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)

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

We have found that, in addition to Bcl-2 and Bax, the expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-xL, Mcl-1) were highly variable in blasts from 78 children with newly diagnosed acute lymphoblastic leukemia (ALL). The patients were enrolled in the national study ALL-7 of the Dutch Childhood Leukemia Study Group. In contrast to Bcl-2 that inversely correlated with %S-phase cells and WBC, and was lower in T than in B-lineage ALL, the Bcl-2 family members were not found to be associated with features at presentation. These expression levels were also compared with drug resistance in in vitro MTT (methyl-thiazol-tetrazolium) assays for prednisolone, vincristine and asparaginase in 46 children. Protein expression levels of the Bcl-2 family were not found to correlate with in vitroresistance to the individual drugs or the combined drug resistance profile. In addition, neither peripheral blast reduction after 1 week of prednisone monotherapy nor long-term disease-free interval or survival showed a correlation with protein expression. Our results indicate that the anti-proliferative function of Bcl-2 dominates its anti-apoptotic function in ALL, but neither Bcl-2 nor the Bcl-2 family members gained prognostic information in the risk-adapted protocol ALL-7.
Leukemia 1999 Oct
PMID:Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome. 1051 59

In vitro resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly understood. Using flow cytometry, we studied the contribution of daunorubicin (DNR) accumulation and retention, cell size, expression of the major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in childhood ALL. The accumulated and retained DNR content was not related to the degree of DNR resistance, nor did the content differ between 53 initial and 20 relapse ALL samples (P >0. 05), although the latter were median two-fold more resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs such as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction, the intracellular DNR concentration was lower in relapsed compared with initial ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR concentration inversely correlated with DNR resistance, both in the accumulation (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The accumulated DNR concentration inversely correlated with expression of LRP (Rs -0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33, P = 0.03). In conclusion, the intracellular DNR concentration and the expression level of LRP may contribute to DNR resistance in childhood ALL. The strength of the correlations also indicates that resistance to anthracyclines can not be explained by one single mechanism.
Leukemia 1999 Dec
PMID:Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. 1060 24

L-Asparaginase is used for the treatment of acute leukemias, but is sometimes ineffective or associated with severe side-effects. We report here that the enzyme arginine deiminase is approximately 100-fold more potent than L-asparaginase in inhibiting the proliferation of cultured human lymphatic leukemia cell lines while it appears to be less effective in leukemia cells of myeloid origin. The inhibition of cell proliferation involves cell growth arrest in the G1- and/or S-phase and eventually apoptotic cell death. Our results suggest the possibility of a future use of arginine deiminase for the therapy of leukemia.
Leukemia 2000 May
PMID:Arginine deiminase inhibits proliferation of human leukemia cells more potently than asparaginase by inducing cell cycle arrest and apoptosis. 1080 13

Genotype and immunophenotype can be used to define biological species of acute lymphoblastic leukemia (ALL). The purpose of these two pilot studies, conducted between 1986 and 1994, was to explore the feasibility and acceptability of classifying ALL in this manner for selection of treatment rather than using conventional risk for failure factors such as age and initial white blood cell count. The possibility that conventional risk factors would be overcome and survival improved by this approach was also considered. Flow cytometry and chromosome analysis were used to classify the ALL of 150 children into one of five biologic categories as defined by cell surface antigens, DNA index and chromosome number and arrangement. Chemotherapy regimens depended on the assigned category. There was no provision for cranial irradiation and use of alkylating agents, anthracyclines and epipodophyllotoxins was restricted in order to reduce risk of late adverse sequelae. All patients are included in the analysis regardless of presenting condition or adherence to protocol. The majority of patients were Mexican-American or African-American. Eight-year event-free survival (EFS) is 60.7% (+/-4%) and 8-year overall survival (OAS) 72.6% (+/-3.7%). EFS and OAS varied significantly among the biologic categories despite differences in chemotherapy regimens. When the patients with B-precursor ALL were retrospectively classified by current Pediatric Oncology Group (POG) criteria, 8-year EFS was 82% (+/-7.3%) for the good risk group, 68.9% (+/-5.9%) for the standard risk and 48.8% (+/-7.6%) for the poor risk, all significant differences. However, when retrospectively classified according to the Rome/NCI prognostic criteria the 8-year EFS for standard risk patients was 69.1% (+/-5.1%) and for high risk 58.8% (+/-6.9%), not a statistically significant difference. Numbers of T cell and B cell patients are too few for comparison. Gender and ethnicity influenced survival as in treatment based on prognostic factors. Initial central nervous system (CNS) relapse occurred in five patients (3%) and combined CNS and hematological relapse in six (3%). Factors significantly associated with CNS and combined relapse were leukemic pleocytosis in the initial CSF sample, pro-B immunophenotype and DNA index <1.16, but not initial white blood cell count. Only three survivors appear to have serious late adverse sequelae, the only neurologic the result of asparaginase-induced cortical vein thrombosis. The results suggest that use of biologic species as defined by immunophenotype and genotype to select therapy of ALL is feasible and acceptable but under the conditions of these studies offered no apparent therapeutic advantage over conventional risk grouping. However, the introduction of molecular genotyping and novel gene targeted therapeutic agents justify further exploration of this approach.
Leukemia 2000 Aug
PMID:Pilot studies of species-specific chemotherapy of childhood acute lymphoblastic leukemia using genotype and immunophenotype. 1094 29

Between May 1987 and January 1991, 1354 patients, 1-21 years old, with standard or poor prognosis B-lineage acute lymphocytic leukemia were treated on the Pediatric Oncology Group Study 8602. One thousand three hundred and twenty-three patients entered remission and 1051 patients were randomized on day 43 to an intensification regimen containing L-asparaginase and intermediate-dose methotrexate (regimen B) or cytarabine and intermediate dose methotrexate (regimen C). After completion of intensification at week 25, all patients received the same maintenance therapy until 3 years from diagnosis. Overall 5-year continuous complete remission (CCR) for regimen B was 72+/-2% (s.e.) and for regimen C, 73+/-2% (P = 0.72 by log-rank analysis). Significant differences between treatments for CCR, testicular, CNS relapses overall or with regard to phenotype (pre-B vs early pre-B), gender, or race were not detected. During intensification, regimen C had significantly more bacterial infections (P = 0.05) and days spent in the hospital (P < 0.001) compared with regimen B, while regimen B had significantly more allergic reactions (P < 0.0001). No significant differences in CCR were noted between patients with pre-B and early pre-B ALL (P = 0.22 stratified by risk group and treatment). This study was unable to detect statistical difference between asparaginase (regimen B) and cytarabine (regimen C) during the intensification phase of therapy in children with B-lineage acute lymphocytic leukemia.
Leukemia 2000 Sep
PMID:Treatment of children with early pre-B and pre-B acute lymphocytic leukemia with antimetabolite-based intensification regimens: a Pediatric Oncology Group Study. 1099 2

The German Co-operative Study Group COALL for treatment of acute lymphoblastic leukemia (ALL) in childhood started the first trial in 1980. This report gives an overview of the long-term results of the four consecutive studies COALL-82, COALL-85, COALL-89 and COALL-92. Besides improvement in long-term survival major objectives were reduction of treatment-related toxicity by transferring asparaginase (ASP) from induction therapy to intensive phase and omitting CNS irradiation by stepwise increase of the initial white blood count (WBC) up to 50 x 10(9)/l (exception T-ALL) as criterion for irradiation. In study COALL-85 in high risk patients slow vs rapid rotational treatment was randomized. In study COALL-92 initial response to daunorubicin (DNR) as a 1-h vs 24-h infusion and its prognostic value was investigated. Furthermore, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were randomized in maintenance treatment. In total, 1191 eligible patients were enrolled. Induction treatment without ASP has been shown to be as effective and less hazardous than the former four-drug induction. CNS control could be obtained in most without cranial irradiation (CNS relapse-free survival >95%). The leukemic cell kill with a 24-h DNR infusion was equivalent to that of a 1-h infusion. DNR response was of less prognostic significance than prednisone response. The rapid rotation regimen failed to improve outcome as well as 6-TG in maintenance treatment. However, intensification of systemic treatment resulted in an increase in overall event-free survival (EFS) to approximately 80% which is comparable to other groups.
Leukemia 2000 Dec
PMID:Co-operative study group for childhood acute lymphoblastic leukemia (COALL): long-term follow-up of trials 82, 85, 89 and 92. 1118 14

The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since 1981. The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, high-dose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1,255 children with newly diagnosed ALL were evaluated on four consecutive protocols: 81-01 (1981-1985), 85-01 (1985-1987), 87-01 (1987-1991) and 91-01 (1991-1995). The 5-year event-free survival (EFS) rates (+/- standard error) for all patients by protocol were as follows: 74 +/- 3% (81-01), 78 +/- 3% (85-01), 77 +/- 2% (87-01) and 83 +/- 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63-82% for NCI high-risk B-progenitor patients, and 70-79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.
Leukemia 2000 Dec
PMID:Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). 1118 16

We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.
Leukemia 2000 Dec
PMID:Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group. 1118 17

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics.
Leukemia 2000 Dec
PMID:Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party. 1118 22


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