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)

The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial in adult patients with lymphoblastic non-Hodgkin's lymphoma. Thirty-nine patients with no central nervous system (CNS) involvement were treated with an induction cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/L-asparaginase regimen and CNS prophylaxis that included intrathecally administered methotrexate given 6 times and 24 Gy midplane cranial radiation in 12 fractions. Thirty-one patients (79%) achieved a complete remission (CR). Of the 31 patients with CRs, 12 relapsed (39%). CNS relapse occurred in three patients. All patients who entered a CR were treated with maintenance CHOP, cytosine arabinoside (AraC), and methotrexate and subsequently with Ara-C and methotrexate. Life-threatening leukopenia or thrombocytopenia was experienced in 69% of patients in the induction phase and in 70% in the maintenance phase. Nineteen of 39 patients (49%) remain in CR with a followup to 9 years. Bone marrow involvement was associated with a significantly worse survival (P = 0.03).
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PMID:Long-term follow-up of a CHOP-based regimen with maintenance therapy and central nervous system prophylaxis in lymphoblastic non-Hodgkin's lymphoma. 786 77

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.
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PMID:GM-CSF and asparaginase potentiate ara-C cytotoxicity in HL-60 cells. 788 38

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.
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PMID:Poor outcome of intensive chemotherapy for adult acute lymphoblastic leukemia: a possible dose effect. 776 60

In the last two decades complete remission [CR] rates for adults with acute leukemia has increased to 60 to 80%. In acute myelogenous leukemia [AML], this is due to the application of intensive induction therapies, comprising an anthracycline and a cytarabine. In acute lymphoblastic leukemia [ALL], the introduction of intensive early consolidation and CNS prophylaxis played an additional important role. These myeloablative treatments became feasible because of considerable improvements in the management of infectious and bleeding complications. The standard induction for AML further on remains the '3 + 7' schedule [daunorubicin 45 to 60 mg/m2/day x 3, I.V. and Ara-C 100 to 200 mg/m2/day x 7, 24-h infusion]. In ALL, prednisone, vincristine, L-asparaginase and an anthracyeline are the backbone of the induction therapy. Unfortunately, there has been less improvement for overall long-term survival, which is about 15 to 20% in AML and 20 to 35% in ALL beyond 5 years. More intensive post-remission regimens which include high-dose Ara-C in AML and intermediate-dose methotrexate and cyclophosphamide in ALL seem to improve these results to some extent. Allogeneic bone marrow transplantation has the most powerful anti-leukemic potential; however, because of the high peritransplant mortality [20 to 25%], its use in first CR tends to be restricted to patients with adverse prognostic features predicting early relapse, while good-risk patients are transplanted at the first signs of relapse or in second CR. In both AML and ALL, the optimal form of post-remission treatment needs to be defined.
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PMID:[Current status of therapy and prognosis in acute adult leukemia]. 862 60

The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.
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PMID:Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study. 902 88

Cytosine arabinoside (Ara-C) has earned its recognition as the most important antileukaemic drug currently available for the treatment of acute myeloid leukaemia. Approximately 60-80% of patients less than 60 years of age can be expected to enter complete remission if treated with standard-dose Ara-C (100-200 mg/m2) in combination with an anthracycline. The efficacy of Ara-C appears clinically to be dose and schedule dependent. A 15-30 fold dose escalation in Ara-C can elicit a therapeutic response in patients who have previously failed treatment with standard-dose Ara-C or other anti-leukaemic drugs. The use of high-dose cytosine arabinoside (HDAC 3 gm/m2) appears rational based on cytosine pharmacology. Drug-scheduling is used to exploit drug synergy when HDAC is given in combination with asparaginase or fludarabine (+/- G-CSF) in a schedule-dependent fashion. Toxicity following Ara-C is also dose- and schedule-dependent. Central nervous system toxicity--particularly cerebellar dysfunction--although rare, is particularly serious because it may preclude further use of the drug. Older patients are particularly susceptible. This article will describe the rationale for and the value of HDAC alone or in combination with other cytotoxics in the treatment of acute myeloid leukaemia.
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PMID:High-dose cytosine arabinoside in the treatment of acute myeloid leukaemia. 921 5

Chemotherapy regimens for high-risk (HR) groups for childhood acute lymphoblastic leukemia (ALL) are briefly reviewed in this study. For patients with B-precursor ALL, the HR category includes patients more than 10 years of age who have a WBC count at diagnosis of more than the 50,000/microliter that is becoming a global standard for HR classification. Since 1981, the Children's Cancer and Leukemia Study Group (CCLSG) has developed a series of protocols for HR-ALL. These include the H811, H851, H874, H/HH911 and more recent H/HH941 protocols. With the H874 protocol in particular, patient outcomes with new intensive regimens strengthened by early treatment with cyclophosphamide (CPM) plus cytosine arabinoside (Ara-C), and reinduction therapy with THP-adriamycin, vincristine, prednisone and L-asparaginase seem to be better than outcomes of patients with the previous protocols. An intermediate-dose of CPM plus Ara-C showed a significantly higher event-free survival (EFS) rate than a high-dose regimen with the same drugs. The EFS rates at 4 years based on the H941 and HH941 protocols were 72.8% and 62.8%, respectively. Although the various prognostic factors for acute myelogenous leukemia (AML) have been inconsistent, bone marrow chromosome abnormalities including monosomy 7 an 11q23 rearrangement have become indicators for a poor prognosis, whereas patients with t (15; 17), t (8; 21) and inv (16) have a decreased likelihood of relapse after achieving remission. The 11q23 abnormality is a very important prognostic factor for infant acute leukemia. Based on these findings renewal protocols for AML, including hematopoietic stem cell transplantation, have been conducted by our CCLSG and other study groups.
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PMID:[Treatment for a high-risk group for childhood acute lymphoblastic leukemia]. 1043 75

MTT analysis has yielded data on the sensitivity of leukemia cells isolated from 64 patients with acute leukemia to the cytokines G-KSF?, GM-KSF, interferon-alpha 2b and their combined use with drugs, such as cytosar, vepeside, doxorubicin, vincrastine, L-asparaginase. The mean in vitro survival of leukemia cells in children with acute lymphoblast cell leukemia (ALCL) was 1.9 times less than that in acute myeloblast cell leukemia (AMCL) (p < 0.001), that in new cases of ALL was 2.3 times less than in relapses (p = 0.024). The stimulating effect of GM-KSF on the survival rates of leukemia cells was seen in 64.7% of patients with AML. That of GM-KSF was recorded in 21.4% of cases. The survival of lymphoblast cells isolated from children with ALL did not differ greatly in the absolute majority of cases (by more than 30%) in the presence of growth factor in the medium. The cytotoxicity of XII with medium growth factor decreased in most cases. However, some cases (more frequently in AML than ALCL) displayed a higher cytotoxicity of XII, particularly cytosar in the presence of G-KSF and GM-KSFG; LC50 of Ara-C decreased by 30% or more in the presence of growth factor in 36% of patients. Incubation with interferon alpha 2b caused a reduction in the survival of leukemia cells, which was more pronounced in children with ALL. Interferon-alpha 2b caused an increase in the cytotoxic effect of XII on leukemia cells in ALL to a greater extent; cytosar, vepeside, and doxorubicin enhanced the effect by 1.47, 1.39, and 2.35 times, respectively.
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PMID:[Study of tumor cells sensitivity in patients with acute leukemia to cytokines and their combined use with drugs in vitro by MTT analysis]. 1094 55

Cancer cells may frequently develop cross-resistance to structurally dissimilar chemotherapeutic agents. However, the molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are still partially understood. Antineoplasic drugs have been shown to induce apoptosis in chemosensitive leukemias and solid tumors. In this work, cross-resistance among vincristine (VCR), doxorubicin (DOX) and other antineoplasic agents commonly used in the treatment of leukemia such as etoposide (VP-16), methotrexate (MTX), cyclophosphamide (CTX), dexamethasone (DEX), cytarabine (Ara-C) and L-asparaginase on vincristine resistant (LBR-V160), doxorubicin resistant (LBR-D160) and sensitive (LBR-) murine leukemic T cell lines, was determined. The effect of antineoplasic agents was assayed by tritiated thymidine incorporation. Our results showed that VCR exhibited cross-resistance with DOX, VP-16, DEX and MTX, while DOX demonstrated cross-resistance with VCR, VP-16 and MTX. Ara-C failed to present cross-resistance with any cell line. Apoptosis induced by the above drugs on the same cell lines was analyzed by acridine orange and ethidium bromide staining, DNA hypoploidy (flow cytometry) and oligonucleosomal fragmentation of nuclear DNA showing that therapeutic concentrations of these chemotherapeutic agents induced apoptosis in the LBR- cell line. Our results demonstrated that, except for DEX, none of the drugs presenting cross-resistance were able to induce cell death on LBR-V 160 or LBR-D 160 cell lines.
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PMID:Correlation between decreased apoptosis and multidrug resistance (MDR) in murine leukemic T cell lines. 1169 8

The intensification of post-remission induction therapy has been shown to improve the relapse-free survival for childhood acute lymphoblastic leukaemia (ALL), and is now a standard component of the treatment of childhood acute lymphoblastic leukaemia. For cytosine arabinoside (ara-C), methotrexate, vincristine and corticosteroids, in-vitro studies indicate that the extracellular drug concentration and exposure time are important determinants of cytotoxicity for human leukaemia cell lines. For L-asparaginase, epipodopyllotoxins and cyclophosphamide, there have been few studies of the relationship between cellular pharmacology and cytotoxicity in relation to ALL. The clinical and cellular pharmacology of methotrexate and cytosine arabinoside have been studied in relation to childhood ALL in vivo. For these drugs, there is evidence to suggest that maintenance of plasma concentrations that are biochemically optimal is necessary to maximize anti-leukaemic effects. For cytosine arabinoside in particular, optimal extracellular fluid concentrations are not likely to be achieved or maintained by bolus or short-duration i.v. infusions. A potentially important example of this may be served by the success of antimetabolite-based intrathecal chemotherapy for CNS-directed treatment of childhood ALL. Intrathecal administration of both methotrexate and cytosine arabinoside results in prolonged leukaemic cell exposure to cytotoxic concentrations of the drug. For vincristine, anthracyclines and asparaginase, the actual dose intensity received by children during consolidation therapy may be important, and there is considerable interpatient variation in the pharmacokinetics of cyclophosphamide and teniposide in the therapy of childhood cancers. The importance of this relationship to childhood ALL is not known. The pharmacological and cellular pharmacological studies performed at St Jude Children's Research Hospital (Memphis, TN, USA) have allowed investigation of the relationships between the clinical and cellular pharmacology of methotrexate and prognosis, and have supported the individualization of consolidation therapy with this drug. Cytosine arabinoside has been less well studied in relation to childhood ALL, although evidence exists to suggest that the administration of conventional-dose bolus or infusion schedules may not be optimal in terms of the antileukaemic efficacy of this antimetabolite. For L-asparaginase, ongoing studies may allow the relationship between dose and schedule of administration to be related to pharmacodynamic measures such as asparagine depletion and prognosis. Therefore, through knowledge of clinical and cellular pharmacological properties, it may be possible to optimize the consolidation phase of therapy for childhood ALL, without disrupting the fundamental principles by which the overall treatment is administered. This may be particularly important for children with disease that has inherent or acquired resistance to therapy.
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PMID:Consolidation therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of cytosine arabinoside, epipodophyllotoxins and cyclophosphamide. 1190 27


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