Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In preparation for a clinical trial using GM-CSF on days 4-10 of sequential high-dose cytarabine (ara-C) and asparaginase (ASNase) on days 1-3 and 8-10, potential interactions between the protein synthesis inhibitor ASNase and GM-CSF were evaluated. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can stimulate acute myeloid leukemia (AML) cells to proliferate in vitro and in vivo. Log phase HL-60 cells were exposed to ara-C (10 microM x 3 h) and/or ASNase (10 U/ml during the last 2 h of ara-C). Ara-C and/or ASNase was removed and cells were incubated with or without GM-CSF (10 ng/ml). After 24, 48 and 72 h of GM-CSF there was no significant difference in the S phase fraction of cells exposed to ASNase prior to GM-CSF. Soft agar cloning efficiency was determined after retreatment with ara-C +/- ASNase 24 h into the GM-CSF incubation. GM-CSF enhanced cytotoxicity for all combinations, although this effect was of borderline significance (P = 0.0621); addition of ASNase to the treatment regimen significantly (P = 0.0229) enhanced cytotoxicity without any evidence of a negative interaction with GM-CSF. In addition, ara-C metabolism was assessed during simultaneous exposure to ara-C (10 microM x 3 h) +/- ASNase (10 U/ml the last 2 h) +/- GM-CSF (10 ng/ml beginning 24 h prior to ara-C). Ara-C incorporated into DNA (P = 0.0302) and ara-CTP formation (P = 0.0084 and P = 0.0003 at 2 and 3 h timepoints, respectively) were both increased significantly by GM-CSF, with modest non-significant increases with ASNase exposures. Neither ASNase nor GM-CSF inhibited the effects of the other in this in vitro model. Therefore, when appropriately scheduled, both GM-CSF and ASNase may potentiate ara-C cytotoxicity.
Leukemia 1995 Mar
PMID:GM-CSF and asparaginase potentiate ara-C cytotoxicity in HL-60 cells. 788 38

Two adult patients with acute mixed lineage leukemia (AMLL) having combined Philadelphia chromosome (Ph1) positivity and monosomy 7 are presented. The phenotypes of leukemic blasts from both cases were almost same (early B-lymphoid lineage and myeloid lineage); CD10+, CD13+, CD19+. HLA-DR+, and dual-color analysis showed simultaneous expression of CD10 (CD19) and CD13 antigens in individual blasts (biphenotypic) in both cases. On molecular analysis, the leukemic blasts showed rearrangement in the first intron of the BCR gene with breakpoint just outside of 3' end of m-BCR-2 (bcr 3) in case 1, and in the M-BCR in case 2. Immunoglobulin heavy chain gene (IgH) rearrangement was noted in both cases, but rearrangement of the T-cell receptor beta-chain gene (TCR beta) was detected only in case 1. Clinically, both cases achieved complete remission by the combination chemotherapy consisting of L-asparaginase, doxorubicin, vincristine, and prednisolone (L-AdVP). In remission, all these molecular abnormalities disappeared in both patients. These results suggest that the Ph1-positive and monosomy 7 AMLL in adults is de novo acute leukemia with both early B-lymphoid and myeloid phenotypes and may arise from malignant transformation of pluripotent stem cell, and expresses a heterogenous rearrangement pattern of the BCR gene.
Leukemia 1993 Nov
PMID:Philadelphia-chromosome-positive, monosomy 7 biphenotypic acute mixed lineage leukemia in adults: a pluripotent stem cell disorder. 790 55

The Children's Cancer and Leukemia Study Group (CCLSG) has conducted, since 1981, a series of protocols for treatment of acute lymphoblastic leukemia (ALL) in childhood. In a randomized control study of the 811 protocol (1981-1983) for standard-risk ALL, an intermittent cyclic regimen of an intermediate-dose of methotrexate (MTX) plus 6-mercaptopurine (6MP) showed significant superiority for maintenance chemotherapy as compared with conventional continuous administration of a low dose of the two drugs. The event-free survival (EFS) rate at 10 years was 65.4% for the intermittent cyclic regimen, while the EFS rate of continuous regimen was 36.1% (P < 0.01). The intermittent cyclic regimen may also be effective in preventing extramedullary relapses. In the 841 protocol (1984-1987), the three-drug induction therapy consisting of vincristine (VCR), prednisone (PDN) and L-asparaginase (L-ASP) improved the EFS rate (94.1% at 8 years) as compared with the two-drug therapy consisting of VCR and PDN (64.1%, P < 0.05). In the 874 protocol (1987-1990) two regimens with or without cranial irradiation for standard-risk patients were compared with respect to their ability to prevent central nervous system (CNS) leukemia and to improve overall outcome of ALL. The regimen with cranial irradiation showed a 79.9% EFS rate at 5 years, whereas the regimen without cranial irradiation demonstrated a 69.1% EFS rate (not significantly). Life-table analysis of serial CCLSG protocols for ALL in which the cyclic administration of intermediate-dose MTX plus 6MP has been standardized as maintenance therapy revealed that the outcome of allover ALL has gradually improved with increase of the EFS rate; 41.4% for the 811 protocol, 51.4% for the 841 protocol to 54.4% for the more recent 874 protocol.
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PMID:Improvement in treatment of childhood acute lymphoblastic leukemia: a 10-year study by the Children's Cancer and Leukemia Study Group. 801 9

Pre-T-ALL is an important subgroup of ALL with clinical features different from adult T-ALL. Expression of intracytoplasmic CD3 represents the earliest marker for the prethymic phenotype. We studied four consecutive adult patients with this phenotype. Three of the four patients did not respond to the induction chemotherapy with vincristine, daunorubicin, prednisone and asparaginase. They reached a delayed remission only after chemotherapy with cyclophosphamide and cytosine arabinoside. All four patients relapsed 3, 9, 10 and 13 months after diagnosis. One patient died 2 months after relapse, another one 2 months after allogeneic BMT performed in second relapse. We conclude that patients with early T-cell precursor leukemia do not respond adequately to conventional chemotherapy and should be considered as a high-risk subgroup within the T-lineage ALL.
Leukemia 1994 Aug
PMID:Poor prognosis of prethymic phenotype acute lymphoblastic leukemia (pre-T-ALL). 805 81

Fifty consecutive adult patients with acute lymphoblastic leukemia (ALL) were treated with an intensive cyclical chemotherapy and the mean received dose of individual cytotoxic drug was retrospectively studied. The median age was 28 years. Twenty-one (43%) had white blood cell (WBC) count over 30 x 10(9)/l. Of the 26 patients with successful cytogenetic studies, ten (28%) had unfavorable clonal chromosomal abnormalities (four Philadelphia chromosome, six others). A high complete remission (CR) rate (86%) was achieved. This was associated with delivery of 100% of the planned dosage of vincristine, prednisone, and daunorubicin at induction. Dose reduction of asparaginase, the fourth drug in the induction protocol, was recorded in 20 (40%) patients. The CR rate of these patients was not adversely affected. Dose reduction was recorded during consolidation (38 of 43 remitters) and maintenance (18 of 20 remitters) as a result of treatment toxicity. The mean received dose of teniposide, Ara-C, asparaginase, mercaptopurine, and methotrexate was 73% (SD 7%), 73% (SD 7%), 62% (SD 41%), 65% (SD 15%) and 73% (SD 17%) of the planned dosage, respectively. The 5-year overall survival and leukemia-free survival (LFS) were 11% (95% CI: 0-27%) and 13% (95% CI: 0-26%), respectively. Even standard-risk patients had 4-year LFS of only 26% (95% CI: 0-57%). Among 36 remitters not withdrawn from consolidation, there were 29 treatment failures after a median follow-up of 42 months; 25 (86%) of these were leukemia relapse, three (10%) were toxic death during consolidation, and one patient (4%) died from therapy-related myelodysplastic syndrome. We postulate inadequate drug delivery during postremission therapy contributed to the high relapse rate in the whole group as well as the standard-risk patients.
Leukemia 1994 Sep
PMID:Poor outcome of intensive chemotherapy for adult acute lymphoblastic leukemia: a possible dose effect. 776 60

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

Immunophenotype and age have prognostic value in childhood acute lymphoblastic leukemia (ALL) but how this operates is not understood. In 84 children with ALL at initial diagnosis we studied the correlation between these factors and the in vitro resistance to eight drugs, determined with the 3-(4,5-dimethylthiazol-2-yl-2, 5-diphenyl tetrazolium bromide (MTT) assay. B-lineage ALL samples were classified into four differentiation stages: the CD10- proB ALL; cALL; preB ALL with cytoplasmic mu positive ALL cells; and B-ALL with surface immunoglobulin-positive (Ig+) cells. cALL and preB ALL cases have the best prognosis; proB and T-ALL cases show a worse prognosis and B-ALL the poorest prognosis. Patients aged < 18 months and > 10 years have a poor prognosis compared to patients in the intermediate age group. Our results show that cALL and preB ALL cells were the most drug-sensitive cells compared to the other phenotypes. No differences were found between cALL and preB ALL cases with the exception that preB cells were more sensitive to mustine and mafosfamide (Maf). Compared to cALL and preB ALL cases, T-ALL cases were significantly more resistant to prednisolone (Pred), daunorubicin (DNR), L-asparaginase (L-Asp), cytosine arabinoside (AraC), and Maf; proB ALL cases were more resistant to Pred, DNR, L-Asp, and 6-thioguanine. The three B-ALL cases were resistant to vincristine and DNR. Two out of three B-ALL were resistant to Pred. Compared to cells from patients aged 18 months to 10 years, cells from children < 18 months were more resistant to Pred and DNR; cells from children > 10 years were more resistant to Pred. We conclude that cellular drug-resistance patterns might at least partly explain the prognostic value of immunophenotype and age in childhood ALL.
Leukemia 1993 Mar
PMID:Cellular drug resistance profiles that might explain the prognostic value of immunophenotype and age in childhood acute lymphoblastic leukemia. 844 45

To define better the risk of epipodophyllotoxin-related acute myeloid leukemia (AML) after extended follow-up and to assess responses to intensive salvage therapy, all patients who developed this complication after treatment for acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) in consecutive clinical trials at St Jude Children's Research Hospital from 1979 to 1994 were studied. Cases with 'lineage switch' or 'clonal selection' were excluded. Epipodophyllotoxin-related AML developed in 32 of 1140 patients treated for ALL and in three of 332 treated for NHL; it was a first adverse event in 25 and two cases, respectively. The complication was diagnosed at 12-130 months (median 34 months) after the initiation of treatment with epipodophyllotoxins; all but one of the cases occurred within 73 months, indicating that the risk is negligible after 6 years. The predominant karyotypic feature was 11q23 translocations (71% of cases); 21q22 rearrangements were rare. In a stepwise Cox regression analysis, two factors increased the risk of this complication: weekly or twice weekly administration of epipodophyllotoxins (P < 0.001); and the administration of asparaginase immediately before epipodophyllotoxin therapy (P < 0.001). Initial responses to salvage therapy were comparable to those reported for de novo AML: 92% of the evaluable patients entered complete remission after combination treatment. Single-agent therapy with 2-chlorodeoxyadenosine induced complete or partial remissions in one-half of the patients treated. The long-term survival rate was dismal. Of the 17 evaluable patients treated exclusively with chemotherapy, only one is alive at 84 months, compared to three of 16 patients who underwent bone marrow transplantation (alive at 10, 23 and 73 months). Cases of epipodophyllotoxin-related AML constitute a unique clinical syndrome that will require innovative strategies for cure.
Leukemia 1995 Dec
PMID:Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. 860 7

L-asparaginase from Escherichia coli, an antitumor enzyme, was chemically modified with a comb-shaped copolymer of poly(ethylene glycol) derivative and maleic anhydride (activated PM). The PM-modified asparaginase lost the immunoreactivity with retaining high enzymic activity and also prolonged the clearance time in blood. Intraperitoneal administration of PM-asparaginase markedly increased the mean survival-time of lymphoma L5178Y-bearing mice in comparison with that of unmodified asparaginase. Pretreatment of mice with PM-asparaginase before immunizing with unmodified asparaginase extremely suppressed the anti-asparaginase antibody production.
Leukemia 1997 Apr
PMID:Chemical modification of L-asparaginase with comb-shaped copolymer of poly(ethylene glycol) derivative and maleic anhydride. 920 7

A 13-year-old girl with acute lymphoblastic leukemia (ALL) developed extremely high plasma triglyceride (TG) concentrations of 103 mmol/l (reference value <1.8 mmol/l) during combination treatment with corticosteroids and asparaginase. Corticosteroids are known to induce the production of TG-rich particles. On the other hand, corticosteroids increase the activity of lipoprotein lipase (LPL), a key enzyme in the removal of TG from plasma. Generally, the increased LPL activity prevents an extreme rise in TG levels upon therapy with corticosteroids. In our patient, we found that the corticosteroid-induced LPL activity dramatically declined after therapy with L-asparaginase. This suggests that the extensive hypertriglyceridemia in our patient was due to an L-asparaginase-induced decrease in LPL activity. This hypothesis was further supported by the finding that hypertriglyceridemia was less severe when corticosteroids and asparaginase were given separately.
Leukemia 1997 Aug
PMID:Transient hyperlipidemia during treatment of ALL with L-asparaginase is related to decreased lipoprotein lipase activity. 926 96


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