i.e., VPLB) resulted in 100% survival. By comparison, the combination of "VPL" with daunorubicin (i.e., VPLD) (Median EFS = 69 +/- 31 days) was not more active than VPL. To our knowledge, this preclinical study is the first to demonstrate the feasibility and superb antileukemic activity of immunochemotherapy using anti-CD19 immunotoxin in combination with the standard 3-drug combination "VPL" against BCP ALL.
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PMID:Treatment of human B-cell precursor leukemia in SCID mice by using a combination of the anti-CD19 immunotoxin B43-PAP with the standard chemotherapeutic drugs vincristine, methylprednisolone, and L-asparaginase. 972 Jul 24

The t(12;21) translocation resulting in TEL/AML1 gene fusion is present in approximately 25% of patients with precursor B-lineage pediatric acute lymphoblastic leukemia (ALL). Studies suggest an association with a good prognosis; however, relapse can occur. We studied the relation between t(12;21), determined by fluorescence in situ hybridization or polymerase chain reaction, and in vitro drug resistance, measured by the MTT assay, in childhood B-lineage ALL at diagnosis. A total of 180 ALL samples were tested, 51 (28%) of which were positive for t(12;21). The median LC(50) values did not differ significantly between TEL/AML1-positive and -negative samples for prednisolone, dexamethasone, daunorubicin, thiopurines, epipodophyllotoxins, and 4-HOO-ifosfamide. However, the TEL/AML1-positive patients were relatively more sensitive to L-asparaginase (ASP; 5.9-fold; P =.029) and slightly but significantly more resistant to vincristine (1.5-fold; P =.011) and cytarabine (1.5-fold; P =.014). After matching for unevenly distributed patient characteristics-that is, excluding patients younger than 12 months, patients with CD10-negative immature B-lineage ALL, patients with Philadelphia chromosome, and patients who were hyperdiploid (more than 50 chromosomes) from the TEL/AML1 negative group-the only remaining difference was a relative sensitivity for ASP in the TEL/AML1-positive samples (10.8-fold; P =. 012). In conclusion, the presence of TEL/AML1 gene fusion in childhood precursor B-lineage ALL does not seem to be associated with a high in vitro drug sensitivity, except for ASP, indicating that these patients could benefit from treatment schedules with significant use of this drug.
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PMID:TEL/AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia. 1091 Sep 27

Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of patients treatment still fails. The objectives of the DCLSG study ALL 8 were to decrease the toxicity and to increase the effectivity of BFM-oriented treatment. Decrease of toxicity was aimed at by confirmation of the results of the previous DCLSG study ALL-7, showing that the majority (94%) of children with ALL can successfully be treated with BFM-oriented therapy without cranial irradiation, and by reduction of treatment for standard risk (SRG) patients. To increase the cure rate in medium risk (MRG) patients the efficacy of high doses of intravenous 6-mercaptopurine (HD-6MP) during protocol M and in SRG patients the efficacy of high doses of L-asparaginase (HD-L-ASP) during maintenance treatment was studied in randomized studies. Patient stratification and treatment were identical to protocol ALL-BFM90, with the following differences: no prophylactic cranial irradiation, SRG patients received only phase 1 of protocol I. Four hundred and sixty-seven patients entered the protocol: 170 SRG, 241 MRG and 56 HRG patients. The 5 years event-free survival rate for all patients was 73% (s.e. 2%); for SRG, MRG and HRG patients 85% (s.e. 3%), 73% (s.e. 3%) and 39% (s.e. 7%), respectively. In patients >1 year of age at diagnosis unfavorable prognostic factors were male sex, >25% blasts in the bone marrow at day 15 and initial white blood cell count (WBC) >50 x 10(9)/l. The cumulative risk of CNS relapse rate was 5% (s.e. 1%) at 5 years. These results confirm that the omission of cranial irradiation in BFM-oriented treatment does not jeopardize the overall good treatment results, nor does early reduction of chemotherapy in SRG patients. No benefit was observed from treatment intensification with HD-L-ASP in SRG patients, nor from HD-6MP in MRG patients.
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PMID:BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). 1204 Apr 40

Vincristine (VCR) and L-asparaginase (L-ASP) are commonly used to treat canine lymphoma. As single agents, these drugs are not myelosuppressive. However, in combination, VCR and L-ASP cause severe neutropenia in some dogs. It has been recommended that L-ASP be administered 12-24 hours after VCR to minimize toxicity. The purpose of this retrospective study was to determine the prevalence of neutropenia after VCR/L-ASP induction therapy for canine lymphoma and to evaluate risk factors for myelosuppression, especially the interval between VCR and L-ASP administration. Medical records of 147 dogs were reviewed. L-ASP was given 0 (n = 50), 6 (n = 23), 18 (n = 20), or 24 (n = 54) hours after VCR. Forty percent of the dogs were neutropenic 7 days after VCR/L-ASP, and 18% had neutrophil counts of <1,000 cells/microL. The median neutrophil count was 3,712 cells/microL (range 0-30,968 cells/microL). No correlation was found between administration interval and day 7 neutrophil count (P = .84) or development of gastrointestinal signs, including vomiting (P = .80), diarrhea (P = .52), and decreased appetite (P = .30). No significant predictors of neutropenia were identified. Higher clinical stage and substage b were associated with decreased appetite after treatment (P = .04 and .01, respectively). Sixteen percent of the dogs were hospitalized. This study demonstrates that VCR/L-ASP induction for canine lymphoma may result in neutropenia but that separation of VCR and L-ASP administration may not be necessary to avoid toxicity.
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PMID:Neutropenia associated with vincristine and L-asparaginase induction chemotherapy for canine lymphoma. 1232 8

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.
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PMID:Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study. 1463 74

Acute lymphoblastic leukemia (ALL) in infants under 1 year is strongly associated with translocations involving 11q23 (MLL gene), CD10-negative B-lineage (proB) immunophenotype, and poor outcome. The present study analyses the relationship between age, MLL rearrangements, proB-lineage, and in vitro drug resistance determined using the MTT assay. Compared to 425 children aged over 1 year with common/preB (c/preB) ALL, the 44 infants were highly resistant to steroids (for prednisolone (PRED) more than 580-fold, P=0.001) and L-asparaginase (L-ASP) (12-fold, P=0.001), but more sensitive to cytarabine (AraC) (1.9-fold, P=0.001) and 2-chlorodeoxyadenosine (2-CdA) (1.7-fold, P<0.001). No differences were found for vincristine, anthracyclines, thiopurines, epipodophyllotoxines, or 4-hydroperoxy (HOO)-ifosfamide. ProB ALL of all ages had a profile similar to infant ALL when compared with the group of c/preB ALL: relatively more resistant to L-ASP and PRED (and in addition thiopurines), and more sensitive to AraC and 2-CdA. Age was not related to cellular drug resistance within the proB ALL group (<1 year, n=32, vs >/=1 year, n=19), nor within the MLL-rearranged ALL (<1 year, n=34, vs >/=1 year, n=8). The translocation t(4;11)(q21;q23)-positive ALL cases were more resistant to PRED (>7.4-fold, P=0.033) and 4-HOO-ifosfamide (4.4-fold, P=0.006) than those with other 11q23 abnormalities. The expression of P-glycoprotein, multidrug-resistance protein, and lung-resistance protein (LRP) was not higher in infants compared to older c/preB ALL patients, but LRP was higher in proB ALL and MLL-rearranged ALL of all ages. In conclusion, infants with ALL appear to have a distinct in vitro resistance profile with the proB immunophenotype being of importance. The role of MLL cannot be excluded, with the t(4;11) being of special significance, while age appears to play a smaller role.
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PMID:In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. 1471 91

The purpose of this study was to evaluate response rates, 1st remission duration (FRD), and toxicity in dogs with previously untreated lymphoma receiving an identical CHOP-based combination chemotherapy protocol with or without L-asparaginase (LASP). One hundred fifteen dogs with lymphoma were scheduled to receive an identical CHOP-based chemotherapy protocol that included L-ASP. However, because of manufacturer-imposed random rationing, 31 dogs did not receive L-ASP as scheduled. The 2 treatment groups were statistically similar with respect to signalment and presence of historical negative prognostic factors. No difference was observed in the median FRD whether dogs did or did not receive L-ASP (206 versus 217 days, respectively; P = .67). No difference was observed in the median overall survival times between dogs receiving or not receiving L-ASP (310 versus 308 days, respectively; P = .84). No statistical difference was observed with respect to overall response rate between dogs that did or did not receive L-ASP (89.3% versus 87.1%, respectively; P = .75). Complete response rates between the groups also were no different (83.3% and 77.4% for L-ASP and non-L-ASP groups, respectively; P = .59). Prevalence of toxicity (neutropenia, diarrhea, or vomiting) and treatment delays (P = .80) also were similar between groups. The results of this study suggest that exclusion of L-ASP in this multidrug protocol does not significantly impact outcome. Therefore, it may be more appropriate to reserve the use of L-ASP for treating relapse in dogs with lymphoma that have failed induction therapy.
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PMID:Does L-asparaginase influence efficacy or toxicity when added to a standard CHOP protocol for dogs with lymphoma? 1623 19


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