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)

In preparation for a clinical trial using GM-CSF on days 4-10 of sequential high-dose cytarabine (ara-C) and asparaginase (ASNase) on days 1-3 and 8-10, potential interactions between the protein synthesis inhibitor ASNase and GM-CSF were evaluated. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can stimulate acute myeloid leukemia (AML) cells to proliferate in vitro and in vivo. Log phase HL-60 cells were exposed to ara-C (10 microM x 3 h) and/or ASNase (10 U/ml during the last 2 h of ara-C). Ara-C and/or ASNase was removed and cells were incubated with or without GM-CSF (10 ng/ml). After 24, 48 and 72 h of GM-CSF there was no significant difference in the S phase fraction of cells exposed to ASNase prior to GM-CSF. Soft agar cloning efficiency was determined after retreatment with ara-C +/- ASNase 24 h into the GM-CSF incubation. GM-CSF enhanced cytotoxicity for all combinations, although this effect was of borderline significance (P = 0.0621); addition of ASNase to the treatment regimen significantly (P = 0.0229) enhanced cytotoxicity without any evidence of a negative interaction with GM-CSF. In addition, ara-C metabolism was assessed during simultaneous exposure to ara-C (10 microM x 3 h) +/- ASNase (10 U/ml the last 2 h) +/- GM-CSF (10 ng/ml beginning 24 h prior to ara-C). Ara-C incorporated into DNA (P = 0.0302) and ara-CTP formation (P = 0.0084 and P = 0.0003 at 2 and 3 h timepoints, respectively) were both increased significantly by GM-CSF, with modest non-significant increases with ASNase exposures. Neither ASNase nor GM-CSF inhibited the effects of the other in this in vitro model. Therefore, when appropriately scheduled, both GM-CSF and ASNase may potentiate ara-C cytotoxicity.
 ...
PMID:GM-CSF and asparaginase potentiate ara-C cytotoxicity in HL-60 cells. 788 38

Patients with acute nonlymphocytic leukemia (ANLL) were treated by continuous infusion of ara-C (100 mg/m2/d x 10 days). During ara-C treatment, cellular arabinofuranosyl cytosine triphosphate (ara-CTP) pharmacokinetics was assessed in the circulating blasts of these patients using a high-performance liquid chromatography (HPLC) and an associated radioimmunoassay. Since a strong correlation was found between achievement of complete remission and cellular ara-CTP levels, we propose a calculation scheme that allows steady-state adjustment of ara-CTP levels during administration of ara-C. To improve the complete remission rate in patients with low ara-CTP levels, we sought optimum ara-C dosing. In order to achieve an optimal therapeutic response, in vivo ara-CTP formation has to be > 50 microM in leukemic cells. Conversely, using the same pharmacokinetic approach, the infusion rate at which to administer ara-C in order to reach in vivo ara-CTP concentration threshold and to achieve complete remission could be calculated for each patient.
 ...
PMID:Calculation of individual dosage regimen of cytosine arabinoside (ara-C) based on metabolite levels in leukemic cells. 797 27

The long-term results in 130 patients with newly diagnosed acute myelogenous leukemia treated with continuous infusion high-dose ara-C (1.5 gm/m2/day x 4 days, CIHDAC) were compared with those in 264 patients treated in previous studies with standard dose ara-C (70-90 mg/m2/d x 7 days) plus either adriamycin (Ad-OAP), or amsacrine (AMSA-OAP). All patients have been followed at least 5 years. Patients in first CR at 5 years (FCR5) treated on protocols prior to CIHDAC had only 5% chance of relapse (median subsequent follow-up of 9 years). Therefore, we considered patients in FCR5 potentially cured. The two groups were similar with respect to known prognostic factors and CR rates. Although remission duration and survival were shorter with CIHDAC than Ad-OAP/AMSA-OAP, the percent of patients potentially cured was similar (10 vs. 15%). Marked differences between regimens were seen in inv(16) and t(15;17) patients. CIHDAC was better for patients with inv(16) with more patients in FCR5 (80 vs. 38%), longer remission duration and survival, and lower incidence of CNS relapse (0 vs. 43%). The Ad-OAP/AMSA-OAP protocols were superior in patients with t(15;17). We also measured steady-state ara-CTP concentrations (ara-CTPss) in 54 CIHDAC-treated patients presenting with high-blast count. While there was no correlation between ara-CTPss and response duration, all five patients in FCR5 in whom ara-CTPss was measured had high concentrations. These data support the concept that patients with AML should be treated differently according to cytogenetics. Inv(16) patients should be treated with high-dose ara-C while t(15;17) should rely more on anthracycline exposure.
 ...
PMID:Long-term results following treatment of newly-diagnosed acute myelogenous leukemia with continuous-infusion high-dose cytosine arabinoside. 805 60

The purpose of this paper was to ascertain whether results obtained in cell cultures of AML clonogenic blast cells would provide a useful model for a clinical regimen that combines fludarabine (F-ara-AMP) and cytosine arabinoside (ara-C). In the cultures the nucleoside F-ara-A was used. Blast cells from the continuous lines OCI/AML-2 and OCI/AML-3 were grown, either in methylcellulose to quantify clonogenic cells, or in suspension to measure self-renewal as reflected in changes in numbers of clonogenic cells. F-ara-A, like ara-C, was found to be more toxic to blast stem cells in suspension than in the clonogenic assay, indicating that F-ara-A might, in addition to general cytotoxicity, have some specific inhibitory effects on self-renewing stem cells. F-ara-A was less cytotoxic than ara-C; but, when F-ara-A was given before ara-C, synergism was seen at some F-ara-A doses, as manifested by increased ara-C cytotoxicity. In contrast, when ara-C was given before F-ara-A, protection was observed. Control experiments make it unlikely that this effect is related to changes in the cell cycle following ara-C exposure. We conclude that the cellular studies reported here confirm previous pharmacological data indicating that F-ara-A before ara-C increases the effectiveness of ara-C by increasing the accumulation of ara-CTP. However the present experiments show that the synergism between F-ara-A and ara-C is dependent on both dose and schedule.
 ...
PMID:A cell culture model for the treatment of acute myeloblastic leukemia with fludarabine and cytosine arabinoside. 832 Oct 50

The effect of human recombinant GM-CSF (rGM-CSF) on the metabolism of high dose ara-C was determined in bone marrow mononuclear cells (BMMCs) from eight normal volunteers and from seven patients with acute myelogenous leukemia (AML). We incubated the cells with rGM-CSF alone, ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF for 16 h increased the percentage of cells in S-phase both in normal BMMCs and leukemic marrow cells. The treatment with rGM-CSF alone produced an approximately two-fold increase in the intracellular dCTP pools in normal BMMCs, but this increment was not observed in leukemic marrow cells. Simultaneous exposure to rGM-CSF in combination with ara-C increased cytosine arabinoside triphosphate (ara-CTP) pools in leukemic blasts. In contrast, this treatment decreased ara-CTP pools in normal BMMCs. Moreover, when the cells were preincubated with rGM-CSF for 16 h prior to the exposure to ara-C, leukemic blasts achieved a 7-fold higher ara-CTP/dCTP ratio as compared with normal marrow cells. Treatment of the cells with rGM-CSF, either simultaneously or sequentially, resulted in significantly greater amounts of ara-C incorporation into DNA in leukemic marrow cells than normal counterparts. The higher accumulation of ara-CTP and subsequent increased incorporation of ara-C into DNA in leukemic cells treated with rGM-CSF lead to the enhanced ara-C-mediated inhibition of DNA synthesis as compared with normal BMMCs. The selective accumulation of ara-CTP in leukemic vs normal cells have implications for the efficacy of the treatment of AML patients with high dose ara-C and rGM-CSF.
 ...
PMID:Recombinant GM-CSF modulates the metabolism of cytosine arabinoside in leukemic cells in bone marrow. 832 41

There is a strong association between ability of leukemia blasts to accumulate ara-CTP, the active metabolite of ara-C, and response to ara-C in patients with relapsed or refractory AML. Ara-C dose rates in excess of 0.5 g/m2/h do not produce further ara-CTP formation. In contrast, when given 4 h prior to ara-C at this dose rate, fludarabine, at doses that are free of neurotoxicity in CLL, enhances ara-CTP accumulation. This led us to administer fludarabine and ara-C to 59 patients with AML in relapse or unresponsive to initial therapy. Fludarabine was given at 30 mg/m2 once daily for 5 doses and ara-C at 0.5 g/m2/h for 2-6 h daily for 6 doses. Doses of fludarabine preceded those of ara-C by 4 h. Results with fludarabine and ara-C (FA) were compared with those of patients treated at M.D. Anderson with high-dose ara-C (HDAC) or intermediate-dose ara-C (IDAC). The complete remission rate with FA was 21/59 (36%) and the actuarial median CR duration 39 weeks. FA produced significantly higher remission rates than HDAC or IDAC in patients with initial remissions > 1 yr (14/20 vs 9/23 vs 6/18, p < 0.05). Response rates were similar for all three treatments in patients with initial remissions < 1 yr or with primary refractory disease. The regimen was well tolerated; one patient developed peripheral neuropathy. This low level of toxicity encourages combination with other antileukemia agents.
 ...
PMID:Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. 839 69

Cytosine arabinoside (ara-C) and etoposide are often used in combination in the treatment of acute myelocytic leukemia (AML). The intracellular phosphorylation of ara-C to its 5'-triphosphate (ara-CTP) is a prerequisite for its cytotoxic effects. It has been shown in vitro that etoposide can impair the formation of ara-CTP in leukemia cells. The present study was undertaken in order to elucidate whether this interaction may be of clinical importance. Leukemia cells were isolated from 3 patients with acute myelocytic leukemia and incubated in medium (RPMI-1640) with or without 10% fetal calf serum or in human plasma. When the cells were incubated in RPMI-1640 with ara-C (10 mumol/l) and etoposide during 2 h, the formation of ara-CTP was decreased to 71 +/- 18 (mean +/- S.D.) and 30 +/- 15% of control at 1 and 10 micrograms/ml etoposide, respectively. When the cells were incubated in human plasma, the formation of ara-CTP was not influenced by the presence of etoposide (101 +/- 6 and 103 +/- 20% at 1 and 10 micrograms/ml etoposide). When incubated in RPMI supplemented with 10% fetal calf serum, the corresponding figures were 81 +/- 8 and 70 +/- 20%. Six patients with AML were therefore treated with ara-C 0.5 or 1.0 g/m2 as a 2-h infusion every 12 h and, during 1 h before the second ara-C infusion, 100 or 200 mg/m2 etoposide was administered. The median change in the AUC of cellular ara-CTP between the first and second ara-C dose was 0% (-37 to +21%). The corresponding median change in rate of accumulation of ara-CTP in leukemia cells was 12% (-26 to +110%). The concentration of etoposide in plasma during the ara-C infusion was 18.7 +/- 5.1 micrograms/ml while the non-protein bound etoposide was 0.73 +/- 0.34 micrograms/ml. Thus, despite exposure to higher etoposide concentrations in vivo than in vitro, no impairment of ara-CTP formation was seen in the patients. This corresponds to the results obtained when leukemic cells were incubated in plasma. It is concluded that the inhibition of ara-CTP formation by etoposide seen in vitro is offset by the high protein binding of etoposide in plasma (96%) and that etoposide does not impair the formation of ara-CTP in leukemia cells in vivo during treatment with standard-dose etoposide.
 ...
PMID:On the interaction between cytosine arabinoside and etoposide in vivo and in vitro. 843 10

Analysis of different ribonucleotide reductase inhibitors to modulate arabinosylcytosine (ara-C) metabolism suggested that pretreatment with arabinosyl-2-fluoroadenine (F-ara-A) significantly potentiated the rate of ara-CTP (5'-triphosphate of ara-C) accumulation in both quiescent lymphocytes (p = 0.046) and in cycling blasts (p = 0.017). In vitro incubations of freshly isolated leukemia cells from patients with chronic (n = 7) or acute (n = 5) leukemias with F-ara-A, increased the rate of ara-CTP accumulation by a median of 1.5 or 1.7-fold, respectively, when subsequently incubated with ara-C. The objective of the present investigation was to test the hypothesis that ara-C can be biochemically modulated during therapy of leukemias. To test the biochemical modulation of ara-C in the clinical setting, we designed two protocols to administer fludarabine (clinical formulation of F-ara-A) and ara-C in a pharmacologically directed sequence for patients with chronic lymphocytic leukemia (CLL) refractory to conventional fludarabine therapy or for patients with acute myelogenous leukemia (AML) in relapse. Comparison of ara-CTP pharmacokinetics demonstrated a significant increase in the area under concentration curve (AUC) of ara-CTP both in CLL (median 1.5-fold) and AML cells (median 1.8-fold) after fludarabine infusion. Analyses of different processes involved in the metabolism of ara-CTP indicated that the increase in AUC was due to potentiation of the rate of ara-CTP accumulation. These studies demonstrate that protocols designed on biochemical and pharmacological rationales modulate ara-C metabolism during therapies.
 ...
PMID:Biochemical modulation of arabinosylcytosine for therapy of leukemias. 848 60

Cytosine arabinoside (Ara-C) is one of the most effective drugs in inducing remission in acute nonlymphocytic leukemia (ANLL) patients. However, the high recurrence rate indicates that a subpopulation of leukemic cells escapes drug effect. This cellular heterogeneity in drug response may play a major role in chemotherapeutic outcome. We have recently developed the individual colony-formation assay (ICFA) to study drug effects on the kinetics of proliferation of individual cells and their progeny. Thus parameters of proliferation are calculated for individual colonies. Three categories of drug responses were defined, including immediate growth cessation, delayed growth cessation (growth stops several days after drug exposure) and growth slowdown (logarithmic growth at a reduced rate compared to control). In the experiments included in this report, murine leukemia (L1210) cells were exposed to various concentrations of Ara-C for 1, 6 or 24 hours, and their responses quantified. Regardless of the Ara-C concentration or exposure time, subpopulations of cells were observed in each of the three response categories: immediate or delayed arrest or growth slowdown. As expected, the fraction of cells exhibiting immediate growth cessation generally increased with increasing drug dose and was markedly increased with longer exposure time. Delayed arrest was most prevalent at intermediate drug concentrations at all exposure times. If exposure was limited to 1 hour, at least 30% of cells continued to grow, although at a reduced rate (71% control rate after exposure to 1 mM Ara-C). This limited effect was paralleled by saturation of Ara-C triphosphate (Ara-CTP) formation. Six-hour exposure left at least 6.4% of cells growing, with an average rate of 45% of control. Under these conditions, no saturation in Ara-CTP formation was observed. Even 24-hour exposure to 5 microM Ara-C left 4.8% of colonies growing, at 42% of control rate. Thus a subpopulation of cells continued to grow even after 24-hour exposure to a relatively high concentration of Ara-C. Surviving, but slowly growing, cells may represent a previously unrecognized population that may contribute to therapeutic failure.
 ...
PMID:Characterization of tumor cell heterogeneity of a murine leukemia cell line (L1210) in response to arabinosylcytosine: quantitation using a computerized image analysis system. 851 59

The effectiveness of arabinosylcytosine (ara-C) for the treatment of acute myelogenous leukemia (AML) depends on the formation of its active metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical modulation strategies to increase the accumulation of ara-CTP in leukemia blasts, a clinical protocol was designed combining 2-chlorodeoxyadenosine (CdA), an inhibitor of ribonucleotide reductase, and ara-C for adults with AML. The protocol stipulated an infusion of 1 g/m2 of ara-C over 2 hours on day 1. A continuous infusion of CdA (12 mg/m2/d) begun 24 hours later and continued for 5 days. Identical doses of ara-C were administered on days 3, 4, 5, and 6. Pharmacokinetic and pharmacodynamic interactions between CdA and ara-C during therapy were investigated. To complement these studies, molecular actions of the triphosphate of ara-C and CdA on DNA extension by human DNA polymerase alpha in an in vitro model system was conducted. In the circulating leukemia blasts of 7 of the 9 patients studied, ara-CTP pharmacokinetics showed a median 40% increase in the rate of ara-CTP accumulation after 24 hours of CdA infusion. The ex vivo effect of CdA on accumulation of ara-CTP in AML blasts was similar to that during therapy except that the enhancement was less. The DNA synthetic capacity of the circulating blasts was inhibited to a greater extent by administration of CdA and ara-C in combination than by either one alone. Additionally the lowered level of DNA synthesis was maintained until the next infusion of ara-C. Endogenous levels of deoxynucleotides increased 24 hours after ara-C infusion. Administration of CdA in general lowered the concentrations of all dNTPs. DNA pol alpha incorporated CdATP and ara-CTP with high affinity in a DNA primer extending over an oligonucleotide template of defined sequence. Human DNA polymerase alpha extended DNA primers terminated by CdA monophosphate (CdAMP) at its 3'-end by incorporating ara-C monophosphate (ara-CMP). The tandem incorporation of CdAMP and ara-CMP resulted in nearly complete inhibition of DNA primer extension. The insertion of two analogs in sequence, inhibition of ribonucleotide reductase, and the metabolic potentiation of ara-CTP by CdA infusion may be responsible for sustained inhibition of DNA synthesis in the circulating leukemia blasts during therapy with this combination regimen.
 ...
PMID:Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions. 854 50


<< Previous 1 2 3 4 5 6 7 8 9 Next >>