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

By using a modification of the microtiter solid-phase radioimmunoassay, we have measured Escherichia coli L-asparaginase (L-ASP) specific IgG, IgG4, and IgE antibodies in children who received L-ASP as part of their chemotherapy for leukemia and lymphoma. In 13 children with acute lymphoblastic leukemia induced with vincristine, prednisone, and L-ASP (10,000 IU/M2 i.v. each week for 3 weeks), seven developed high titer specific IgG antibodies. Four of the seven relapsed at the time of their peaking IgG response (6-10 months). None of the six with low or absent L-ASP antibody response have relapsed (followed for 20-35 months). In six children with allergic reactions to L-ASP reinduction, all had high titers of L-ASP specific IgG4 (greater than or equal to 20 U/ml) at the time of their reaction. In 16 other children with low L-ASP IgG4 (less than 13 U/ml), none demonstrated allergic reactions to rechallenge. Specific IgE was not consistently detectable in either group. In 21 patients with leukemia or lymphoma on L-ASP with cyclophosphamide-containing regimens, none developed significant IgG antibody response, compared with seven of 13 not receiving cyclophosphamide (p less than 0.001). We conclude: (a) development of L-ASP antibodies may have prognostic significance; (b) the detection of specific IgG4 can predict L-ASP allergy; and (c) cyclophosphamide-containing regimens reduce antibody formation to L-ASP and may allow repetitive (without anaphylaxis) and more effective (avoiding neutralizing antibodies) use of L-ASP.
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PMID:Antibody response to Escherichia coli L-asparaginase. Prognostic significance and clinical utility of antibody measurement. 352 39

Thirty patients with advanced acute leukemia and lymphoma were treated with the sequential combination of high dose ARA-C (HiDAC 3 gm/m2 infused i.v. over 3 h at 0, 12, 24, 36 h) and asparaginase (ASP 6.000 IU/m2 i.m. at hour 42). The sequence was given on day 1 and 8 irrespective of the degree of myelosuppression. Of 22 patients with leukemia there was only one who was absolutely refractory to therapy. Complete remission was induced in 3 patients with ANLL (30%) and in 3 with ALL (30%). Three patients became hypoplastic but recovered with blasts and 12 died from infection, complicated by intracranial hemorrhage in 3, during hypoplasia. Of 8 patients with lymphoma, 2 were clearly refractory to therapy, one died from sepsis and the remaining 5 all entered remission (2 CR + 3 PR, 62%). Activity of HiDAC/ASP against CNS disease is suggested by the clinical response seen in patients with overt meningeal or intracerebral involvement. Toxicity associated with HiDAC/ASP was mainly hematologic. All but one patient experienced hypoplasia and severe pancytopenia; documented infections and major hemorrhages occurred in 80 and 20% of patients respectively. We conclude that HiDAC/ASP is a regimen with definite activity against acute leukemia and lymphoma including CNS disease. Alternate treatment schedules should be explored in order to reduce marrow toxicity.
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PMID:Sequential combination of high dose ARA-C (HiDAC) and asparaginase (ASP) for the treatment of advanced acute leukemia and lymphoma. 647 2

Thirty eight patients with acute lymphoblastic leukemia were treated protocol 0171 (VCR, PRED, MTX, cyclophosphamide +/- +/- 6-MP) and protocol 0276/A (VRC, PRED, L-ASP, MTX, 6-MP, cyclophosphamide). Overall complete remission rate in both studies was 84--85%, and additional treatment in protocol 0171 resulted in complete remission rate of 92%. Median duration of complete remission in protocol 0171 was 23 months and median survival of all patients was 33 months. Six patients randomized to regimen "A" (without 6-MP in intensification) had median duration of complete remission 8 months and media survival was 13 months. Seventeen patients treated with regimen "B" (with 6-MP in intensification) had median duration of complete remission 25 months and median survival was 39 months. Median survival of patients allocated on protocol 0276/A in 21+ months and median duration of complete remission is 23 months at present. Twelve percent of patients treated with the best regimen have survived more than 66 months in continuous complete remission. The incidence of drug related death in complete responders was 6%. The relapses were most frequent during the first two years of remission. Extramedullary leukemia as the initial site of relapse was observed in 9% of patients.
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PMID:Treatment of adult acute lymphoblastic leukemia: results of two trials. 702 59

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

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.
Leukemia 2002 Jun
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

The orphan receptor C5L2 has recently been described as a high affinity binding protein for complement fragments C5a and C3a that, unlike the previously described C5a receptor (CD88), couples only weakly to G(i)-like G proteins (Cain, S. A., and Monk, P. N. (2002) J. Biol. Chem. 277, 7165-7169). Here we demonstrate that C5L2 binds the metabolites of C4a and C3a, C4a des-Arg(77), and C3a des-Arg(77) (also known as the acylation-stimulating protein or ASP) at a site distinct from the C5a binding site. The binding of these metabolites to C5L2 does not stimulate the degranulation of transfected rat basophilic leukemia cells either through endogenous rat G proteins or when co-transfected with human G(alpha 16). C3a des-Arg(77)/ASP and C3a can potently stimulate triglyceride synthesis in human skin fibroblasts and 3T3-L1 preadipocytes. Here we show that both cell types and human adipose tissue express C5L2 mRNA and that the human fibroblasts express C5L2 protein at the cell surface. This is the first demonstration of the expression of C5L2 in cells that bind and respond to C3a des-Arg(77)/ASP and C3a. Thus C5L2, a promiscuous complement fragment-binding protein with a high affinity site that binds C3a des-Arg(77)/ASP, may mediate the acylation-stimulating properties of this peptide.
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PMID:The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein. 1254 Aug 46

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.
Leukemia 2004 Mar
PMID:In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. 1471 91

L-Asparaginase (l-ASP), a bacterial enzyme used since the 1970s to treat acute lymphoblastic leukemia, selectively starves cells that cannot synthesize sufficient asparagine for their own needs. Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase (ASNS) expression and DNA copy number with sensitivity to l-ASP in the leukemia and ovarian cancer cell subsets. To assess whether the ovarian relationship is causal, we used RNA interference to silence ASNS in three ovarian lines and observed 4- to 5-fold potentiation of sensitivity to l-ASP with two of the lines. For OVCAR-8, the line that expresses the least ASNS, the potentiation was >500-fold. Significantly, that potentiation was >700-fold in the multidrug-resistant derivative OVCAR-8/ADR, showing that the causal relationship between ASNS expression and l-ASP activity survives development of classical multidrug resistance. Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as other tumor types. Overall, this pharmacogenomic/pharmacoproteomic study suggests the use of l-ASP for treatment of a subset of ovarian cancers (and perhaps other tumor types), with ASNS as a biomarker for patient selection.
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PMID:Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells. 1708 36

L-Asparaginase (L-ASP) is an enzyme drug that has been an asset to leukemia treatment regimens for four decades. Variability in its clinical efficacy, however, has prompted the search for biomarkers capable of distinguishing responders from non-responders. In that regard, the NCI-60 cell line panel has served as a biomarker discovery platform and has led to the identification of a correlation between L-ASP efficacy and asparagine synthetase (ASNS) expression in cultured cells. The presence of that correlation in the ovarian subpanel of the NCI-60 has made a case for repositioning L-ASP to ovarian cancer. This review presents an overview of the biomarker development process, summarizes the efforts that have been invested thus far in developing ASNS as a biomarker for ovarian cancer treatment, highlights the role of RNAi and the limitations of the NCI-60 in that process, and addresses important considerations for next steps in the development of ASNS as a predictive biomarker.
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PMID:Asparagine synthetase: a new potential biomarker in ovarian cancer. 1920


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