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)

Human acute myelocytic leukemia (AML) marrow cells respond to stimulation with increased proliferation and enhanced intracellular metabolism of the cytotoxic antimetabolite 1-B-D arabinofuranosylcytosine (ara-C). Our previous studies have focused on the drug-induced humoral stimulatory activity (HSA) present in serum following initial cytoreduction which augments in vitro growth and biochemical pharmacology. The activity of HSA likely relates to the presence of multiple stimulators. The effect of 18-hr culture in purified recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (1 ng/ml) on in vitro AML marrow cell [3H]dThd incorporation into DNA, intracellular ara-C activation to the triphosphate form (ara-CTP), and subsequent ara-CTP retention were determined in leukemic cells of 11 patients and compared with cells similarly cultured in HSA-containing sera. The stimulatory effects of rhGM-CSF and HSA on both growth and pharmacologic parameters were comparable for each AML population, with maximal response to both regulators detected for FAB M2. These data demonstrate that GM-CSF acts similarly to HSA as an active stimulator of leukemic cell proliferation and net intracellular ara-C metabolism in vitro, and support clinical trials designed to examine the role of rhGM-CSF in enhancing ara-C cytotoxicity by increasing the growth fraction of drug-responsive target cells in vivo.
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PMID:Effects of rhGM-CSF on intracellular ara-C pharmacology in vitro in acute myelocytic leukemia: comparability with drug-induced humoral stimulatory activity. 220 33

We evaluated relationships between ara-CTP pharmacokinetics in myeloblasts, response, and karyotype in 147 patients with newly diagnosed AML treated on three protocols each initiated by a 3 g/m2 ara-C dose given over 2 h. Area under the curve of ara-CTP concentration times time (AUC) or peak ara-CTP concentration after this dose did not predict response or response duration, suggesting that inability to form ara-CTP is an unlikely mechanism of ara-C resistance. Following high-dose bolus ara-C therapy patients with INV [16] or del [16q] had long remissions despite low AUC and peak values while patients with -5, del [5q], -7, or del [7q] were frequently resistant despite average AUC and peak values. In 55 patients treated with high-dose continuous infusion ara-C as a single agent, steady-state ara-CTP concentrations were significantly lower in resistant patients (who again were disproportionately those with -5, del [5q], -7, or del [7q]) although there was no correlation with CR duration.
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PMID:Cellular ara-CTP pharmacokinetics, response, and karyotype in newly diagnosed acute myelogenous leukemia. 230 61

The potential usefulness of cytosine arabinoside (ara-C) in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) was studied by measuring the influx of ara-C into the lymphoblasts and the conversion of ara-C to its triphosphate form (ara-CTP) in lymphoblasts from the bone marrow of eighteen patients of T-ALL. Intracellular accumulation of ara-CTP was 3.5 times greater in T-cell lymphoblasts than in non-T or AML blasts. The increased formation of ara-CTP in T-ALL cell may be correlated with the good clinical response of T-ALL patients to the treatment with ara-C in combination with mitoxantrone.
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PMID:Efficient formation of cytosine arabinoside-5'-triphosphate in leukemic blasts of human T-cell acute lymphoblastic leukemia. 258 46

We hypothesized that the steady-state concentration of intracellular cytarabine 5'-triphosphate (ara-CTPss) in leukemia cells is proportional to the dose rate of cytarabine (ara-C) during continuous infusion. To evaluate this possibility, patients with acute myelogenous leukemia in relapse were treated with two sequential schedules of serially increasing ara-C dose rates over a total of 36 hours. Schedule I consisted of serial infusions of 250, 500, and 750 mg/m2 each over 12 hours. Subsequently, patients entered on schedule II received 500, 1,000, and 1,500 mg/m2 serially, each over 12 hours. Steady-state levels of ara-CTP were achieved within four hours after beginning ara-C infusion and, in separate studies of a single ara-C dose rate, were shown to be maintained beyond 36 hours. Four patients treated with schedule I and two patients treated with schedule II showed a linear dose rate-dependent increase-of ara-CTPss at all three dose rates. The cells of one patient on schedule I and two patients on schedule II had a dose rate-dependent ara-CTPss increase only over the first two dose levels, while no increase or lower ara-CTPss was observed at the third dose rate. The ara-CTPss of one patient on schedule II did not change. These results suggest that there is a proportionality between the continuous infusion dose rate of ara-C and the ara-CTPss in circulating leukemia cells within the dose range of 250 to 1,000 mg/m2 over 12 hours. This opens the possibility that pharmacologic determinations may be used to redirect the ara-C dose rate to achieve a desired ara-CTPss level in leukemia blasts during therapy.
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PMID:Patient-specific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia. 270 90

The accumulation of cytosine arabinoside-5'-triphosphate (ara-CTP), the activities of nucleotide-metabolizing enzymes and the nucleoside transport capacity were examined in eleven human leukemic cell lines differing in phenotype. The highest amount of ara-CTP was accumulated in T-acute lymphoblastic leukemia cells (T-ALL), followed by myeloid leukemia cell lines (AML), and the least accumulation was observed in common acute lymphoblastic leukemia (c-ALL) and B-acute lymphoblastic leukemia cells (B-ALL). The levels of enzymes involved in ara-C metabolism (deoxycytidine kinase, pyrimidine monophosphate kinase and deoxycytidylate deaminase) did not correlate with ara-CTP accumulation. The sensitivity of the leukemic cell lines to ara-C, which was measured in terms of decrease of clonogenic survival, correlated with the amount of ara-CTP formed. Moreover, the nucleoside transport capacity, estimated from the binding of the radiolabeled nucleoside analogue, [3H]nitrobenzylthioinosine, showed a good correlation with ara-CTP accumulation. The mean numbers of nucleoside-binding sites in T-ALL cells were significantly greater than in B-ALL cells. We conclude that the cellular nucleoside transport capacity is the most important factor for the formation and accumulation of ara-CTP in the cells.
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PMID:Formation of cytosine arabinoside-5'-triphosphate in cultured human leukemic cell lines correlates with nucleoside transport capacity. 311 33

Plasma level of cytosine arabinoside (Ara-C) and intracellular cytosine arabinoside triphosphate (Ara-CTP) in peripheral blood and bone marrow were measured in 8 patients with non treated acute myelogenous leukemia. Ara-C was administered by 1 hr infusion (3 g/m2 and 500 mg/m2) and was followed for 12 hrs. The AUC of Ara-C in plasma following 3 g/m2 infusion were greater than the 500 mg/m2 (p less than 0.05). Intracellular Ara-CTP in peripheral blood following 3 g/m2 and 500 mg/m2 infusions were on the same level, after 1 hr. But AUC of intracellular Ara-CTP following 3 g/m2 infusion was greater than 500 mg/m2. There was a correlation between AUC of Ara-C in the peripheral blood (p less than 0.01). Intracellular Ara-CTP in the bone marrow and peripheral blood showed a similar level. Intracellular Ara-CTP in bone marrow was lower than in peripheral blood, however, there was no correlation between intracellular Ara-CTP in bone marrow and in peripheral blood.
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PMID:[Relation between plasma Ara-C and intracellular Ara-CTP levels by intermediate dose and high dose Ara-C administration in the treatment of AML]. 316 69

Human recombinant GM-CSF (rGM-CSF) is under investigation as a growth-protective agent for normal hematopoietic elements in phase I trials of myelosuppressive chemotherapy and in bone marrow transplantation. We determined the effect of rGM-CSF on the metabolism of high dose Ara-C in bone marrow mononuclear cells (BMMCs) from healthy volunteers and patients with ANLL. Cells were incubated with rGM-CSF alone, Ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF alone yielded approximately a twofold increment in intracellular dCTP pools in normal BMMCs but not in leukemic blasts. Exposure to rGM-CSF in conjunction with Ara-C corrected Ara-C-mediated declines in dCTP levels and decreased cytosine arabinoside triphosphate (Ara-CTP) accumulation in normal BMMCs but not in their leukemic counterparts. Furthermore, when exposure to Ara-C was preceded by treatment with rGM-CSF for 18 hr, an even greater reduction in the Ara-CTP/dCTP pool ratio was observed in normal versus leukemic elements; however, this did not significantly change Ara-C DNA incorporation in the two cell types. The differential effect of rGM-CSF on the phosphorylation of Ara-C in normal BMMCs versus leukemic blasts has potential implications for the use of a regimen consisting of rGM-CSF and high dose Ara-C in the treatment of ANLL with chemotherapy or autologous bone marrow transplantation.
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PMID:Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. 326 63

The cytotoxic effect of cytosine arabinoside (ara-C) depends on the capacity of cells to form and retain intracellularly the phosphorylated metabolite cytosine arabinoside triphosphate (ara-CTP). In this study accumulation and cellular retention of ara-CTP have been measured in vitro in the bone marrow cells of 69 patients with acute leukemia. Cells were incubated with 3H-ara-C and the amount of ara-CTP formed was determined after separation of the nucleotides by thin-layer chromatography. Phosphorylation of ara-C to ara-CTP appeared to be a saturable process. The Km-equivalents varied between 1.1 and 16.2 microM ara-C. Maximal ara-CTP formation ranged from 12 to 125 pmol ara-CTP/10(6) cells in 30 min. The phosphorylation activity did not correlate with the percentage of S-phase cells. The intracellular half-life time of ara-CTP measured in vitro ranged from 53 to 210 min. Phosphorylation of ara-C was comparable in patients with acute myeloid leukemia (n = 51) and in patients with acute lymphoblastic leukemia (n = 18). Ara-CTP elimination appeared slower in lymphoblasts than in myeloblasts. The average intracellular ara-CTP level in relapsed patients (n = 34) appeared higher than in previously untreated patients (n = 52). The less favourable outcome of second remission induction therapy with conventional doses of ara-C compared to the first remission induction treatment is not explained by an alteration in the intracellular metabolism of ara-C.
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PMID:In-vitro studies on phosphorylation and dephosphorylation of cytosine arabinoside in human leukemic cells. 347 May 78

In consideration of the full spectrum of hematologic and nonhematologic toxicity juxtaposed to the response rates (Tables 2-5), it appears that for relapsed patients with AML, six to eight consecutive doses of HDara-C or four doses started on days 1 and 8 have the optimal therapeutic index. These regimens are associated with a 25% CR rate and have comparable tolerable and reversible toxicity spectra. An increase in the total number of doses to 12 does not appear to increase the remission frequency in relapsed patients but does decidedly increase the spectrum, frequency, and severity of toxic manifestations. Studies of important pharmacologic determinants such as membrane transport and cellular accumulation of ara-CTP suggest that a lower unit dose may be just as effective, an approach that could potentially lower the frequency and severity of toxicity. However, these concepts must be tested in suitably designed clinical trials. In contrast to the response rate noted in patients with relapsed AML, patients with refractory AML have a substantially lower CR rate (approximately 10%) when treated with HDara-C alone. These lower CR rates are comparable to those reported for other recently introduced new drugs such as m-AMSA and mitoxantrone. In this setting of primary refractory leukemia, multi-institutional and cooperative group trials of HD-ara-C----ASNase show a consistently higher response rate in the range of 30% to 50%. Why ASNase should especially contribute to this particular group is unknown at present. Studies show that the gene for asparagine synthetase is repressed in AML cells. It is speculated that in the initial leukemia cell population (as encountered in refractory AML), the gene for asparagine synthetase is repressed and hence, the leukemia is sensitive to ASNase. In contrast, in the relapsed patient with recurrent leukemia, the gene for asparagine synthetase may be derepressed and the leukemia would be ASNase-insensitive. The therapeutic index of HDara-C----ASNase is schedule dependent. In leukemic mice, pretreatment or concurrent administration of ASNase and HDara-C leads to antagonism of both the therapeutic and toxic effects of HDara-C. These effects are consistent with similar effects of other protein synthesis inhibitors on ara-C toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sequential high-dose ara-C and asparaginase versus high-dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias. 358 97

We examined the ability of high concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) to reverse the cytotoxicity of high (eg, greater than or equal to 10(-5) mol/L) concentrations of 1-B-D arabinofuranosylcytosine (Ara-C) toward normal (CFU-GM) and leukemic myeloid progenitor cells (L-CFU). Leukemic myeloblasts from patients with acute nonlymphocytic leukemia (ANLL) and normal human bone marrow mononuclear cells were cultured in soft agar in the continuous presence of 10(-5) to 5 X 10(-5) mol/L of Ara-C together with dCyd (10(-4) to 5 X 10(-3) mol/L). Administration of 10(-5) mol/L of Ara-C alone eradicated colony formation in all samples tested. Coadministration of 10(-3) mol/L of dCyd restored 72.2% of control colony formation for CFU-GM, but only 10.9% for L-CFU. When higher concentrations of Ara-C (eg, 5 X 10(-5) mol/L) were administered, dCyd-mediated protection toward CFU-GM decreased, but remained significantly greater than that observed for L-CFU. Incubation with 10(-3) mol/L of dCyd reduced the 4-hour intracellular accumulation of the triphosphate derivative of Ara-C (Ara-CTP) in both normal and leukemic cells by greater than 98%; under identical conditions, a significant expansion of the intracellular of the triphosphate derivative of dCyd (dCTP) pools was observed in normal bone marrow mononuclear cells but not in leukemic blasts. This finding was associated with a greater reduction in Ara-C DNA incorporation in normal elements. These in vitro studies suggest that dCyd may preferentially protect normal v leukemic myeloid progenitor cells from the lethal actions of high-dose Ara-C.
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PMID:Deoxycytidine preferentially protects normal versus leukemic myeloid progenitor cells from cytosine arabinoside-mediated cytotoxicity. 360 88


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