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)

The dose-response relationship between extracellular concentration of cytosine arabinoside (ara-C) and intracellular formation of the putative active metabolites of ara-C [ara-C incorporation into DNA and intracellular pools of ara-C in triphosphate form (ara-CTP)] was investigated in blast cells obtained from patients with acute nonlymphocytic leukemia (ANLL) by exposing these cells in vitro to 10, 100, or 1,000 nmol/L of ara-C. We studied 23 untreated patients who subsequently achieved complete remission (CR) with a regimen using daunorubicin and conventional doses of ara-C (ara-C-sensitive group), and 30 patients judged to be ara-C-resistant either by failing initial induction therapy (16 patients) or by having relapsed on an ara-C-containing maintenance regimen (14 patients). In both patient groups, ara-C incorporation into DNA and intracellular ara-CTP both displayed statistically significant increases in response to increasing extracellular concentrations of ara-C (P = .0001 in both cases), with the rate of increase of ara-CTP greater than that of ara-C incorporation. Moreover, blast cells from all patients, even those who were most clinically resistant to ara-C, were able to form ara-CTP and to incorporate ara-C into DNA. Each tenfold increment in extracellular ara-C concentration caused an 8.5-fold increase in ara-CTP, but only a 3.6-fold increase in ara-C incorporation into DNA. Thus, the efficiency of incorporation of ara-C into DNA (defined as the ratio of ara-C incorporation to ara-CTP pools) decreased by 58% with each tenfold increment in the extracellular concentration of ara-C (P less than .0001), presumably as a result of the inhibitory effect of ara-CTP on DNA polymerase. Using an analysis of covariance, modest differences were found in the levels of the ara-C metabolite variables in the ara-C-sensitive group as compared with the resistant group. However, because there was considerable overlap in ara-C metabolite formation among the patient groups, it was not possible to predict clinical outcome by these in vitro assessments of ara-C metabolism.
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PMID:Metabolism of ara-C by blast cells from patients with ANLL. 371 4

Cytosine arabinoside (Ara-C) is the most effective agent in the treatment of acute myelogenous leukemia. This agent incorporates in leukemic cell DNA, and the extent of this incorporation correlates with loss of clonogenic survival. The incorporated Ara-C residue behaves as a relative DNA chain terminator, and the extent of (Ara-C)DNA formation correlates with inhibition of DNA synthesis. The incorporation of Ara-C into DNA requires the formation of Ara-CTP, and previous measurements of this metabolite have also been correlated with cytotoxicity. Because it is clinically relevant to define biochemical parameters predictive of Ara-C cytotoxicity, the present studies were undertaken to determine the relationship among Ara-CTP pools, formation of (Ara-C)DNA, and loss of clonogenic survival. The results demonstrate that the incorporation of Ara-C into DNA is the single most powerful predictor of cell lethality. Furthermore, although there is a correlation between Ara-CTP pools or continuous cellular exposure to Ara-CTP and cell kill, these relationships are less significant than that obtained with formation of (Ara-C)DNA. The extent of Ara-C incorporation into DNA can be predicted by the product of the Ara-CTP level and time (T), thus supporting the concept that Ara-C incorporation is dependent on continuous exposure to the triphosphate metabolite. These findings support the formation of (Ara-C)DNA as a highly predictive parameter of lethal cellular events.
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PMID:Relationships among Ara-CTP pools, formation of (Ara-C)DNA, and cytotoxicity of human leukemic cells. 658 17

As an in vitro model for the chemotherapy of acute myeloid leukemia with cytarabine (ARA-C), the cytotoxicity of this drug was investigated using a human promyelocytic cell line (HL-60) and different drug schedules. The continuous exposure to ARA-C was shown to be more cytotoxic than the intermittent exposures at identical concentrations or under conditions where the concentrations multiplied by time of exposure were the same. In a comparison of exposures, as the intervals between drug exposures were reduced, the cytotoxicity of ARA-C increased. Flow microfluorometric analysis of DNA content showed that a 3-hour exposure to ARA-C every 6 hours produced a greater accumulation of cells in S phase than the same exposure repeated every 12 hours. After a 3-hour exposure to 20 micrograms/ml of ARA-C, the cells recovered 38% and 85% of their capacity to synthesize DNA within 4 and 8 hours, respectively. These findings can be explained in part by the short half-life of the intracellular nucleotide pool of ARA-CTP in these cells (about 60 minutes). These data indicate that when there is a prolongation of the interval between exposures to ARA-C, a greater fraction of cells recover from the inhibitory effects of this drug and escape its cytotoxic action. These observations may be important with respect to the design of more optimal schedules of high-dose ARA-C therapy for the treatment of patients with acute leukemia.
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PMID:Effect of the interval between exposures to cytarabine on its cytotoxic action on HL-60 myeloid leukemic cells. 659 37

A method for the detection and quantitation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the active metabolite cells and leukemic cells of the peripheral blood from patients receiving ara-C therapy is described. ara-CTP is separated from normal cellular nucleotides by high-pressure liquid chromatography and is quantitated by its absorbance of ultraviolet light at 280 nm with a lower limit of sensitivity of 25 pmol/2 x 10(7) cell equivalents. During separate courses of continuous infusion of different therapeutic doses of ara-C, ara-CTP accumulated in the leukemic bone marrow cells of a patient with acute myelogenous leukemia in proportion to the dose of ara-C. Continuous infusion of ara-C (90 mg/sq m/day) resulted in plateau levels of ara-CPT in peripheral blast cells after 24 hr (115 pmol/1 x 10(7) cell equivalents). A priming dose of ara-C(125 to 250 mg/sq m) followed by a 1-hr infusion of an equal dose of ara-C to patients with acute myelogenous leukemia facilitated the determination of ara-CTP retention in bone marrow and peripheral blood leukemic cells in vivo. This procedure should be useful for extended studies of the biochemical pharmacology of ara-CTP in vivo.
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PMID:Quantitation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in the leukemic cells from bone marrow and peripheral blood of patients receiving 1-beta-D-arabinofuranosylcytosine therapy. 693 39

Ara-C phosphorylation and Ara-C deamination was measured in vitro, using intact marrow myeloblasts from 25 patients with previously untreated acute myeloid leukaemia. At Ara-C concentrations above 10 microM there was no longer a linear relationship of phosphorylation to Ara-C concentration. Ara-U production was measured by sampling the incubation medium. This method showed greater Ara-U production than previous methods sampling the cell pellet alone. However, Ara-CTP/Ara-U ratios from intact myeloblasts were much higher than those recorded in studies using lysed myeloblasts. Using 1 microM Ara-C, a concentration representative of in vivo concentrations, deamination and phosphorylation were related to therapeutic response to Ara-C-containing drug regimens. There was no significant correlation of these variables with response, although 5/16 non-responders had low Ara-C phosphorylation (less than 1.5 pmol/10(6) cells/45 min/l pm Ara-C) compared with 0/9 responders. Measuring deaminase activity did not help in selecting non-responders. Even in patients with low phosphorylation increasing Ara-C concentration increased Ara-CTP levels proportionally, but up to 10 times conventional doses may be necessary to exceed endogenous dCTP levels.
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PMID:The relationship of Ara-C metabolism in vitro to therapeutic response in acute myeloid leukaemia. 695 91

Bone marrow cells of five patients with acute myeloid leukemia were fractionated by means of counterflow centrifugation (elutriation). The different fractions were enriched with cells belonging to subsequent stages of the cell cycle. Cytokinetic evaluation of these cell fractions was performed by [3H]thymidine autoradiography, [3H]thymidine incorporation and DNA/RNA-flow cytometry. Phosphorylation of cytosine arabinoside (ara-C, 1-beta-D-arabinofuranosylcytosine) in the different fractions was measured by incubation of the cells for 30 min with 1.07 microM [3H]ara-C. Phosphorylation of ara-C in the whole bone marrow samples ranged from 5.9 to 33.2 pmol/10(6) cells. In the fractions containing only G1-phase cells, phosphorylation ranged from 1.2 to 19.5 pmol/10(6) cells. The phosphorylation seems to increase before DNA synthesis starts. Maximal activities were found in the fractions enriched with cells in late G1- or S-phase of the cell cycle. In these fractions the ara-C phosphorylating activity was 1.5-8 times higher compared to the fractions with the lowest activity. One may therefore assume that not only S-phase cells are killed by ara-C, but that G1-phase cells which can phosphorylate ara-C, may also be doomed when they enter S-phase, since the elimination of the intracellular cytosine arabinoside tri-phosphate (ara-CTP) is a relatively slow process. The fraction of G1-phase cells phosphorylating ara-C, may be an important determinant in the extent of the cell-killing effect of ara-C treatment in the different leukemias.
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PMID:Variations of the phosphorylation of 1-beta-D-arabinofuranosylcytosine (ARA-C) in human myeloid leukemic cells related to the cell cycle. 696 70

Two areas of investigation are discussed: (a) the identification of critical biochemical parameters that may lead to prediction of response of tumor cells to antimetabolites, such as 1-beta-D-arabinofuranosyl-cytosine (ara-C) and 5-FU, and (b) the potential use of normal purine and pyrimidine metabolites in the selective and specific modulation of critical parameters related to ara-C and 5-FU activity. The results presented indicate a strong correlation between ara-CTP formation and retention in leukemic cells and response of animals with leukemias or patients with acute myelocytic leukemia (AML) treated with ara-C or a protocol containing ara-C. Furthermore, thymidine was found to be an effective modulator of the intracellular pools of dCTP and ara-CTP in rats, bone marrow, small intestine, and colon tumor cells. The mechanism of this effect is unclear, but initial evidence indicates that specific scheduling of the sequential administration of the metabolite and the antimetabolites may be important in determining increased selectivity of antitumor effects. In vivo studies with fluorinated pyrimidines have focused on quantitating 5-fluorodeoxyuridine monophosphate (FdUMP) pools and their retention, and on the incorporation of fluorouridine (FUR) into RNA of sensitive and resistant L1210 cells. The results suggest that the retention of intracellular FdUMP pools above a threshold may be a more critical determinant in selectivity than the initial FdUMP levels achieved in target cells. Thymidine has been demonstrated to alter the pharmacokinetic parameters of 5-FU in man and in mice, but a selective modification of the antitumor activity of 5-FU has not yet been unequivocally demonstrated.
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PMID:Determinants of response to antimetabolites and their modulation by normal purine and pyrimidine metabolites. 704 69

The current study was undertaken to determine the relevance of leukemic blast cell proliferative activity, cellular parameters of Ara-C metabolism and the in vitro sensitivity to GM-CSF in association with the clinical response to TAD-9 induction therapy in 66 patients with de novo acute myeloid leukemia (AML). Proliferative activity was assessed by 3H-thymidine (3H-TdR) incorporation and thymidine kinase (TK) activity, parameters of Ara-C metabolism comprised the activities of deoxycytidine kinase (DCK) and DNA polymerase alpha (poly alpha) as well as Ara-CTP concentrations and 3H-Ara-C uptake into DNA. GM-CSF sensitivity was determined by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4 h concurrent exposure to GM-CSF and 3H-TdR (0.5 microCi/ml). The following results were obtained as expressed by median values and ranges: 3H-TdR incorporation: 1.07 pmol/10(5) cells (0.0-10.1), TK: 7.3 pmol/min/mg protein (1.3-56.0), DCK: 9.3 pmol/min/mg protein (0.77-47.1), poly alpha: 1.7 pmol/min/mg protein (0.00-28.9), Ara-CTP: 53.3 ng/10(7) cells (13.3-211.0), 3H-Ara-C uptake: 0.06 pmol/10(5) cells (0.0-0.57). 3H-Ara-C uptake was correlated with 3H-TdR incorporation (r = 0.74) and with the (S-phase dependent) activities of TK (r = 0.73) and poly alpha (r = 0.71, but not with DCK activity or intracellular Ara-CTP content. Blast cells of 37 from 55 analyzed patients were found to be sensitive to GM-CSF stimulation as defined by an increase in 3H-TdR incorporation > or = 1.5-fold over control values after the 48 h GM-CSF exposure. In vitro data were related with clinical response to TAD-9 induction therapy in 43 patients with newly diagnosed AML, taking the blast cell reduction at day 10 or 16 to < 5% or > or = 5% residual blasts as early parameter for adequate or inadequate response, respectively. While neither 3H-Ara-C uptake, nor intracellular Ara-CTP concentration, TK nor DCK activity were predictive for response, a high 3H-TdR incorporation and a high poly alpha activity were associated with adequate blast cell reduction. Median values of 3H-TdR incorporation were 2.26 pmol/10(5) cells for patients with adequate blast cell clearance and 0.80 pmol/10(5) cells for patients with inadequate blast cell clearance (P = 0.11), the respective values for poly alpha were 3.22 pmol/min/mg protein for responders and 1.1 pmol/min/mg protein for non-responders (P = 0.0085).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Blast cell proliferative activity and sensitivity to GM-CSF in vitro are associated with early response to TAD-9 induction therapy in acute myeloid leukemia. 747 75

Twenty-seven patients with acute myelogenous leukemia (AML) were given remission induction treatment with mitoxantrone, etoposide and cytosine arabinoside (ara-C). The pharmacokinetics in leukemic blood cells of mitoxantrone, etoposide and the active metabolite of ara-C, ara-CTP, were determined during the first day of treatment. There was a large interpatient variability of the area under the time versus concentration curve (AUC) for all three drugs. On the individual level, there was no correlation between the AUCs of the different drugs. Neither did the AUC of any individual drug nor the calculated total intracellular drug exposure have any association with the outcome of treatment or hematological toxicity, measured as duration of leukopenia/thrombocytopenia. In conclusion, when combination chemotherapy with mitoxantrone, etoposide and ara-C is given to patients with AML, intracellular drug concentrations, achieved after the first dose of each drug, do not seem to be predictive for treatment response or hematological toxicity.
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PMID:Pharmacokinetics of mitoxantrone, etoposide and cytosine arabinoside in leukemic cells during treatment of acute myelogenous leukemia--relationship to treatment outcome and bone marrow toxicity. 750 Jun 54

High spontaneous proliferation of acute myeloid leukemia (AML) in vitro is an unfavorable, tumor-specific prognostic factor. We investigated the frequency of drug-resistant tumor cells with high proliferating capacity in de novo AML and analyzed the expression of multiple resistance parameters in relation to the response to chemotherapy and overall survival. Thirty-eight patients were included in this study. P-glycoprotein (P-gp) expression was found in 28/38 patients and was associated with lower intracellular accumulation of DNR (P = 0.0001). Thirty-five out of 38 patients were treated with 1-2 regimens of daunorubicin (DNR)/cytarabine (Ara-C), and 57% attained a complete remission (CR). Failure to achieve a CR correlated with autonomous growth (P = 0.0064), CD34 and P-gp expression alone (P = 0.0005 and P = 0.048 respectively), and with simultaneous expression of P-gp and CD34 (P = 0.0001), but not with expression of the non-P-gp drug resistance associated-protein (p110), the multidrug resistance-associated protein (MRP), Ara-CTP formation or Ara-C incorporation, respectively. AML cells with CD34/P-gp double expression were more frequently observed in samples with high autonomous growth (P = 0.003). The median survival was 6 months in CD34+/P-gp+ patients as compared with 15 months in other AML patients (P = 0.003). In patients with de novo AML who fail on chemotherapy, a population of autonomously proliferating, immature AML cells with a multidrug resistant phenotype can be recognized. These cells thus show primary resistance to chemotherapy and have the potential for rapid regrowth, leading to resistant disease.
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PMID:Multidrug resistant cells with high proliferative capacity determine response to therapy in acute myeloid leukemia. 754 Oct 95


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