Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes. 5 55

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.
 ...
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.
 ...
PMID:Formation of 1-beta-D-arabinofuranosylcytosine diphosphate choline in neoplastic and normal cells. 27 75

1 The pharmacokinetics of cytosine arabinoside were studied after a single i.v. bolus of 2 mg/kg ara-C in patients with newly diagnosed untreated AML, using a bioassay and GC-MS method to measure the plasma concentrations. 2 Most patients showed a bi- or tri-phasic decline in plasma concentrations with time. Plasma clearance was 3.9 to 18.1 l/min as measured by the GC-MS method, and terminal half-lives varied from 7--107 min. 3 There was poor correlation of the GC-MS assay with the bioassay, probably because the latter was interfered with by the release of endogenous nucleosides from blasts after after ara-C. 4 Plasma concentrations were measured by GC-MS during continuous infusions in 14 patients. Plasma clearances were much lower than after a bolus, 0.39 to 5.25 l/min. 5 There was no correlation of response (remission or fall in peripheral blast count) with exposure to ara-C calculated from infusion dose, clearance and duration of infusion. 6 This study shows that ara-C pharmacokinetics varies markedly from patient to patient and that there is a wide range in the plasma concentrations associated with therapeutic response.
 ...
PMID:Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia. 29 36

Forty-six previously untreated patients with acute nonlymphocytic leukemia were treated with a remission induction regimen consisting of three daily doses of Adriamycin (30 mg/m2/day) and a ten-day continuous infusion of cytosine arabinoside (ara C) (100 mg/m2/day). The overall remission rate was 72%, with 88% of the patients less than 50 and 62% of patients greater than 50 years old achieving complete remission status. Thirty-one of the 33 complete remissions occurred after a single course of chemotherapy. Retrospective comparison of this regimen with its predecessor (identical, except that a seven-day infusion of ara C was administered) demonstrated that the increase in duration of ara C administration resulted in greater antileukemic effectiveness without an increase in hematologic toxicity to the patient.
 ...
PMID:Remission induction in acute nonlymphocytic leukemia: comparison of a seven-day and ten-day infusion of cytosine arabinoside in combination with adriamycin. 54 91

Fourteen of 21 adult patients (67%) with acute nonlymphocytic leukemia achieved a complete remission (CR) after receiving combination chemotherapy with daunorubicin and cytosine arabinoside (ara-C). Eight of the 14 CRs developed after a single course and four of 14 after two courses of induction therapy making initial hospitalization relatively brief (median, 38 days). Four of five patients greater than 60 years old achieved CR. The induction therapy was repeated monthly up to the dosage limits imposed by daunorubicin cardiotoxicity in an attempt to lengthen subsequent remission duration. The media duration of CR was 12 months which compares favorably with previously reported series. In this series, treatment with 3 days of daunorubicin and 7 days of ara-C proved to be a highly effective induction regimen for patients with acute nonlymphocytic leukemia regardless of age. The improved duration of CR may be a manifestation of the extent of initial leukemic cell-kill in successful induction and consolidation therapy rather than an effect of maintenance therapy cycles.
 ...
PMID:Chemotherapy for adult acute nonlymphocytic leukemia with daunorubicin and cytosine arabinoside. 92 49

Cytoplasmic and mitochondrial deoxythymidine kinase isozymes derived from the blast cells of acute myelocytic leukemia differ in their substrate specificity and kinetic behavior. These enzymes require divalent cations for their activity. The data suggest that the major role of idvalent cations is to chelate with ATP; the complex thus formed serves as the phosphate donor for the reaction. The activity of various triphosphate nucleosides as a phosphate donor for cytoplasmic deoxythymidine kinase is as follows: ATP = dATP greater than ara-ATP greater than GTP greater than CTP greater than dGTP = dCTP greater than dUTP, whereas for mitochondrial deoxythymidine kinase, the order of activity is ATP greater than CTP greater than UTP = dATP greater than ara-ATP greater than dGTP = dCTP greater than dUTP. Neither IdUTP nor dTTP could serve as a phosphate donor in the reaction catalyzed by either isozyme. From the many pyrimidine analogues tested for their binding affinity to each of these isozymes, I-dUrd and Br-dUrd had high good affinity which was equivalent to that of deoxythymidine. 5-Allyl-dUrd, 5-ethyl-dUrd, and 5-propyl-dUrd were only weakly bound to each isozyme. 5-I-dCyd, 5-Br-dCyd, dCyd, and 5-vinyl-dUrd were tightly bound to mitochondrial deoxythymidine kinase but not to the cytoplasmic isozyme. dTTP and I-dUTP are potent inhibitors of the reaction catalyzed by both isozymes. In contrast, dCTP and ara-CTP are potent inhibitors only of the mitochondrial isozyme, but not of the cytoplasmic isozyme. ATP-MG2+ acts as a sigmoidal substrate of the cytoplasmic isozyme with a"Km" of 0.22 mM, and as a regular substrate of the mitochondrial isozyme with a Km of 0.1 mM. Deoxythymidine acts as a regular substrate for both cytoplasmic and mitochondrial isozyme with a Km of 2.6 and 5.2 muM, respectively. Initial velocity as well as product inhibition studies suggest that the cytoplasmic isozyme catalyzes the reaction via a "sequential" mechanism. In contrast, mitochondrial deoxythymidine kinase catalyzes the reaction via a "ping-pong" mechanism.
 ...
PMID:Human deoxythymidine kinase II: substrate specificity and kinetic behavior of the cytoplasmic and mitochondrial isozymes derived from blast cells of acute myelocytic leukemia. 106 65

We examined the feasibility of maintaining specific plasma concentrations of ara-C and VP-16 in children with AML. Sixty-one children were treated with 6 sequential cycles of intensive chemotherapy consisting of: (1) cytarabine (ara-C)/VP-16, (2) ara-C/daunorubicin (Dauno), (3) VP-16/amsacrine (m-AMSA), (4) VP-16/5-azacytidine (5-Az), (5) ara-C/Dauno, and (6) ara-C/VP-16. Fifty-nine children had de novo AML, and 2 had a previous myelodysplastic syndrome. The number of patients with each specific FAB subtype was: M0-1; M1-7; M2-24; M3-7; M4-5; M5-11; and M7-6. Simultaneous continuous infusions of ara-C and VP-16 (cycle 1) given at individualized doses to achieve drug plasma concentrations of 1 microM and 30 microM, respectively, produced complete remission (CR) in 26 of 61 patients (43%); an additional 17 patients entered CR after Dauno/ara-C (cycle 2), and one patient required 4 cycles of chemotherapy to achieve CR (total CR rate = 72%). The preliminary 2-year event-free survival (EFS) for patients with FAB-M1 and -M2 AML was only 15% versus 40% for those with FAB-M4 and -M5 AML. Overall, 21 of the 61 patients remain in CR (2-yr EFS = 29%). We conclude that intense treatment with ara-C and VP-16 at doses individualized to achieve target plasma concentrations is feasible although severely myelosuppressive. It results in an acceptable CR rate, but does not improve EFS.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Current strategies for treatment of acute myeloid leukemia at St Jude Children's Research Hospital. 137 92

Between 1976 and 1988 we treated 228 children age 18 years or less with AML on three consecutive protocols: Vapa, 80-035 and Hi-C Daze. All three protocols used intensive consolidation chemotherapy. VAPA and 80-035 used an anthracycline with standard dose cytosine arabinoside (ara-c) for remission induction followed by twelve to fourteen months of intensive sequential chemotherapy. Results were similar for these two treatment protocols. 90/125 (72%) of the patients achieved a complete remission with 45% projected disease free survival for the complete responders, and an event free survival of 31%. 8/26 (VAPA) and 3/21 (80-035) relapses were primary CNS. No factor significantly influenced the rate of complete remission, but M4 and M5 FAB subtypes and WBC greater than 100,000/ul predicted for shorter remission duration. 103 children received Hi-C DAZE. The protocol differed by utilizing high-dose ara-c during induction and consolidation and pairing VP-16 with azacytidine. Hi-C DAZE was modified after the first 33 patients (group 1) because of CNS toxicity; VP-16/azacytidine were substituted for high dose ara-c/daunorubicin as the second induction course for the next 70 patients (group 2). Twenty eight of 33 (85%) of group 1 and 54/70 (77%) of group 2 entered remission.
 ...
PMID:Intensive sequential chemotherapy for children with acute myelogenous leukemia: VAPA, 80-035, and HI-C-Daze. 137 93

Two culture methods are available for the study of the blast cells of acute myeloblastic leukemia (AML); first, a minority of blast cells will form colonies in methylcellulose cultures in the presence of suitable growth factors. Second, clonogenic blast cells will increase in suspension cultures. Both methods can be used to assess the sensitivity of blasts to chemotherapeutic drugs, but different dose-response curves are obtained with each. Thus cytosine arabinoside (ara-C) is more toxic to clonogenic blasts in suspension than in methylcellulose, while for 5-azacytidine (5-aza) the reverse is seen. Arabinofuranosyl-5-Azacytosine (ara-AC) combines the chemical features of the two drugs. That is, its sugar moiety has the same diastereomeric change in the furanose ring as ara-C and its pyrimidine ring has the same substitution of nitrogen for carbon at the 5' position as 5-aza. We compared the sensitivity of AML blasts with ara-Ac in suspension and in methylcellulose. As a control, the same comparison was made for the sensitivities to ara-C. Blast cells were less sensitive to ara-AC than to ara-C under all conditions; but, ara-AC sensitivity was greater for cells in methylcellulose than for cells in suspension. Thus, AML blasts respond to ara-AC in culture with a pattern similar to that of 5-aza and opposite to that of ara-C. Since ara-C is a more useful drug in the treatment of AML than 5-aza, we interpret the culture results as predicting that ara-AC may not be effective in AML.
 ...
PMID:A comparison of the lethal effects in culture of cytosine arabinoside and arabinofuranosyl-5-azacytosine acting on the blast cells fo acute myeloblastic leukemia. 138 80


1 2 3 4 5 6 7 8 9 10 Next >>