Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 effect of L-asparaginase (L-asp) pre-treatment on etoposide-induced DNA strand breakage and cytotoxicity was investigated. In a T-lymphoblastoid cell line, Molt 4, etoposide-induced DNA strand breaks, DNA-protein cross-links and cytotoxicity were reduced by pre-treatment with L-asp for 15 hr, but it did not cause these changes in a promyelocytic-leukemia cell line, HL-60, which is less sensitive than Molt 4 to L-asp. However, pre-treatment of Molt 4 cells with L-asp did not significantly alter the accumulation of [3H]-etoposide. Cell-cycle analyses showed an increase in G1-phase cells, a significant decrease in both S-phase cells and G2/M-phase cells pre-treated with L-asp in Molt 4 cells, but L-asp exposure did not result in any significant changes in HL-60 cells. On the other hand, L-asp pre-treatment did not affect topoisomerase-I (Topo-I) inhibitor, camptothecin (CPT)-induced DNA strand breaks or toxicity in Molt 4 cells. Our data imply that a decrease in S- and G2/M-phase cells following L-asp treatment may explain the reduction of etoposide-induced DNA lesions and cytotoxicity in Molt 4 cells, since topoisomerase-II (Topo-II) content or activity is a function of cellular proliferation status.
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PMID:Pre-treatment of a human T-lymphoblastoid cell line with L-asparaginase reduces etoposide-induced DNA strand breakage and cytotoxicity. 153 31

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

The diagnosis of 'ALL with maturation' (ALLm) is proposed. One hundred and one patients with untreated ALL were entered into this study. The diagnosis of ALLm was made when more than 20% of all nucleated elements in the bone marrow showed maturation beyond prolymphocytes by light microscopic examination. The mature-appearing leukemic cells showed the same immunophenotype to remaining lymphoblasts. The number of ALLm cases was 19 (18.8%). The mean age at presentation of ALLm was 29 +/- 18, older than that of 18 +/- 16 of the remaining typical ALL (ALLt) (P = 0.015). Remission was induced with daunorubicin, vincristine, prednisone and L-asparaginase. Only two of 19 ALLm patients achieved CR after 4 weeks induction chemotherapy. In contrast, 57 of 82 (69.5%) ALLt patients achieved CR after the same induction chemotherapy. There was no significant difference in immunophenotype of ALLm compared with ALLt. Labeling index of DNA topoisomerase IIalpha (TopoLI) was studied by immunohistochemistry. Initial TopoLI of ALLm (221 +/- 147) was much lower than that of ALLt (609 +/- 262, P = 0.005). Furthermore, the remaining leukemic cells after chemotherapy were not labeled with anti-DNA topoisomerase IIalpha. The P53 protein was expressed in nine of 18 ALLm cases (50.0%) and P-glycoprotein was not expressed in ALLm cases. Twelve of 19 ALLm cases were studied for carrying bcr/abl fusion by karyotyping and/or fluorescent in situ hybridization. Only two cases revealed bcr/abl fusion. In conclusion, ALLm is a separate entity of ALL which has a very poor clinical course and is independent of other prognostic factors. The morphologically mature leukemic cells are in resting GO phase.
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PMID:Acute lymphoblastic leukemia with maturation--a new entity with clinical significance. 963 14

The major established cause of acute myeloid leukemia (AML) in the young is cancer chemotherapy. There are two forms of treatment-related AML (t-AML). Each form has a de novo counterpart. Alkylating agents cause t-AML characterized by antecedent myelodysplasia, a mean latency period of 5-7 years and complete or partial deletion of chromosome 5 or 7. The risk is related to cumulative alkylating agent dose. Germline NF-1 and p53 gene mutations and the GSTT1 null genotype may increase the risk. Epipodophyllotoxins and other DNA topoisomerase II inhibitors cause leukemias with translocations of the MLL gene at chromosome band 11q23 or, less often, t(8;21), t(3;21), inv(16), t(8;16), t(15;17) or t(9;22). The mean latency period is about 2 years. While most cases are of French-American-British (FAB) M4 or FAB M5 morphology, other FAB AML subtypes, myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) occur. Between 2 and 12% of patients who receive epipodophyllotoxin have developed t-AML. There is no relationship with higher cumulative epipodophyllotoxin dose and genetic predisposition has not been identified, but weekly or twice-weekly schedules and preceding l-asparaginase administration may potentiate the risk. The translocation breakpoints in MLL are heterogeneously distributed within a breakpoint cluster region (bcr) and the MLL gene translocations involve one of many partner genes. DNA topoisomerase II cleavage assays demonstrate a correspondence between DNA topoisomerase II cleavage sites and the translocation breakpoints. DNA topoisomerase II catalyzes transient double-stranded DNA cleavage and rejoining. Epipodophyllotoxins form a complex with the DNA and DNA topoisomerase II, decrease DNA rejoining and cause chromosomal breakage. Furthermore, epipodophyllotoxin metabolism generates reactive oxygen species and hydroxyl radicals that could create abasic sites, potent position-specific enhancers of DNA topoisomerase II cleavage. One proposed mechanism for the translocations entails chromosomal breakage by DNA topoisomerase II and recombination of DNA free ends from different chromosomes through DNA repair. With few exceptions, treatment-related leukemias respond less well to either chemotherapy or bone marrow transplantation than their de novo counterparts, necessitating more innovative treatments, a better mechanistic understanding of the pathogenesis, and strategies for prevention.
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PMID:Secondary leukemias induced by topoisomerase-targeted drugs. 974 98

Among 511 patients with therapy-related myelodysplastic syndrome or acute leukemia (t-MDS/t-AL) and balanced chromosome aberrations, 162 (32%) had translocations involving 11q23. The recurring translocation partners were 9p22 (48%), 19p13.3 (11%), 19p13.1 (10%), 4q21 (9%), 6q27 (6%), 1p32 (2%), 16p13.1 (2%), 10p13 (1%), and 17q25 (1%); in 9%, the translocations were seen only once. The remaining 349 patients were divided into five subgroups based on the balanced aberration: 21q22, inv(16), t(15;17), Rare, and Unique aberrations. Patients in the 11q23 subgroup had a sole cytogenetic abnormality more often than those in the 21q22, inv(16), Rare, and Unique subgroups, and a complex karyotype or -5/del(5q) and/or -7/del(7q) less often than patients in the 21q22, Rare, and Unique subgroups. Clinically, 11q23 patients had acute lymphoblastic leukemia (ALL) more often as their primary disease and a shorter latency from start of treatment for the primary disease to their t-MDS/t-AL diagnosis, except when compared with the inv(16) subgroup. The 11q23 subgroup demonstrated a younger age at t-MDS/t-AL diagnosis, but this finding was not significant when patients with AL as their primary diagnosis were excluded. Survival from the time of diagnosis of t-MDS/t-AL was significantly shorter for the 11q23 subgroup compared with that of the 21q22, inv(16), and t(15;17) subgroups (median 8 vs. 14, 28, and 29 months, respectively). Inferior survival occurred even though 11q23 patients were younger and more often received blood or marrow transplantation (BMT). Even among patients receiving BMT, 11q23 patients had a shorter median survival (9 vs. 12-31 months for the other subgroups). However, among 11q23 patients, those receiving BMT survived longer, with 1- and 5-year survivals of 43% and 18% compared with 23% and 7% for patients not transplanted. With regard to prior therapy, 11q23 patients, compared with other patients, received radiotherapy less often as their sole therapy and chemotherapy more often. They had received VP16, methotrexate, 6MP/6TG, L-asparaginase, daunorubicin, cytarabine, and VM26 more often, likely attributed to the high frequency of AL as their primary disease. More patients in the 11q23 subgroup had received doxorubicin, except in comparison with the 21q22 subgroup; more vincristine, except in comparison with the Rare and Unique subgroups; and more prednisone, except in comparison with the Unique subgroup. Patients in the 11q23 subgroup more often received alkylating agents (AAs) (86% vs. 59-82% for the other subgroups), and topoisomerase II inhibitors (TIs) (84% vs. 49-75%), and they more often reported exposure to AAs plus TIs without radiotherapy (33% vs. 12-21%), except in comparison with the 21q22 subgroup (36%). We performed a multivariate analysis to determine whether the adverse survival of 11q23 patients compared to other Workshop patients was explained by factors other than the presence of the 11q23 abnormality. Covariates in the final model were the five cytogenetic subgroup indicators, where the 11q23 subgroup was the referent (P < 0.0001); age at t-MDS/t-AL (P = 0.0036); previous exposure to lomustine (P < 0.0001) and mitoxantrone (P = 0.0225); BMT for t-MDS/t-AL (P = 0.0006); and karyotype complexity (P = 0.0114). The risk of death for 11q23 patients relative to patients in the 21q22, inv(16), t(15;17), and Unique subgroups was significant, even after adjustment for other risk factors (relative risks 2.3, 3.6, 3.1, and 1.5, respectively; P < 0.0001 for the first three comparisons and P = 0.0125 for the last). When a multivariable model was constructed, excluding patients with AL or MDS as their primary diagnosis, the relative risk of death for 11q23 patients was significantly higher than that of all five other cytogenetic subgroups. We conclude that among t-MDS/t-AL patients with balanced aberrations, 11q23 translocations are an independent adverse risk factor. Although BMT is the current therapy of choice, new treatment is required.
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PMID:11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. 1192 Dec 71

The essential oil (EO) composition of the aerial parts of Erigeron multiradiatus (Lindl.ex DC.) Benth growing wild in the central Himalayan region of Uttarakhand, India, was analyzed by capillary gas chromatography with a flame ionization detector and gas chromatography-mass spectrometry. A sum of 12 constituents was identified, representing 97.81% of the oil composition. The oil was composed mainly of oxygenated monoterpenes (88.95%), sesquiterpene hydrocarbons (5.61%), oxygenated sesquiterpenes (3.05%), and monoterpene hydrocarbons (0.20%). Major constituents identified were trans-2-cis-8-matricaria-ester (77.79%), cis-lachnophyllum ester (11.04%), zingiberene (4.43%), and spathulenol (1.59%). Further, the leishmanicidal effect of EO and the purified compound trans-2-cis-8-matricaria-ester has been investigated against Leishmania donovani promastigotes and intracellular amastigotes. EO and trans-2-cis-8-matricaria-ester were safer for the hamster peritoneal macrophage and lethal to promastigotes and intracellular amastigotes at different concentrations. Further, using an in silico approach, these four compounds were tested against 10 major proteins of L. donovani associated with its virulence. Out of them, only trans-2-cis-8-matricaria-ester was found to be effective against the four target proteins, namely, l-asparaginase-1-like protein, metacaspase 2, metacaspase 1, and DNA topoisomerase II of L. donovani. The results indicate that EO contains trans-2-cis-8-matricaria-ester as a major component and showed antileishmanial activity which may facilitate discovery of new lead molecules for developing herbal medicines against visceral leishmaniasis.
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PMID:Identification of trans-2-cis-8-Matricaria-ester from the Essential Oil of Erigeron multiradiatus and Evaluation of Its Antileishmanial Potential by in Vitro and in Silico Approaches. 3152 20

In the past decades, new cancer treatments have been introduced in pediatric oncology leading to improvement in clinical outcomes and survival rates. However, due to inter-individual differences, some children experience severe chemotherapy-induced toxicities or a poor clinical outcome. An explanation for the diversity in response to chemotherapy is genetic variation, leading to differences in expression and activity of metabolizing and transport enzymes as well as drug targets. Pharmacogenetic testing has emerged as a promising tool to predict and limit acute and long-term adverse effects in patients. However, in pediatric oncology, limited number of patients and a considerable diversity in study results complicate the interpretation of test results and its clinical relevance. With this review, we provide an overview of new developments over the past four years regarding relevant polymorphisms related to toxicity in pediatric oncology. The following chemotherapeutics and associated toxicities are discussed: alkylating agents, anthracyclines, asparaginase, methotrexate, platinum compounds, steroids, thiopurines, topoisomerase inhibitors, and vinca alkaloids. Our review identifies several questions regarding the role of genetic variants in chemotherapy-induced toxicities. Ambiguities in the literature stem from small population sizes, differences in (statistical) interpretation and variations in sequencing technologies as well as different clinical outcome definitions. Standardization of clinical outcome data and toxicity definitions within electronic health records combined with the increased availability of genomic sequence techniques in clinical practice will help to validate these models in upcoming years.
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PMID:Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology. 3284 87

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