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)

Between 1973 and 1985, 553 children with childhood acute lymphoblastic leukemia were treated on Dana-Farber Cancer Institute/Children's Hospital, Boston, protocols. The programs featured intensive remission induction therapy, CNS treatment with cranial irradiation and intrathecal drugs, doxorubicin intensification with or without asparaginase, and 2-21/2 years of conventional continuation therapy. There has been progressive improvement in event-free survival for each successive program. Leukemia control concerns pertain to: 1. late relapses (at greater than 5 years) in "standard-risk" patients; 2. an increased incidence of CNS relapses, especially in "standard-risk" patients, as preventative treatment is reduced in intensity; and 3. bone marrow relapses in "high-risk"patients. Comparisons of patients receiving the more intensive arm of each protocol with those receiving the less intensive arm support the hypothesis that more intensive chemotherapy results in improved event-free survival.
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PMID:More is better! Update of Dana-Farber Cancer Institute/Children's Hospital childhood acute lymphoblastic leukemia trials. 218 37

Therapy of acute myelogenous leukemia (AML) with sequential high-dose ara-C and asparaginase (HiDAC----ASNase) on a day 1 and 8 schedule was designed to exploit potential recruitment of residual leukemia cells following initial cytoreduction from day 1 treatment. DNA flow cytometry was used to evaluate the proliferative index (%S + G2M) of bone marrow leukemia cells from pretreatment and day 8 marrow samples. The proliferative index on day 1, day 8, and incremental change (day 8 minus day 1) were analyzed for their correlation with bone marrow aplasia on day 15 and with the attainment of subsequent complete remission. Pretreatment (day 1) and the change in proliferative index did not correlate (p greater than 0.10) with day 15 marrow aplasia or with clinical outcome. However, the magnitude of the day 8 proliferative index did relate to the attainment of bone marrow aplasia on day 15 (p = 0.05) and the attainment of complete remission (p = 0.002). Recruitment of residual leukemia cells into the proliferative phases of the cell cycle may contribute to the unique efficacy of the day 1 and 8 schedule of HIDAC----ASNase. Additionally, the cytokinetics of residual leukemia after initial chemotherapy may be predictive of outcome and could be useful as a marker for the design of optimal therapeutic regimens.
Leukemia 1990 May
PMID:Correlation of the proliferative index of residual leukemia with outcome in patients treated with sequential high dose ara-C and asparaginase. 238 77

A human histiocytic lymphoma cell line, U937, is highly sensitive to L-asparaginase with an ID50 of about 0.0001 U/ml after 72 hr of culture. When U937 cells were made resistant to either L-asparaginase (1 U/ml) or asparagine deprivation, the activity of asparagine synthetase increased to 80- or 7-fold of the wild type, respectively. The phenotype of the resistance to L-asparaginase turned out to be stable under nonselective conditions for over several months. The hybrids between L-asparaginase sensitive (Molt4) and resistant (HL-60) cell lines revealed the latter phenotype in terms of L-asparaginase sensitivity and the activity of asparagine synthetase. Furthermore, U937 cells resistant to L-asparaginase could survive in glutamine-free media with 1.5-fold elevation of glutamine synthetase activity. These results altogether clarify the role of asparagine synthetase in L-asparaginase toxicity and have a good implication for the clinical use of L-asparaginase.
Leukemia 1989 Apr
PMID:Biochemical characterization of U937 cells resistant to L-asparaginase: the role of asparagine synthetase. 256 53

Human DNA ligase was purified from different kinds of immunocompetent cells: thymocytes, normal and stimulated lymphocytes, blasts from ALL (Burkitt and non-T, non-B) and ANLL (M1, M2, and M5). Based upon the protocol for the treatment of these leukemias, the purified enzymes were assayed in the presence of routinely used combinations of antileukemic drugs. At the range of concentration tested (between 0.1 and 5 microM) some drugs taken separately were totally inactive on the enzyme from the different sources. For those being inhibitory, when used in combination their effect was always different from what was observed when the compound was tested alone. Some combinations were more effective in inhibiting the enzyme from leukemic than from normal cells (vincristine + cyclophosphamide + prednisone in ALL and rubidazone + Ara-C, Ara-C + m-AMSA, in ANLL). However, some combinations of drugs are without effect on ligase from leukemic cells at this dose range (vincristine + rubidazone + Ara-C + prednisone and adriamycin + asparaginase + Ara-C in ALL or etoposide + Ara-C, adriamycin + cyclophosphamide in ANLL). This is the first direct observation of the effect of cytostatic drugs on DNA ligase, a key enzyme of the DNA replication and repair process. The clinical consequences of these observations are discussed in an attempt to selectively inhibit replication, thereby division, of cancer cells.
Leukemia 1988 Jun
PMID:Effects of clinical combinations of antileukemic drugs on DNA ligase from human thymocytes and normal, stimulated, or leukemic lymphocytes. 325 60

Methotrexate (MTX) and L-asparaginase (ASP) are effective agents in the treatment of acute lymphoblastic leukemia (ALL). The effects of combining MTX and ASP are schedule dependent. To investigate this schedule dependency, the Cancer and Leukemia Group B (CALGB) employed vincristine and prednisone with progressive dose escalation of moderate-dose MTX (125 mg/m2) followed 24 h later with ASP (6,000 U/m2) in refractory adult ALL. We treated 38 patients with refractory or first relapse adult ALL. Most patients had received prior ASP (92%) and MTX (72%). A complete remission was achieved in 25% with a median duration of remission of 21 weeks. The median survival for the entire group was 7.4 months. Therapy was well tolerated and toxicity was acceptable. Our response rate was lower than other tandem MTX and ASP adult ALL trials. Therapy was similar with other series, with the exception of the dose of ASP employed. We conclude that tandem MTX and ASP, in the doses and schedule used here, has only modest activity in previously treated adult ALL. This regimen offers little advantage to other salvage regimens.
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PMID:Therapy of refractory adult acute lymphoblastic leukemia with vincristine and prednisone plus tandem methotrexate and L-asparaginase. Results of a Cancer and Leukemia Group B Study. 346 28

The amino acid contents of tumor cells that are either sensitive or resistant to treatment with L-asparaginase were measured. These amino acid concentrations were measured as a function of incubation time with L-asparaginase or as a function of the L-asparaginase dose. The cell types compared were the mouse leukemia lines L5178Y (sensitive to L-asparaginase treatment) and L5178Y/L-ASE (resistant to L-asparaginase treatment). Upon L-asparaginase treatment both cell lines lost most of their cellular asparagine but, whereas the resistant cells exhibited the ability to rebound to about 50% of initial values, the sensitive cells did not. While previous work had suggested that asparagine-dependent glycine synthesis was essential for sensitive cells (but not in resistant cells), we found no difference in the glycine content of either of the two cell lines as a function of either time or dose that would support this hypothesis. Major differences between the two cell lines were seen in the content of the essential amino acids before treatment with L-asparaginase. After incubation without L-asparaginase the contents of the two cell lines became similar. These results are discussed in terms of possible mechanisms of L-asparaginase sensitivity and resistance.
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PMID:Amino acid content of L5178Y and L5178Y/L-ASE cells after L-asparaginase treatment. 408 39

Acute Lymphatic Leukemia (ALL) patients seen during the period 1974-1978 at the Tata Memorial Hospital. Bombay, are analyzed retrospectively to evaluate the clinical features at presentation, results of sequential therapy, and prognostic factors. A total of 301 patients were registered during the study period. There were 153 evaluable patients. Of these 73 patients received induction therapy with vincristine and prednisolone (VP) followed by cranial prophylaxis (cranial radiotherapy, 2,400 rads, and 10 weekly intrathecal injections of methotrexate 7.5 mg/m20 and continuous oral maintenance with daily 6-mercaptopurine and weekly methotrexate (group A). Another 39 patients (group B) received pulse therapy with vincristine and prednisolone during maintenance therapy. Finally 41 patients (group C) received L-asparaginase during induction and pulse therapy in addition to drugs as in group A. Of the 153 patients, 88 (58%) achieved complete response after induction treatment. Induction remission was 53% with vincristine and prednisolone (group A and group B), whereas it was 70% in group C. The difference in complete response rate in group C was statistically significant (P less than 0.05). The 3-year survival in our series was 22%, with median survival of 11 months. Group C patients receiving L-asparaginase along with vincristine and prednisolone showed 41% 3-year survival compared to 16% for group B. The 3-year survival in group A patients was only 7%, probably owing to lack of pulse therapy during maintenance treatment. The prognostic factors such as age, sex, WBC count, and mediastinal node were compared for induction remission and total survival. Possible factors relating to poor results in our series as compared to developed countries are discussed.
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PMID:Acute lymphoblastic leukemia: end-result analysis of treatment and prognostic factors in Indian patients. 657 29

This paper reported on a series of 49 elderly patients over 60 years of age affected by acute lymphoblastic leukemia (ALL), observed at our institution from 1969 to 1993. The biological characteristics considered, median WBC count, FAB classification, immunophenotype at onset of disease, were no different from those of our adult ALL series. Overall complete remission (CR) rate of these patients was 59%, 18% had resistant disease and 23% died during induction. Overall median survival was 9 months and overall median duration of CR was 7 months. All patients were divided according to treatment into two groups: group A (13 patients) received an intensive treatment including vincristine (VCR), prednisone (PDN), daunorubicin (DNR) and L-asparaginase (L-Asp), while in group B (36 patients) were included patients who received mild conventional induction with VCR and PDN. In group A, 77% of patients achieved CR and 23% died during induction. All patients were hospitalized during induction treatment. During follow-up, among 10 CRs, five (50%) died in CR because of hemorrhage (two), infections (two) and myocardial infarction (one); five (50%) relapsed. Median survival was 4 months and median duration of CR was 3.5 months. In group B, 53% of patients obtained CR, 25% had resistant disease and 22% died during induction. During induction, 44% of patients were hospitalized. During follow-up, among 19 CRs, 14 (74%) relapsed and three (15%) died in CR because of infection (two) and cardiorespiratory failure (one). Three patients (15%) are still alive: two in first CR and one in second CR. No statistical differences between the two groups in terms of CR rate or survival were noted. Standardized therapeutic trials are needed better to evaluate results in these patients, considering also the introduction of new therapeutic agents or supportive treatments, such as growth factors.
Leukemia 1995 Oct
PMID:Acute lymphoblastic leukemia in the elderly: results of two different treatment approaches in 49 patients during a 25-year period. 756 3

The risk for induction of epipodophyllotoxin-related acute myeloid leukemia (AML) depends largely on the schedule of drug administration and, to a lesser degree, the cumulative dose. Concomitant use of other genotoxic drugs, such as alkylating agents and cisplatin, can increase the hazard further. We have treated 154 consecutive higher-risk cases of acute lymphoblastic leukemia in our recent Total Therapy Study XIII with an intensive post-remission regimen of chemotherapy that included etoposide given every other week or less often-a schedule associated with a relatively low cumulative incidence of secondary AML in our Study XI. Unexpectedly, four patients have developed secondary AML at 12 to 23 months from the start of treatment (median, 16 months). The 2-year cumulative risk estimate significantly exceeds that for 185 historical controls in Study XI whose continuation regimen included epipodophyllotoxins every other week: 5.4% (95% confidence interval, 0-11%) compared with 1.1% (0-2.6%), P = 0.046. Compared to patients treated in Study XI, those enrolled in Study XIII receive fewer scheduled doses of epipodophyllotoxin (48 (all etoposide) vs 63 (30 etoposide, 33 teniposide)) but 16 to 19 additional doses of L-asparaginase and eight additional doses of high-dose methotrexate, all within the week preceding etoposide treatment. We attribute the apparently increased rate of secondary AML in Study XIII to the use of L-asparaginase immediately before etoposide administration. On this schedule, the enzyme could increase systemic exposure to etoposide or its catechol metabolites and reduce the ability of cells to repair DNA damage.
Leukemia 1995 Oct
PMID:L-asparaginase may potentiate the leukemogenic effect of the epipodophyllotoxins. 756 9

From 1985 to 1989, 69 patients with non-Hodgkin's lymphoma (NHL) were treated by members of the Children's Cancer and Leukemia Study Group of Japan with a protocol consisting of vincristine, prednisolone, cyclophosphamide, doxorubicin, high-dose methotrexate (HD-MTX), mercaptopurine and cytarabine; central nervous system (CNS) prophylaxis with intrathecal MTX and hydrocortisone (NHL855). The 4-year event-free survival (EFS) was 78% (S.E., 10%) for patients with localized disease (n = 18) and 38% (S.E., 7%) for those with advanced disease (n = 51). Among the patients with advanced disease, those with non-lymphoblastic lymphoma tended to have a better 4-year EFS than those with lymphoblastic lymphoma (52% vs. 25%). Based on these findings, we initiated a new protocol NHL890 in which patients were assigned to two different chemotherapies according to the histology. Non-lymphoblastic subtype was treated almost identically to NHL855 while asparaginase and VP-16 were newly added in the consolidation-maintenance phase in advanced-stage lymphoblastic lymphoma. Sixty-seven patients with advanced disease were assessable. The overall 4-year EFS for advanced disease improved to 69% (S.E., 6%). A significant improvement was gained in the lymphoblastic lymphoma with a 4-year EFS of 56% (S.E., 11%) as compared with 25% (S.E., 9%) in the preceding study (P < 0.05). These findings suggest the importance of histology in the treatment of advanced-stage non-Hodgkin's lymphoma in childhood.
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PMID:Improved treatment results of non-Hodgkin's lymphoma in children: a report from the Children's Cancer and Leukemia Study Group of Japan. 773 16


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