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)

Since the differentiating effect of high-dose methylprednisolone (HDMP) on myeloid leukemic cells has been shown in one of our patients with acute myeloblastic leukemia (AML-M4), 27 previously untreated children with AML were given HDMP (20-30 mg/kg per day) combined with cytosine arabinoside (Ara-C; 3 mg/kg) for the first 2 weeks of induction therapy. Marked clinical improvement was observed in all patients with the exception of one who died within 24 hours of the treatment. Enlarged liver and spleen (greater than 5 cm) became nonpalpable in 3 (37%) out of 8 and 5 (100%) out of 5 patients, respectively, and bone marrow blasts decreased below 5% in 7 patients (27%) within 2 wk of HDMP and Ara-C treatment. Adriamycin (1 mg/kg) was added 2 wk after initiation of induction therapy. Twenty-two (84.6%) of the 26 patients achieved complete remission, 3 (11.5%) had partial remission and no response was obtained in one. Treatment was well tolerated. The addition of HDMP as a differentiating and/or cytolytic agent to conventional anti-leukemic chemotherapy increased the complete remission rate and prolonged the duration of remission of our AML patients.
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PMID:High remission rate in acute myeloblastic leukemia in children treated with high-dose methylprednisolone. 159 2

The in vitro growth activities and drug sensitivities of leukemic blast progenitors were compared among the subgroups of acute myelocytic leukemia (AML) classified according to the French-American-British (FAB) cooperative group. Leukemic cells separated from the peripheral bloods of AML patients were cultured in methylcellulose media, and the plating efficiencies of primary colonies (PE1) and secondary colonies after replating (PE2) were determined. PE1 and PE2 have been considered to reflect the capacities of terminal divisions and self-renewal of leukemic blast progenitors, respectively. PE1 and PE2 were variable among AML patients; these findings suggest that AML is a heterogeneous disease in terms of the proliferative activities of leukemic cells. No significant correlation was noted between PE1 or PE2 and the AML subtype. The sensitivities to cytosine arabinoside (Ara-C) of leukemic blast progenitors were studied in methylcellulose and suspension cultures. Ara-C sensitivity was not significantly correlated with the AML subtype, either. In contrast, there was statistically significant correlation between PE2 and the remission outcome of the patients, whereas PE1 was not significantly associated with the clinical outcome. The results in the present study indicate that the proliferative activity, especially self-renewal capacity, of leukemic blast progenitors is highly predictive of the prognosis of AML patients but is not significantly correlated with the AML subtype classified by the blast morphology.
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PMID:The in vitro growth patterns and drug sensitivities of leukemic blast progenitors among the subtypes of acute myelocytic leukemia. 162 9

Thirty-four consecutive patients with either relapsed (n = 28) or primary refractory AML (n = 6) were treated with one or two cycles of intermediate-dose (ID) cytosine arabinoside (Ara-C) (1 g/m2 i.v. q 12 h days 1-6) and amsacrine (m-AMSA) (120 mg/m2 i.v. days 5-7). Patients reaching complete remission (CR) were consolidated with one cycle of Ara-C 3 g/m2 i.v. q 12 h days 1-4 and m-AMSA 120 mg/m2 i.v. day 5. The median duration of the preceding remission was 8 months and median time from last chemotherapy until relapse 3.1 months. Of the relapsed patients, 22/28 (79%) achieved CR regardless of the type of prior intensive maintenance (HD Ara-C/m-AMSA/5-azacytidine) (AZA) or daunorubicin (DNR/CD-Ara-C). Three of the 28 (11%) patients died during hypoplasia; 3/28 (11%) were refractory to 2x ID-Ara-C/m-AMSA. Three of the 28 patients died in CR during hypoplasia after intensive consolidation with HD-Ara-C. Predictive factors for remission were duration of preceding remission and the time from last chemotherapy to relapse. Three patients were transplanted in second CR. One of the six refractory patients reached CR, two remained refractory, and three died during hypoplasia. The median duration of disease-free survival (DFS) of relapsed patients was 3.3 months without further treatment; median survival of responding patients (20 relapsed patients, 1 refractory patient) was 4.5 months, overall survival (n = 29) was 4.8 months. Patients receiving BMT were censored at the time of BMT. Seven patients experienced lung toxicity due to Ara-C, four of whom died.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intermediate-dose Ara-C/m-AMSA for remission induction and high-dose Ara-C/m-AMSA for intensive consolidation in relapsed and refractory adult acute myelogeneous leukemia. 169 Nov 34

Clinical, haematological, cytogenetic features and therapeutic problems of 51 patients with MDS were examined. Patients were distributed in 5 FAB subgroups: RA 21, SA 7, RAEB 8, RAEB-t 9 and MMCL 6 patients. Leukaemic transformation occurred in 3 RA, 3 RAEB, 7 RAEB-t and 3 MMCL patients. No SA patient suffered from leukaemic transformation. Cytogenetic alterations occurred in 13 of 29 examined patients; 5q- was the most common abnormality. We did not find any relation between chromosomal anomalies and FAB subgroups. Leukaemic transformation, however, was more frequent in patients with cytogenetic aberrations. In some cases it was not easy to determine the precise diagnostic allocation according to FAB subgroups; it is possible, however, to subdivide MDS prognosis into 2 classes. The more satisfactory therapy of leukaemic transformation is often due to low doses of Ara-C; this therapy allowed a better survival and sometimes to obtain CR which in a M6 ANLL patient continued for 24 months.
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PMID:Myelodysplastic syndromes: analysis of 51 cases. Therapy with low doses of arabinosyl cytosine of leukaemic transformation. 169 90

The concept of biologic modification of proliferation and differentiation of myeloid leukemia cells has attracted much attention over the past years. One promising strategy involves the recruitment of leukemic cells into the cell cycle by hematopoietic growth factors in combination with cycle-specific cytotoxic drugs. Because cytosine arabinoside (Ara-C), which targets only cells in S-phase of the mitotic cell cycle, is included in most chemotherapeutic regimens for the treatment of acute myelogenous leukemia, we explored the hypothesis that the recruitment of quiescent immature leukemic blasts into the cell cycle by the early acting growth factor interleukin 3 (IL-3) can increase the efficacy of Ara-C for kill of leukemic stem cells. We show that IL-3 increases the fraction of blasts in S-phase, as assessed by DNA histogram analysis with propidium iodide staining, leading to an enhancement of kill of clonogenic blast cells when combined with Ara-C. Expression of the protooncogenes c-myc, c-fms, and c-fos, known to be linked to cellular proliferation and differentiation, was also altered by IL-3 in Ara-C-treated cultures, further substantiating the role that IL-3 plays as an enhancer of the cytotoxicity of Ara-C.
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PMID:Effect of interleukin 3 on cytosine arabinoside-mediated cytotoxicity of leukemic myeloblasts. 169 4

Interferons (IFN) have clinical efficacy in certain hematologic malignancies. Combining IFN with conventional cytotoxic agents has been proposed as a means of improving therapy for diseases such as chronic myelogenous leukemia (CML). In this study, we examined the effect of recombinant interferons alone and in combination with Ara-C on normal and leukemic human hematopoietic progenitor cells (CFU-GM) in vitro. Mononuclear cells from normal bone marrow, peripheral blood of patients with CML, or the acute nonlymphocytic leukemia cell line HL-60 were incubated with alpha-, beta-, or gamma-IFN (0-1,000 units/ml) followed by the addition of Ara-C. The survival of normal CFU-GM was significantly increased if cells were treated with IFN 1 h before 3 h of Ara-C exposure. Similar IFN pretreatment of CML and HL-60 progenitors failed to protect leukemic CFU-GM from Ara-C-induced toxicity. This selective protection of normal CFU-GM may have clinical application.
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PMID:Interferon protects normal human granulocyte/macrophage colony-forming cells from Ara-C cytotoxicity. 170 60

70% of patients with newly diagnosed and 50% of patients with relapsed acute myeloid leukemia (AML) can achieve a complete remission with intensive chemotherapy. However, the treatment-associated mortality can be as high as 30% increasing with age, previous chemotherapy and intensity of chemotherapy. GM-CSF was first applied in 36 patients with high risk AML after chemotherapy to reduce the time of critical neutropenia. The early death rate was significantly lower in the GM-CSF group compared to 56 patients of a historic control group with similar risk factors and identical chemotherapy (p less than 0.009). The rate of complete remissions was also significantly higher in the GM-CSF group (p less than 0.09). More recently, GM-CSF was used as a priming agent 24 h prior to start of chemotherapy. 25 patients have entered the study up to now. The cell biological effects of GM-CSF in vivo include an immediate increase of leukemic blasts and of normal myeloid cells in the peripheral blood with a median of 2.0, an increase of cells in the S-phase of the cell cycle in bone marrow biopsies, an increase in DNA polymerase activity, an increase in Ara-C cytotoxicity and immunophenotypic changes compatible with differentiation of leukemic blasts along the pathway of normal myeloid progenitors. GM-CSF has a dual effect on normal and leukemic myeloid cells. It can be safely applied in patients with AML. Prospective randomized trials have to be performed to establish its role in reducing treatment toxicity and in improving the overall treatment results.
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PMID:In vitro and in vivo effects of rh GM-CSF in acute myeloid leukemia (AML). 180 88

Differentiation inducing agents in double and triple combinations can induce differentiation in primary culture of more than 80% of blast cells from some AML patients. In the present study, the interactions between these differentiating agents have been analysed using Berenbaum's general algebraic solution and three new, potentially clinically useful synergistic combinations: have been identified all trans retinoic acid (RA) + hexamethylene bisacetamide (HMBA), cytosine arabinoside (Ara-C) + HMBA and RA + Ara-C + HMBA. A measure of the effectiveness of these combinations was that the doses of Ara-C and HMBA required to induce 50% differentiation were decreased about 10-fold and 5-fold, respectively, in combination with 1 microM RA. The new synergistic combinations are important not only to limit toxicity but also because multiple drug combinations may better overcome the inherent molecular heterogeneity of the differentiation defect in AML patients. They warrant clinical trial in AML patients who are either unsuitable for or are unresponsive to conventional cytotoxic chemotherapy.
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PMID:New synergistic combinations of differentiation inducing agents in the treatment of acute myeloid leukaemia. 181 64

Between 1982 and 1986, 326 evaluable patients with acute myeloid leukemia (AML) were randomized to receive cytarabine (Ara-C) at 200 mg/m2 (A200) or 100 mg/m2 (A100) for induction and maintenance therapy. Cycle 1 of induction therapy consisted of 7 days of continuous intravenous (IV) Ara-C and 3 days of i.v. daunorubicin (DNR); cycle 2, if needed, consisted of 5 days of Ara-C and 2 days of DNR. Complete responders (CR) then received monthly subcutaneous (SC) Ara-C at the respective doses (A100 or A200) with 6-thioquanine (6TG) at months 1 and 5, with vincristine (VCR) and prednisone at months 2, 4, 6, and 8, and with DNR at months 3 and 7. Complete response rates were 58% (A100) and 64% (A200) (P = .29). Median survival was 46 weeks (A100) and 38 weeks (A200) (P = .64); 5-year survival was 10% (A200) and 8% (A100). Median time to remission was 6.7 weeks (A200) and 8.1 weeks (A100) (P = .18). Median disease-free survival was 41 weeks (A200) and 44 weeks (A100) (P = .86). Deaths were attributed to therapy-related toxicities in 21% (A200) and 13% (A100) (P = .05). The 5-year survival was 15% for patients with performance status (PS) 0, 8% for PS 1 to 2, and 2% for PS 3 to 4, 18% for patients less than 40 years, 8% for ages 40 to 59, and 3% for age 60 or greater. Stratification of data by age and PS suggested that A200 may improve survival in patients less than 60 years with a good PS 0 (P = .05). This trial does not support the superiority of A200 over A100 in the treatment of AML.
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PMID:A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. 182 49

Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL-3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.
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PMID:Treatment with interleukin-3 plus granulocyte-macrophage colony-stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts. 182 60


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