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)

Deoxycytidine kinase, which phosphorylates deoxycytidine (CdR) and its analog, cytosine arabinoside (ara-C), has been purified 71-fold from human leukemic cells. Biochemical properties of the partially purified enzyme included a molecular weight of 68,000, Kms of 7.8 muM for CdR and 25.6 muM for ara-C, and optimal activity with ATP and GTP as phosphate donors. Ara-C phosphorylation was strongly inhibited by CdR (Ki = 0.17 muM) and dCTP (Ki = 7.3 muM) and was weakly inhibited by ara-CTP (Ki = 0.13 mM). Purification by calcium phosphate gel elution and DEAE chromatography effectively separated this enzyme from cytidine deaminase, which deaminates both CdR and ara-C, and from uridine-cytidine kinase, the enzyme which phosphorylates 5-azacytidine. CdR kinase activity was found to decrease and cytidine deaminase to increase with maturation of normal and leukemic granulocytes. Myeloblasts purified by Ficoll sedimentation revealed an average kinase activity of 15.4 U/mg protein in acute myelocytic leukemia and 12.3 U/mg protein in blastic crisis of chronic myelocytic leukemia (CML). The average ratio of CdR kinase to deaminase activity in crude cell extracts varied from 0.197 in AML and 0.089 in blastic crisis to 0.0004 in normal granulocytes, reflecting the changes which take place with cellular maturation. The absolute levels of kinase and deaminase and the ratio of these two enzymes varied considerably among patients with AML, indicating that quantitative differences may be found in the metabolism of CdR and its analogs in leukemic cells.
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PMID:Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes. 5 55

In 14 patients with acute myeloid leukemia (AML) the plasma concentration of cytosine arabinoside (Ara-C) was determined at the start of the first course of treatment at various intervals after a bolus injection. In 10 patients plasma concentration/time data were fitted to a biexponential equation and pharmacokinetic parameters were estimated from the coefficient and exponents of such equations. The plasma half-life (t1/2) of Ara-C of the first phase varied from 1.2 to 1.9 min (mean 1.6). The t1/2 of the second phase varied from 8.8 to 18.9 min. All patients were treated with Ara-C alone in a dose of 100 mg/m2 for 10 or 14 days. There was poor treatment response in five patients with second-phase t1/2 of Ara-C ranging from 6.6 to 10.7 min whereas there was complete remission in nine patients with t1/2 exceeding 12.7 min. In three patients plasma Ara-C concentrations were measured during constant-rate infusion of different amounts of drug. It appeared that the plateau concentrations were directly proportional to the dose, which indicated that in the therapeutic range no enzyme capacity-limited elimination occurs.
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PMID:Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia. 26 28

Arabinosylcytosine (ara-C) was administered by prolonged intravenous infusion with a portable liquid infusion system (LIS) to patients with acute myelogenous leukemia. With the use of tritiated ara-C and this portable system, pharmacologic studies were performed in 8 patients. Most of the plasma radioactivity is in the deaminated product, arabinosyluracil (ara-U). After continuous intravenous infusion, a constant ara-C level is achieved slowly in the plasma. Unless a loading (priming) dose is administered immediately before beginning the infusion, a steady-state ara-C level cannot be achieved until 8 to 24 hr after the infusion. The infusion system has two mechanisms--one for giving a loading dose (3 ml/min) and the other for regular infusion at a rate of 0.5 to 2.0 ml/hr. If a loading dose is given before continuous infusion, a steady-state are-C level is achieved within an hour. The plasma ara-C disappearance curves are biphasic with a terminal half-life of 104 min, which is the same as that of a single injection. The cumulative urinary excretion after approximately 23 hr of infusion varied from 14% to 35% in different patients; more than 90% is ara-U and the remainder is ara-C. Our results have demonstrated that LIS can be used conveniently to sustain a constant plasma level of ara-C. The LIS increases mobility of both inpatients and outpatients and is particularly convenient for ambulatory patients.
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PMID:Pharmacologic studies of continuous infusion of arabinosylcytosine by liquid infusion system. 26 46

1-beta-D-Arabinofuranosylcytosine diphosphate choline was formed from 1-beta-D-arabinofuranosylcytosine (ara-C) during incubation in vitro of peripheral myeloblasts from patients with acute myelogenous leukemia and cultured cells (nonleukemic human lymphocytes, mouse lymphoma L5178Y, and HeLa); as well, 1-beta-D-arabinofuranosylcytosine diphosphate choline was formed in vivo in mouse leukemia L1210 cells and mouse liver. 3-Deazauridine enhanced the anabolism of ara-C in nonleukemic lymphocytes in vitro and leukemia L1210 cells in vivo but did not influence ara-C anabolism in the other cell types. In acute myelogenous leukemia myeloblasts incubated in vitro with ara-C, concentrations of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate were maximal after 8 hr of incubation and formation of the latter preceded that of 1-beta-D-arabinofuranosylcytosine diphosphate choline.
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PMID:Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline in neoplastic and normal cells. 27 75

The use of cytosine arabinoside (Ara-C) infused at kinetically suggested intervals is reported in 40 pediatric patients with acute myelogenous leukemia (AML) and its subtypes. Response was observed in 17 of the 34 evaluable patients. However, the severe, often fatal effects of the regimen prevent its recommendation as a standard induction regimen in AML in children.
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PMID:Remission induction in acute myelogenous leukemia using cytosine arabinoside synchronization: a Southwest Oncology Group Study. 28 96

Paraplegia following prophylactic intrathecal cytosine arabinoside (Ara-C) is described in a patient with acute myelogenous leukemia in remission who received doses of 100 mg/m2/d for 5 consecutive days. Cerebrospinal fluid examination prior to the last dosage of cytosine arabinoside revealed a mononuclear pleocytosis and increased protein. The neurological manifestations developed within one week after the last dose of Ara-C and persisted for over 8 weeks. Administration of intrathecal Ara-C in the same dose over longer intervals within 3-5 days between consecutive doses resulted in mild, transient neurological symptoms (paresthesias) in only one of 30 patients so treated.
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PMID:Paraplegia following intrathecal cytosine arabinoside. 28 37

Cytarabine and thioguanine therapy for acute myelomonocytic leukemia initiated in the tenth week of pregnancy (with the addition of vincristine and rubidomycin at 17 weeks) led to a short complete remission of the leukemia in a 24-year-old primigravida. This is the first case to be reported in which cytarabine was administered in the first trimester and a prostaglandin termination of pregnancy performed at 20 weeks produced an apparently normal fetus. A review of the literature suggests a slightly less than 50% chance of producing a live healthy baby if acute myelogenous leukemia is diagnosed in the first half of pregnancy, with materna mortality approaching 100% by six months postpartum. Current therapy may improve these figures.
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PMID:Consequences of acute myelogenous leukemia in early pregnancy. 33 24

One hundred-sixty-three children with acute nonlymphocytic leukemia (ANLL) were treated with a multiple-drug induction program (PATCO) consisting of prednisone (PDN), cytosine arabinoside ((Ara-C), 6-thioguanine (6-TG), cyclophosphamide (CPM), and Oncovin (VCR). Ninety-six, 59%, obtained a remission. Remission was maintained with daily 6-TG and four-day pulses of Ara-C and CPM with a single dose of VCR every 28 days. The median duration of remission was 11.5 months. Certain prognostic factors affected induction rate and remission duration. Initial white blood count (WBC) was a significant factor in achieving a remission, whereas age, sex, and type of ANLL had no effect. Initial WBC, age, and sex had a significant effect on remission duration, but type of ANLL had no effect. Relapsing patients were treated with daunomycin and 5-azacytidine. The reinduction rate was 53% with a median second remission duration of 190 days. Overall survival for the 163 patients is 55.4% at 12 months, 31.5% at 24 months, 21.4% at 36 months, and 19% at 48 months.
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PMID:Increased survival in childhood acute nonlymphocytic leukemia after treatment with prednisone, cytosine arabinoside, 6-thioguanine, cyclophosphamide, and oncovin (PATCO) combination chemotherapy. 35 21

Adriamycin is now firmly established as a drug with a very broad spectrum of antitumor activity. It has had a major impact on the therapy of sarcomas. The dose response effect in this tumor is steep and combinations which compromise the dose of adriamycin too greatly are showing inferior results. In lung and breast cancer combinations with adriamycin have been extensively tried. The FAC Regimen in breast cancer has given excellent results at the M.D. Anderson Hospital. The inclusion of adriamycin in combinations has had an impact in the poor prognosis histologies of non-Hodgkin's lymphomas. The CHOP regimen is one of the best developed to date for diffuse histiocytic lymphomas. In the leukemias adriamycin is probably equivalent to daunorubicin which has been more extensively used in this country. A new analog called Rubidazone has shown good activity in AML with a smooth induction and its incorporation into combination with Ara-C, vincristine and prednisone in a regimen called ROAP is being investigated. Adriamycin in complex with DNA has been clinically evaluated, but at this time, no advantage for this approach can be demonstrated.
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PMID:Adriamycin and other anthracycline antibiotics under study in the United States. 36 Mar 30

Thirteen leukemic patients with disease refractory to conventional chemotherapy were treated with 1.0 to 7.5 g/m2 of Cytosine Arabinoside (Ara-C) over 29 drug cycles. Drug infusions were spaced at 12-hour intervals; a maximum of four doses was administered over 36 hours. After single dose tolerance had been established, three or four dose cycles were given at 2- to 30-day intervals. There were three partial remissions (PR) and one complete remission (CR) in a treatment group of four patients with AML, five with ALL, two with lymphoma converted to leukemic phase, one CML in blast crisis, and one promyelocytic leukemia. Five of the patients were septic and considered terminally ill at the time of treatment. All other patients had evidence of drug responsiveness. The nadir of the white count occurred from 3 to 12 days after treatment, with subsequent recovery of the peripheral granulocyte count between days 12 and 28. Toxicity included nausea and vomiting (GI symptoms) in twelve patients, central nervous system (CNS) disturbances in eight patients, one episode of inappropriate antidiuretic hormone syndromes (SIADH), one of hyperuricemia, and fever in eleven patients. There was no evidence of hepatic or renal dysfunction. These high doses of Ara-C appear useful for treatment of patients with refractory leukemia. Hospitalization is brief and toxicity acceptable.
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PMID:High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. 49 9


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