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 optimal dose of cytarabine for induction chemotherapy is unknown. Most studies have utilized doses of 100-200 mg/m2/d, although higher doses have been proposed to increase the concentration of the active metabolite ara-CTP within leukaemia cells. To address this question 101 adults with newly diagnosed acute myeloid leukaemia were randomized to receive treatment with daunorubicin and either conventional-dose cytarabine (200 mg/m2/d by continuous infusion) or an intermediate-dose of cytarabine (500 mg/m2 every 12 h). 36/51 (71%) patients assigned to conventional-dose cytarabine achieved complete remission compared to 37/50 (74%) who achieved remission with intermediate-dose cytarabine (P = 0.9). Patient age significantly affected remission rate. 8/17 patients age greater than 60 assigned to conventional-dose cytarabine and 10/17 assigned to intermediate-dose cytarabine achieved complete remission compared to 27/33 patients under age 60 assigned to the conventional dose and 28/34 patients assigned to the intermediate dose arm (P = 0.004). Actuarial 4-year disease-free survival for patients assigned to conventional-dose cytarabine was 20 +/- 16% versus 28 +/- 17% for patients assigned to intermediate-dose cytarabine (P = 0.9). We conclude that intermediate dose cytarabine did not substantially improve results of induction chemotherapy for acute myeloid leukaemia.
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PMID:A randomized study of intermediate versus conventional-dose cytarabine as intensive induction for acute myelogenous leukaemia. 164 14

Complete and sustained hemopoietic function following myeloablative therapy can be successfully achieved by autologous transfusion of blood derived hemopoietic stem cells. It was the purpose of this study to compare autologous blood stem cell transplantation (ABSCT) in 20 patients with autologous transplantation of a mafosfamide purged marrow (pABMT) in 23 patients; all were transplanted in first complete remission (CR) of acute myelogenous leukemia (AML) using the same pretransplant regimen (14.4 Gy total body irradiation and 200 mg/kg cyclophosphamide). The autografts, mostly differing in source of hemopoietic stem cells, cell composition and CFU-GM number, were evaluated for their ability to reconstitute hemopoiesis and induce long-term disease-free survival (DFS). Prior to harvest, hemopoietic stem cells were mobilized by inducing transient myelosuppression (ara-C 100 mg/m2 every 12 h s.c. days 1-5 and daunorubicin 45 mg/m2, days 3 and 4) followed by an overshooting of peripheral stem cell concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autologous blood stem cell (ABSCT) versus purged bone marrow transplantation (pABMT) in standard risk AML: influence of source and cell composition of the autograft on hemopoietic reconstitution and disease-free survival. 167 24

A Phase I clinical trial of 1-beta-D-arabinofuranosyl-5-azacytosine (ara-AC or fazarabine) given as a 72-h continuous infusion on a 21-day cycle was conducted in 27 adult patients with refractory cancer. The major toxicity was reversible granulocytopenia and thrombocytopenia. Dose-limiting toxicity was observed at a dose rate of 1.96 mg/m2/h in which Grade IV leukopenia (WBC less than 1,000/mm3) occurred in 4 of 11 patients and Grade IV thrombocytopenia (platelets less than 25,000/mm3) occurred in 3 of 11 patients. Plasma steady-state levels ranged from 0.13 to 0.6 microM for doses of 1.25 to 5.94 mg/m2/h. Mean total body clearance was 647 ml/min/m2. Minor clinical responses were seen in one patient with testicular cancer, one patient with colon cancer, one patient with breast cancer, and one patient with acute nonlymphocytic leukemia. Another patient with adenocarcinoma of unknown primary had stable disease during 13 cycles of therapy. Based on the results of this study, the recommended dose for Phase II studies of 1-beta-D-arabinofuranosyl-5-azacytosine administered as a 72-h continuous infusion is 2.0 mg/m2/h (48 mg/m2/day).
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PMID:Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272). 168 36

Eighteen adult patients under 55 years of age with acute myelogenous leukemia (AML) who entered remission with induction chemotherapy (AMSA-OAP) received two remission intensification cycles. The first intensification used amsacrine and high dose ara-C (AMSA-HDAC), and the second intensification utilized high dose cyclophosphamide, BCNU and VP-16 (CBV) plus unpurged autologous bone marrow transplantation. This double intensified program features two highly active, non-cross-resistant intensification regimens. We observed a 56% long-term disease free survival rate in this group of patients followed for a minimum time of 40 months, with very tolerable toxicity and no transplantation-related deaths. The bone marrow collected after AMSA-HDAC probably contained very low numbers of leukemic cell (in vivo purge). A multivariate logistic regression model may better define the patient population that benefits from this regimen. If these promising findings are confirmed with larger, randomized studies, this treatment strategy could be used in newly diagnosed patients with AML.
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PMID:Double intensification with amsacrine/high dose ara-C and high dose chemotherapy with autologous bone marrow transplantation produces durable remissions in acute myelogenous leukemia. 169 35

Recombinant growth factors have been shown to alter the sensitivity of acute myeloblastic leukemia (AML) blast cells to cytosine arabinoside (ara-C) in culture. The mechanism is controversial and suggestions for it include changes in ara-C metabolism, changes in cell cycle parameters, and changes in the balance between self-renewal and determination in blast stem cells. We addressed this issue by measuring the cisplatin sensitivity of freshly obtained AML blasts in rG-CSF, rGM-CSF, or the two together. For comparison, simultaneous measurements of ara-C sensitivity were made. We found that exposure to different factors in suspension altered the cisplatin sensitivity of AML blasts in the same direction as the change observed in ara-C sensitivity. Similar changes in cisplatin sensitivity were seen when cells were briefly exposed to the drug, washed, and then grown in suspension in the presence of different growth factors. Control experiments showed that the conditions in suspension, not in the clonogenic assay in methylcellulose, were responsible for the changes in cisplatin sensitivity. The capacity of high specific activity to inactivate clonogenicity was tested at several times under growth conditions which altered the sensitivity of cells to cisplatin. Whereas changes in survival after 3HTdR and cisplatin both were seen with time, growth conditions that altered cisplatin sensitivity were not associated with changes in 3HTdR toxicity. The data do not support explanations of the effects of growth conditions on drug toxicity which depend either on drug metabolism or cell cycle effects. Instead, the findings are consistent with a model that postulates an association between drug sensitivity and the balance between self-renewal and differentiation in the blast population.
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PMID:Effects of rGM-CSF and rG-CSF on the cisplatin sensitivity of the blast cells of acute myeloblastic leukemia. 170 68

This paper describes the properties of a continuous cell line derived from the blast cells of a patient with acute myeloblastic leukemia (AML), secondary to the treatment of Hodgkin's disease. The line grows slowly without stimulation but responds to interleukin-3 (IL-3), GM-CSF and mast cell growth factor (MGF), a ligand for the receptor encoded by the c-kit oncogene. When OCI/AML-4 cells are exposed to MGF with IL-3 or GM-CSF, additive or synergistic effects are seen. Combinations of MGF and G-CSF, IL-6 or CSF-1 give less growth than MGF alone. OCI/AML-4 cells are sensitive to retinoic acid; a dose related decrease in clonogenic cells is observed when OCI/AML-4 cells are exposed to retinoic acid in suspension culture. OCI/AML-4 cells are sensitive to cytosine arabinoside (ara-C), but the ara-C dose-response curve can be changed by altering the regulatory milieu in suspension culture. The cells are more ara-C sensitive in MGF or G-CSF than in IL-3 or GM-CSF. Following a 24 h exposure to retinoic acid, the ara-C sensitivity increases; in contrast, after a similar exposure to hydrocortisone, the cells become less ara-C sensitive. These changes in ara-C sensitivity occur in cells that are actively making DNA, as indicated by the reduction in colony formation after exposure to tritiated thymidine. Since OCI/AML-4 cells respond to many of the regulators that affect the growth of freshly obtained AML blast cells, it is proposed that this cell line may be useful for the study of regulation on AML in general and the interaction between different regulators in particular.
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PMID:OCI/AML-4 an acute myeloblastic leukemia cell line: regulation and response to cytosine arabinoside. 171 61

The blast cells of acute myeloblastic leukemia (AML) usually require growth factors for optimum proliferation in cell culture. Growth factors also affect the sensitivity of AML blast cells to cytosine arabinoside (ara-C). Others have reported that factor-treated cells are more ara-C sensitive than blasts in culture without factors. These authors have reported previously that AML blasts grown with rG-CSF, with or without GM-CSF, are more sensitive than cells in GM-CSF alone. This paper reports experiments which show that changes in the ara-C sensitivities of blast cells in different growth factors are not explained by changes in the percentage of cells in the DNA synthesis (S) phase of the cycle. Blasts freshly obtained from five AML patients were cultured in either rG-CSF, rGM-CSF, or rIL-3; they were then exposed to 20 min pulses of either high specific activity tritiated thymidine (3HTdR) or a high concentration of ara-C. Regardless of the factor present, the pulse of 3HTdR decreased the number of clonogenic cells by about 50%, the result expected for actively proliferating cells with an S phase occupying about half the cycle time. The same result was found for four of the five blast cell populations grown in G-CSF and pulsed with ara-C; in contrast, clonogenic cells grown in GM-CSF or IL-3 from these four populations were not killed by ara-C. The blasts from the fifth patient were ara-C resistant under all conditions. It was concluded that exposure to GM-CSF or IL-3 decreased ara-C sensitivity in blasts that were actively making DNA. The observation was explored in more detail using a cell line (OCI/AML-1a) that is both ara-C sensitive and growth factor dependent. These studies showed that about 15 h of growth in factor are required for a change in ara-C sensitivity.
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PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 protect leukemic blast cells from ara-C toxicity. 171 8

The effect of dipyridamole (DP) on the cellular retention of 1-beta-D-arabinofuranosylcytosine (ara-C) and its metabolites was examined in leukemic blasts that had been isolated directly from bone marrow aspirates from patients afflicted with acute myeloid leukemia (AML). When AML cells were loaded for 2 h with 1 microM [3H]-ara-C and then transferred to ara-C-free medium, total intracellular concentrations of radiolabel and [3H]-ara-C 5'-triphosphate [3H]-ara-C-CTP rapidly declined. After 8 h, total intracellular levels of tritium were 4.4 times higher if 10 microM was included in the washout medium; however, the majority of this intracellular radiolabel corresponded to [3H]-uridine arabinoside ([3H]-ara-U) and [3H]-ara-C. DP significantly increased the mean t1/2 for [3H]-ara-CTP from 102 to 136 min (P less than 0.01), but this effect was much less pronounced than that obtained for total tritium and the increase was quite variable (0-70%; median, 19%). The presence of DP in the washout medium also increased the incorporation of ara-C into DNA and the formation of ara-CDP-choline. The level of ara-CDP-choline continued to increase in both DP-containing and DP-free media for the first 4 h following drug removal and the formation of ara-CDP-choline continued during the first few hours in ara-C-free medium. At the end of the 8-h wash in DP-containing medium, the cellular concentration of ara-CDP-choline was equivalent to that found at the beginning of the washout period. Although statistically significant, the effect of DP on ara-CTP retention in AML blasts was much less pronounced than that previously observed in L5178Y leukemia. The former cells exhibited only 10% as many nucleoside transport carriers as did the L5178Y cells as measured by their capacity to bind [3H]-nitrobenzylmercaptopurine riboside (NBMPR). The effect of DP in prolonging ara-CTP retention was proportional to the number of [3H]-NBMPR binding sites. This suggests that in patients cells that exhibit extremely low transport capacity, most of the net catabolism occurs via deamination, and further inhibition of transport by DP in an effort to improve cellular retention of ara-C has little effect on ara-CTP catabolism.
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PMID:Modulation of the cellular pharmacokinetics of ara-CTP in human leukemic blasts by dipyridamole. 173 57

We have prospectively evaluated a regimen of mitozantrone and cytosine arabinoside (Ara-C) as first-line therapy in elderly patients with acute myeloid leukaemia (AML). One hundred and four patients with a median age of 68 (range 60-81) were studied, in whom 86 had de-novo AML, and 18 had preceding myelodysplasia or secondary AML. Complete remission was achieved in 64% of de-novo cases, in 28% of MDS/secondary cases, and in 58% overall. The incidence of early death within 28 d of chemotherapy was 11%. The median disease-free survival (DFS) was 11 months with an actuarial DFS of 15% at 43 months. The median overall survival was 9 months with an actuarial survival of 10% at 44 months. The incidence of non-haematological toxicity was acceptably low, and usually of mild to moderate severity. Quality of life was improved, or unchanged, in 90% of responders. We conclude that mitozantrone and ara-C is an effective and well-tolerated regimen which produces high remission rates in elderly patients with AML.
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PMID:Mitozantrone and cytosine arabinoside as first-line therapy in elderly patients with acute myeloid leukaemia. 158 Dec 25

Bone marrow leukemia cells from eight adults with untreated acute myeloid leukemia (AML) were evaluated before and after three daily leukaphereses to determine if mechanical cytoreduction can modulate the cell cycle distribution. The percentage of cells in S-phase and the proliferative fraction (PF = %S + %G2M) were determined by flow cytometry after dual labeling with bromodeoxyuridine and propidium iodide. Prior to pheresis the median %S and PF were 5.4 and 15.4%, respectively. The median change in %S was +2.5% (range -5.5 to +18.8) with increases greater than or equal to 3.7% in 4/8 patients. The median change in PF was +6.1% (range -13.8 to +25.3) with an increase of greater than or equal to 3.6% in 6/8 patients. The median absolute changes of 2.5 and 6.1% represent increases of 47% for %S and 40% for PF compared to the day 1 (pre-pheresis) median values. As the number of nucleoside transporters in the cell membrane [nitrobenzylmercaptopurine riboside (NBMPR) binding sites] has been related to the percentage of cells in S-phase and to cytosine arabinoside (ara-C) cellular pharmacology, these were also measured before and after leukapheresis. Changes in the number of NBMPR binding sites varied widely with a median increase of 365 sites per cell (range -26,061 to +10,396). The change in NBMPR sites was significantly and positively correlated with changes in %S (r = 0.829, p = 0.042). These data suggest that mechanical cytoreduction by leukapheresis can increase the fraction of leukemia cells in S-phase and the PF in some patients with AML. The increase in %S is accompanied by an increase in NBMPR binding sites per cell. These changes in leukemia cell characteristics would be expected to result in an increase in efficacy of ara-C or other S-phase specific agents.
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PMID:Leukapheresis induced changes in cell cycle distribution and nucleoside transporters in patients with untreated acute myeloid leukemia. 177 52


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