Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytidine deaminase, an enzyme that catalyses the deamination of both cytidine and its nucleoside analogues including the antineoplastic agents cytosine arabinoside (ara-C) and 5-azacytidine (5-azaC), has been partially purified from normal and leukemic human granulocytes. The purification procedure included heat precipitation at 70 degrees C, ammonium sulfate precipitation, calcium phosphate gel ion exchange, and Sephadex G-150 gel filtration. The enzyme has mol wt 51,000, isoelectric pH of 4.8, and maximum activity over a broad pH range of 5-9.5. The enzyme is stabilized by the presence of the sulfhydryl reagent, dithiothreitol. Cytidine deaminase from normal human granulocytes has a greater affinity for its physiologic substrate cytidine (K(m) = 1.1 x 10(-5) M) than for ara-C (8.8 x 10(-5) M) or 5-azaC (4.3 x 10(-4) M). Halogenated analogues such as 5-fluorocytidine and 5-bromo-2'-deoxycytidine also exhibited substrate activity, with maximum velocities greater than that of the physiologic substrates cytidine and deoxycytidine. No activity was observed with nucleotides or deoxynucleotides. The relative maximum velocity of the enzyme for cytidine and its nucleoside analogues remained constant during purification, indicating that a single enzyme was responsible for deamination of these substrates. Tetrahydrouridine (THU) was found to be a strong competitive inhibitor of partially purified deaminase with a K(i) of 5.4 x 10(-8) M. The biochemical properties of partially purified preparations of cytidine deaminase from normal and leukemic cells were compared with respect to isoelectric pH, molecular weight, and substrate and inhibitor kinetic parameters, and no differences were observed. However, normal circulating granulocytes contained a significantly greater concentration of cytidine deaminase (3.52+/-1.86 x 10(3)/mg protein) than chronic myelocytic leukemia (CML) cells (1.40+/-0.70 x 10(3) U/mg protein) or acute myelocytic leukemia (AML) cells (0.19+/-0.17 x 10(3) U/mg protein). To explain these differences in enzyme levels in leukemic versus normal cells, the changes in cytidine deaminase levels associated with maturation of normal granulocytes were studied in normal human bone marrow. Myeloid precursors obtained from bone marrow aspirates were separated into mature and immature fractions by Ficoll density centrifugation. Deaminase activity in lysates of mature granulocytes was 3.55-14.2 times greater than the activity found in the lysates of immature cells. Decreased enzyme activity was also found in immature myeloid cells from a patient with CML as compared to mature granulocytes from the same patient. These observations support the conclusion that the greater specific activity of cytidine deaminase in normal mature granulocytes as compared to leukemic cells is related to the process of granulocyte maturation rather than a specific enzymatic defect in leukemic cells.
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PMID:Purification and properties of cytidine deaminase from normal and leukemic granulocytes. 452 17

A human leukemia-associated differentiation antigen has been identified by a monoclonal antibody (A12) raised to the lymphoblastoid cell line NALM-1. The A12 antigen was expressed on the surface of leukemic cells from patients with common acute lymphoblastic leukemia (c-ALL) as well as on cells of the hematopoietic cell lines NALM-1, Reh-6, Raji, Daudi, CEM, and 8402 as determined by an antibody-binding radioimmunoassay, as well as by indirect immunofluorescence and FACS analysis. This antigen was not detected on normal blood lymphocytes, normal bone-marrow cells or leukemic cells from patients with acute myeloid leukemia (AML). The A12 antigen had an apparent molecular weight of 100 kD as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and appeared to be related to if not identical with the acute lymphoblastic leukemia antigen CALLA described by others. Cross-blocking experiments indicated that preincubation of NALM-1 cells with antibody A12 or J5 (anti-CALLA) could block subsequent binding of 125I-labeled A12 and J5 antibody. These results suggest that the two monoclonal antibodies recognize identical or closely located antigenic sites. The surface membrane expression of A12 antigen in NALM-1 cells was modulated when the cells were cultured in the presence of A12 antibody. Under these conditions, the expression of Ia antigens was unaffected. Re-expression of A12 antigen occurred within 24 h after transfer of the modulated cells into medium devoid of monoclonal antibody.
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PMID:Characterization of a monoclonal antibody (A12) that defines a human acute lymphoblastic leukemia-associated differentiation antigen. 620 73

A membrane antigen with an apparent specificity to B lymphocytes was detected with immunochemical techniques and its properties were analyzed. Anti-B-CLL serum was raised in a rabbit by immunization with B-cell chronic lymphocytic leukemia (B-CLL) cells. This anti-B-CLL serum was absorbed with erythrocytes, liver homogenate and insolubilized immunoglobulins. After further absorption with T-CLL cells, chronic myelocytic leukemia (CML) cells and acute myelocytic leukemia (AML) cells, the anti-B-CLL serum still reacted with peripheral blood B lymphocytes, B-CLL cells and hairy cell leukemia (HCL) cells. In contrast, no reactivity was seen with peripheral blood T lymphocyte or monocytes, or leukemia cells of non-B cell origin. An immunoprecipitation of radiolabeled cell surface proteins was attempted using the anti-B-CLL serum in the presence of Staphylococcus Aureus Cowan 1 (SaCl), and the precipitates were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). A membrane antigen with an apparent molecular weight of 76,000 daltons (P-76) was immunoprecipitated with the anti-B-CLL serum from the lysates of normal B lymphocyte, B-CLL cells and HCL cells. The antigen (P-76) is not composed of disulfide-linked subunits and has no structural relationship with HLA-DR (Ia-like) antigens or other known antigens. These results suggest that this antigen is B-lymphocyte specific, and favour the B-lymphocyte nature of HCL cells.
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PMID:A human B lymphocyte antigen (P-76) shared by B-cell chronic lymphocytic leukemia cells and hairy cell leukemia cells. 634 Jul 59

A total of 47 patients with relapsed or primarily refractory leukemia were treated with mitoxantrone alone or in combination with vincristine sulfate and prednisone or cytarabine. Eligible patients included those with adequate renal and hepatic function, normal left ventricular ejection fraction, and those who had received previous treatment. When mitoxantrone was given alone in a once daily times five schedule, 5 of 12 acute lymphoblastic leukemia patients achieved complete remission; 4 of these patients had been refractory to reinduction and 1 to induction chemotherapy with anthracycline-containing treatments. Four of these patients had progressive disease, and three died during induction. Of 12 patients with acute myeloid leukemia, 1 had a complete remission, 1 had a partial remission, 8 had progressive disease, and 2 died during induction. Mitoxantrone was also found to be active in two patients in the blastic transformation of chronic myeloid leukemia with a response in one patient lasting 17 weeks. Combinations of mitoxantrone with vincristine sulfate and prednisone resulted in complete remission in four of nine acute lymphoblastic leukemia patients and one of four patients with Tdt-positive chronic myeloid leukemia in blast crisis. Three of these patients had not experienced a prior remission following anthracycline-containing treatments. Partial remission occurred in two of the acute lymphoblastic leukemia patients and one of the Tdt-positive chronic myeloid leukemia patients. Two of this latter group of patients died in induction. Treatment with mitoxantrone and cytarabine resulted in two acute myeloid leukemia patients achieving complete remission and one a partial remission; two patients had progressive disease, and one died in induction. No response was seen in a patient with Tdt-negative chronic myeloid leukemia after two courses of treatment. One patient with acute leukemia in the course of myelofibrosis died in induction. All the patients achieving complete remission are alive and have been in complete remission from 2 to 12 months. Side effects included mild nausea and vomiting in 9 of 13 patients treated with the mitoxantrone-vincristine sulfate-prednisone combination, and in 3 of 8 patients treated with the mitoxantrone-cytarabine combination. Other side effects of the combination treatments include drug-induced oral mucositis (of a lesser degree than with mitoxantrone alone), transient hepatic abnormalities, and infectious complications, such as sepsis, Candida sp colonization of the upper digestive tract, and soft tissue cellulitis, in a few patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mitoxantrone as a single agent and in combination chemotherapy in patients with refractory acute leukemia. 638 64

Leukemic myeloid, myelomonocytic, and monocytic cells will incorporate radiolabeled sulfate into newly synthesized macromolecules. We developed a liquid culture technique to examine the in vitro effects of chemotherapeutic agents on the incorporation of radiolabeled sulfate into cells of patients with acute nonlymphocytic leukemia (ANLL). Cells recovered from bone marrow or peripheral blood of 25 patients with ANLL were incubated in vitro for one hour with saline (control) or a variety of chemotherapeutic agents. Cells were washed free of the drug and grown in liquid cultures containing nutrient medium and 35SO4. The percent of 35SO4 incorporated into the drug treated as compared with control cells was determined after one, three, and seven days of culture. Patients whose drug-treated cells incorporated less than 30% of 35SO4 when compared with the control after three or seven days of culture achieved a complete response to these agents in vivo (P less than .05). Thus, the in vitro effects of various chemotherapeutic agents on the incorporation of 35SO4 into cells obtained from patients with ANLL may help predict clinical response to these agents in vivo.
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PMID:A rapid in vitro drug-sensitivity assay in acute nonlymphocytic leukemia. 663 11

Forty-six cases with hematological malignancies were treated with vindesine sulfate (VDS); a new semisynthetic vinca alkaloid. Six cases with ALL, 5 cases CML in blastic crisis, 3 Hodgkin's disease (HD) and 4 non-Hodgkin's lymphoma (NHL) were treated with VDS alone. Five out of 6 cases ALL, 2 out of 5 CML in blastic crisis were induced into partial remission with VDS alone. All of 3 HD, and 4 NHL were induced in complete remission (CR) or partial remission (PR). Out of 5 cases AML in CR who received VDS as the maintenance therapy in combination with cyclophosphamide, 6-MP and prednisone, one case relapsed during the treatment, but other four cases maintained CR for 4 to 24 months. One case of APL in relapse, which was treated with VDS and 6-MP, reinduced into CR after one month. Out of 16 cases with malignant lymphoma treated by combination chemotherapy including VDS, eleven cases entered in CR or PR. Out of four cases in which the disease became refractory to vincristine (VCR) or vinblastine (VLB) clinically, two achieved PR. VDS was administered intravenously with 3 mg/body/week. When undesirable effect such as leucocytopenia was observed, the dose was reduced to 2-2.5 mg/body/week or 3 mg/body/2 weeks or month. Neurotoxicity (i.e. Paresthesia 21.7%), alopecia (21.7%), leucocytopenia (19.6%), constipation (10.9%) and fever (6.5%) were main side effects of VDS. The neurotoxicity of VDS, however, seemed far less intensive than VCR.
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PMID:[Administration of vindesine sulfate for the treatment of malignant hematological tumors]. 676 3

The enzyme uracil DNA-glycosylase has been purified from blast cells of patients with acute myelocytic leukemia. A 1000-fold purification has been achieved and the enzyme appears highly enriched for the uracil glycosylase activity as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The apparent molecular weight of the purified enzyme is 30,000. Uracil DNA-glycosylase exhibits activity in the absence of any added metal and the addition of MgCl2, MnCl2, CaCl2, NaCl, or KCl causes inhibition. EDTA as well as EGTA can inhibit enzyme activity. An interesting finding is the biphasic effect of spermine. At a concentration of 25 microM, spermine will cause a 2.5-fold activation of enzyme activity, whereas at concentrations of 100 microM and higher, spermine will inhibit enzyme activity. An Arrhenius plot of glycosylase activity in the presence of 25 microM spermine shows a biphasic curve with the transition temperature being 36 degrees C. Initial velocity studies in the presence of varying concentrations of spermine indicate a change in both the apparent Km and Vmax of the enzyme. Various uracil analogs were tested to establish a structure-activity relationship for this enzyme. It appears from this data that uracil DNA-glycosylase is very specific for uracil moieties. Uracil, acting as a product inhibitor, gives a Ki value of 220 microM.
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PMID:Uracil DNA-glycosylase. Purification and properties of this enzyme isolated from blast cells of acute myelocytic leukemia patients. 676 36

For children with acute myelocytic leukemia, 5-day courses of Cytosar in combination with cyclophosphamide (with or without vincristine sulfate and prednisone) has shown excellent, age related results in relapse patients. The regimen known as Mini-COAP has been incorporated into front-line studies. Cytosar given intrathecally in combination with methotrexate has produced superior results in treating meningeal disease in the African presentation of Burkitt disease. This "synchronizing" technique has been incorporated into a high Cytoxan-high methotrexate regimen with coordinated intrathecal therapy with good results. Triple (Cytosar, methotrexate, and hydrocortisone) intrathecal prophylaxis is now demonstrated to have equivalent effectiveness to conventional CNS prophylaxis employing radiotherapy 2400 R and 5 doses of intrathecal methotrexate.
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PMID:Use of cytosar in pediatric acute myelocytic leukemia and leukemic meningitis. 696 19

Using isoelectric focusing and sodium dodecyl sulfate two-dimensional gel electrophoresis, 9 M urea-extractable nuclear proteins from four human tumor cells (HeLa, Namalwa, acute myelogenous leukemia, and lymphoma) and four normal human cells (IMR-90, WI-38, liver, and lymphocytes) were compared. Two protein spots, 140/7.7 and 54/6.6, were found in all four tumor cells but not in the four normal cells studied. Two protein spots, 56/6.7 and 56/6.9, were found in all four normal cells but not in any of the tumors studied. None of these proteins was common to those found in the earlier studies on rat tumors (H. Takami et al., Cancer Res., 39: 2096-2105, 1979).
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PMID:Comparison of nuclear proteins of several human tumors and normal cells by two-dimensional gel electrophoresis. 744 73

This laboratory has been characterizing protein serine/threonine kinase reactions of hematopoietic tissues, whose most distinguishing characteristics in vitro are stimulation with vesicular phosphatidyl glycerol, and the ability to function using Mn2+ as the sole divalent cation. The major protein substrates are a 73-kD protein and a protein migrating near ovalbumin on sodium dodecyl sulfate polyacrylamide gel electrophoresis. The 47-kD protein was partially purified from cells harvested by leukapheresis from a patient with acute myelogenous leukemia, using ammonium sulfate precipitation and ion exchange chromatography. This partially purified ion-exchange fraction contained an endogenous kinase activity with characteristics similar to those we previously described of protein kinase P (protein kinase, phospholipid-stimulable: PK-P), but not typical of any form of protein kinase C (PK-C). With longer phosphorylation, the 47-kD band showed increasingly lower mobility demonstrable both by Coomassie blue staining and autoradiography, suggesting both that it was multiply phosphorylated, and that the excisable band was pure. The protein was thus eluted from preparative gel slices and digested with endoproteinase lys C. Sequence data from the fragments identified the protein as the 47-kD calpain fragment of talin, a protein found in focal adhesion plaques and some cell-cell contacts. PK-C phosphorylated the 47-kD protein, as has been reported previously, and phosphopeptide mapping disclosed a similar pattern of phosphorylation using either PK-C or the endogenous activity. The 47-kD protein labeled with the endogenous kinase contained predominantly phosphoserine, with some phosphothreonine and a trace of phosphotyrosine. Intact, purified talin was also phosphorylated by PK-P in a phospholipid-stimulable manner, but at 1/20 the rate of the 47-kD fragment.
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PMID:The 47-kD fragment of talin is a substrate for protein kinase P. 824 4


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