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)

Of 4 lines of myelogenous rat leukemias induced by N-nitrosobutylurea (NBU), DBLA-6 was selected as a screening model for antileukemic agents because of the following characteristics: a) High transplantability either by intravenous (i.v.) or intraperitoneal (i.p.) inoculation; b) linear relationship between inoculum size and survival time; c) marked increase of leucocyte counts in the peripheral blood as the tumor progresses after intravenous inoculation. To investigate reliability in its predicting clinical efficacy, its sensitivity to known antileukemics was studied. To determine the effects, a change of leucocyte counts in the peripheral blood together with the prolongation of life span was checked in the following systems; i.v.-i.v. (i.v.-inoculation, i.v.-injection), i.v.-i.p., i.p.-i.p., i.p.-i.v. Fifty percent cure was obtained with Vincristine, Vinblastine, Daunorubicin, 6-Mercaptopurine, and alkylating agent 838D or 864T. The success of treatment was measured by decrease of leucocytes. Methotrexate, cytosine arabinoside (Ara-C), and cyclophosphamide showed only poor effects, and Mitomycin C, L-asparaginase, and Bleomycin were ineffective. In addition, the chemotherapeutic effects of Vincristine and 864 on this leukemia were quite dependend both on the route of drug injection and on the site of tumor inoculation. Subsequently, our studies are being extended to cover the correlation between drug distribution and tumor localization or dissemination.
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PMID:Sensitivity of DBLA-6 leukemia of rats to known antitumor agents in relation to their clinical effects. 116 99

Cancer and Leukemia Group B undertook a randomized trial of intensification treatment in adults aged 15 to 79 years with acute lymphocytic leukemia (ALL) in complete remission (CR). Daunorubicin (DNR), prednisone, vincristine (VCR), intrathecal (IT) methotrexate (MTX), and asparaginase produced 177 CRs in 277 patients. One hundred fifty-one patients were randomly assigned to receive treatment as follows: 74 received intensive cytarabine and DNR, and 77 received cycles of mercaptopurine (6-MP) and MTX, followed by 6MP, MTX, VCR, and prednisone for 3 years in all. One hundred twelve patients received CNS prophylaxis. Intensification produced major myelosuppression but did not improve remission duration (median, 21 months). Of the 151 patients with CRs who entered the intensification phase, 29% remain in continuous CR (43 to 117 months); in 19 patients, CRs have lasted for longer than 7 years. No relapses occurred after 60 months. Median survival from the time of randomization was 30 months. Those under 30 years of age responded more frequently, with longer CR and survival. While 53% of those aged 15 to 19 years remain in continuous CR, 92% of patients over 59 years have relapsed. The presence of a myeloid antigen on the leukemic cells was adversely prognostic for CR achievement and for survival. Pretreatment WBC and platelet levels independently affected CR duration and survival. Early M1 marrow development presaged longer remissions. CNS relapse occurred in 47 of 256 patients with normal CSF before treatment, in 29 before CNS prophylaxis. CNS disease occurred after CNS prophylaxis in 18 patients: 13 of 61 who had received standard premaintenance and five of 51 who received intensification. No advantage in CR duration or survival resulted from intensive treatment with DNR and cytarabine following induction of CR.
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PMID:The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B. 194 Oct 59

From May 1979 to March 1983, 76 evaluable patients with lymphoblastic lymphoma (LBL) were treated by members of the Pediatric Oncology Group (POG). Forty-six children treated by the six-drug A-COP+ regimen (Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], vincristine, prednisone, cyclophosphamide, methotrexate, and hydrocortisone) were compared in a prospective randomized trial with 30 patients receiving the modified ten-drug LSA2-L2 (cyclosphosphamide, vincristine, methotrexate, Daunomycin [daunorubicin cerubidine; Wyeth Laboratories, Philadelphia], prednisone, cytarabine, thioguanine, asparaginase, hydroxyurea, and carmustine) regimen. After adjusting for stage (I and II v III v IV), there was no statistically significant difference (P = .19) between A-COP+ and LSA2-L2 regimens on the basis of 3-year survival and disease-free survival (62% v 72% and 53% v 58%, respectively for the two treatment regimens) but the power of analysis and thus the ability to detect a clinically meaningful difference in the outcome with the two regimens was limited by the small number of patients. Neither therapy was effective for most patients with stage IV disease, with failure occurring in six of seven children receiving A-COP+ regimen and eight of 11 patients receiving LSA2-L2. Although the LSA2-L2 regimen was more toxic during the induction of remission, the toxicity during maintenance was acceptable and similar for both treatments. CNS relapse was not a significant problem whether cranial radiation with intrathecal (IT) therapy (A-COP+) or IT therapy alone (LSA2-L2) were used. Our results confirm the overall effectiveness of the LSA2-L2 regimen in children with LBLs, especially those initially free of bone marrow or CNS involvement, but were inconclusive as to the inferiority or superiority of this regimen over the A-COP+ regimen.
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PMID:Lymphoblastic lymphoma in children--a randomized trial comparing LSA2-L2 with the A-COP+ therapeutic regimen: a Pediatric Oncology Group Study. 327 50

Human bone marrow cells from 20 patients as well as the permanent human B-cell lines RPMI 1788, Raji, Daudi, T-cell lines Molt, CEM, Jurkat and the promyelocytic line HL 60 were assayed by means of a newly developed in vitro flow cytometric cytostatic drug assay. The cells were exposed to cytosine-arabinoside, L-asparaginase, daunorubicin, prednisone or vincristine. Surviving cells were stained after an incubation period of 2 to 7 days with esterase and pH-indicator dye ADB (1,4-diacetoxy-2,3-dicyanobenzene), dead cells with DNA-dye PI (propidium iodide). Dose-response curves were established using percent surviving cells. It was possible to evaluate bone marrow samples from 16 out of 20 patients. Seven samples were leukemic (acute myeloid leukemia (AML) n = 6, Non-Hodgkin's Lymphoma (NHL) n = 1). Nine samples were from patients either in complete remission or with benign diseases. Daunorubicin and cytosine-arabinoside were cytotoxic in both groups, whereas vincristine was effective mainly in the leukemic group (p less than 0.05). There was significant heterogeneity in the reactivity of AML-marrow cells from different patients to different drugs. The cell lines exhibited different patterns of sensitivity. Vincristine arrested cells in G2/M-phase, cytosine-arabinoside caused an increase of cells in the S-phase.
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PMID:Cytostatic drug testing in human leukemias by means of multiparametric flow cytometry. 367 21

The aim of our study was to characterise, for the first time, the chemo- and radiation sensitivity of seven pediatric acute lymphoblastic leukemias xenotransplanted into immunodeficient NOD/SCID mice and to correlate the findings with the expression of three drug resistance proteins, P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP1) and lung resistance protein (LRP). Mice were treated with single drugs used in clinical protocols: daunorubicin, doxorubicin, cyclophosphamide, vincristine, cytarabine, asparaginase and methotrexate. Two ALL samples, established from primarily diagnosed patients, responded to 5 or 6 of the tested cytostatics, respectively, while 3 out of 5 ALLs from relapse patients were only sensitive towards 2-4 drugs tested. Daunorubicin was more efficient than doxorubicin. The response of xenografted ALL toward vincristine and cyclophosphamide was inversely correlated with the expression of P-gp, LRP and MRP1 (R2 = 0.71, 0.70 and 0.64 for vincristine and 0.44, 0.70 and 0.60 for cyclophosphamide). A good correlation could be detected between the expression of P-gp and LRP (R2 = 0.88), P-gp and MRP1 (R2 = 0.75) and LRP and MRP1 (R2 = 0.90). The highest co-expression of the drug resistance proteins in the leukemia ALL-SCID 6 coincided with a high resistance to radiation and chemotherapy. Prediction of the individual drug resistance profile of a patient on the basis of results from the ALL-SCID xenograft studies was not possible because of the relatively long time necessary and because of the changes in the expression of P-gp, LRP and MRP1 during the murine generations. We conclude that in the drug resistance phenotype of ALL not only the above mentioned proteins but a variety of different molecules are involved.
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PMID:Chemo- and radiation sensitivity of xenografted acute lymphoblastic leukemias--correlation to the expression of multidrug resistance proteins. 1289 54

We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.
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PMID:In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia. 1593 Aug 91