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 THERMOmax microplate reader was adapted for monitoring the growth kinetics of human leukaemic OCI/AML-2 and mouse tumour J-774.1 cell lines in continuous culture. Fluid evaporation from wells, CO2 escape and contamination were prevented by hermetic sealing of the microcultures in wells of a 96-well microplate, thus enabling the cells to grow exponentially for 72 h under the conditions of the incubated microplate reader. For both OCI/AML-2 cells, which grow in suspension, and adherent J-774.1 cells, a linear correlation was demonstrated between the number of unstained cells seeded in a given microplate well and the optical density (OD) of that well. Therefore, the OD/time curve of the culture could be deemed to be its growth curve. By the use of the linear fit equation, the actual number of the cells in the wells was computable at any time point of the assay. In the chemosensitivity test, an inhibitory effect of ARA-C on the growth of the cells could be estimated by viewing of the growth curves plotted on the screen. The maximum kinetic rates (Vmax) of the curves in the control and the ARA-C-treated wells were compared, yielding a growth inhibition index (GII). Comparison of results of the kinetic chemosensitivity assay with those of a [3H]thymidine incorporation assay revealed that the novel assay is suitable for precise quantitation of the cell chemosensitivity, is more informative and has the added technical advantage of performance without recourse to radioactive or chemically hazardous substances.
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PMID:A novel microculture kinetic assay (MiCK assay) for malignant cell growth and chemosensitivity. 783 20

The aim of this study was to assess the influence of dose and dose intensity (DI) of induction and consolidation chemotherapy on relapse rates in 264 de novo patients with acute nonlymphocytic leukemia (ANLL). Patients were randomised to receive cytosine arabinoside (ARAC) 100 mg/m2 continuous infusion for 7 days and daunorubicin (DNR) 50 mg/m2 IV day 1-3 (7-3) or the same drugs with the addition of etoposide 75 mg/m2 IV days 1-7 (7-3-7). Cox proportional hazards regression models were used throughout to identify prognostic factors, including dose delivery parameters, influencing the rate of relapse. Of 152 patients who achieved a complete remission (CR), 104 have relapsed with a median duration of CR of 15.8 months. Actual dose delivered was prospectively documented. Cox regression analysis identified the most significant prognostic factors jointly influencing duration of CR as performance status groups (p < 0.0001), percentage peripheral blasts (p = 0.0015), 7-3-7 arm (p = 0.0075), age < 40 years (p = 0.022) and induction dose ARA-C plus DNR (p = 0.029). In this analysis patients randomized to the 7-3-7 arm had an estimated 43% reduction in the relapse rate and each 10% reduction of doses ARA-C and DNR was associated with an estimated 45% increase in the relapse rate. The number of induction courses, delays in treatment and induction dose intensity did not significantly influence the duration of CR nor did any of the consolidation treatment parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The influence of induction chemotherapy dose and dose intensity on the duration of remission in acute myeloid leukemia. Australian Leukemia Study Group. 785 5

A case of leukemic evolution from essential thrombocythemia (ET) is described. The patient developed acute myeloid leukemia (AML) six months after diagnosis while receiving hydroxyurea (HU). He died in four days in spite of treatment with low-dose cytarabine (ARA-C).
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PMID:Essential thrombocythemia and acute leukemia. 817 35

Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m2 in three patients, 1,200 mg/m2 in five patients), tetrahydrouridine (THU: 2,800 mg/m2 in two patients, 2,646 mg/m2 in one patient, 2,100 mg/m2 in five patients), and carboplatin (900 mg/m2 in four patients, 720 mg/m2 in one patient, 450 mg/m2 in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630 +/- 1170 ng/ml).
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PMID:Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin. 845 88

The efficacy of chemotherapy in acute myeloid leukaemia (AML) is limited by clinical drug resistance. We determined in vitro resistance to cytosine arabinoside (ARAC), daunorubicin (DNR), mitoxantrone (MITOX), m-amsacrine (AMSA) and etoposide (VP16) in 49 adults with de novo AML using the MTT assay. Results showed that nonresponders to chemotherapy were, in vitro, 2.9-fold more resistant to DNR, but not more resistant to ARA-C, compared to complete responders. However, complete responders who were in vitro resistant to ARA-C had a 4-fold higher risk of relapse (95% CI 1.3-12.5-fold) compared to complete responders in vitro sensitive to ARA-C. With a mean follow-up of 12 months the probability of continuous complete remission (CCR) for patients in vitro sensitive to ARA-C was 61% at 34 months (95% CI 28-82%), whereas all patients in vitro resistant to ARA-C relapsed within 18 months from diagnosis. This difference appeared to be independent of other clinical features such as sex, age, white blood cell count, FAB classification, and CD34 expression. In vitro resistance to DNR was not related to the probability of CCR. We conclude that in vitro drug resistance assessed with the MTT assay appears to be associated with short- and long-term clinical outcome in AML. Confirmatory studies comprising a sufficient number of patients for multivariate analyses should prove whether in vitro resistance to ARA-C will appear to be an independent risk factor.
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PMID:In vitro resistance to cytosine arabinoside, not to daunorubicin, is associated with the risk of relapse in de novo acute myeloid leukaemia. 870 24

The GOELAM group conducted 2 consecutive trials on the treatment of de novo acute myeloblastic leukemia (AML) in adults. In the GOELAM1 protocol 786 patients aged 15-65 were randomized between two induction treatments (ARA-C 200 mg/m2/day for 7 days plus either Idarubicin 8 mg/m2/day for 5 days or Rubidazone 200 mg/m2/day for 4 days). Out of 731 evaluable patients, 521 (71%) achieved complete remission (CR) without significant difference between the 2 anthracyclines. For patients aged 51-65, the CR rate was significantly higher with Idarubicin (75%) than with Rubidazone (61%) (p = 0.03). In this group of patients the post-remission therapy consisted in only one course of high dose ARA-C plus m-Amsa and the 6 year disease free survival (DFS) was 24% (intention to treat analysis). For patients aged 15-50 years, the post remission therapy was either allogeneic bone marrow transplantation (BMT) (patients up to 40 years of age with an HLA identical sibling) or a first course of intensive consolidation chemotherapy (ICC) followed by a randomization between autologous unpurged bone marrow transplantation (ABMT) and a second course of ICC. There was no significant difference in the 4 year DFS between allogeneic BMT (42%) and the other types of intensive post remission-therapy (40%). The 4 year DFS was 42% for ABMT and 38% for ICC (p = 0.46) (intention to treat analysis). However the median duration of thrombocytopenia was much longer after ABMT (109.5 days versus 18.5 days p = 0.0001). The GOELAM SA3 randomized placebo-controlled protocol tested the impact of GM-CSF given during and after induction treatment for elderly patients (55-75 years). In this study, 232 evaluable patients received induction chemotherapy (Idarubicin 8 mg/m2/day for 5 days plus ARA-C 100 mg/m2/day for 7 days) plus placebo or GM-CSF 5 micrograms/kg/day from day 1 until the end of neutropenia. The CR rate was 61.5%. The median duration of neutropenia was shorter in the GM-CSF arm (22 days versus 27 days p = 0.0001). There was no overall significant advantage for the GM-CSF arm, in terms of CR rate and survival. However for patients age 55-64 the 2 year DFS was significantly higher in the GM-CSF arm (43% vs 17% p = 0.0013).
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PMID:Treatment of acute myeloblastic leukemia in adults. The GOELAM experience. 891 68

We have designed in vitro assays to investigate the possible association between apoptosis and chemotherapeutic sensitivity in acute myeloid leukemias (AMLs). Consistent low levels of spontaneous apoptosis were observed in myeloid cells from normal bone marrow samples, while untreated cells collected from 56 de novo AML patients showed variable apoptosis. Control myeloid cells showed increased apoptosis after in vitro treatments with daunomycin (DNR), cytosine arabinoside (ARA-C), or gamma irradiation (RAD). Most AML samples showed less treatment-associated apoptosis, suggesting that apoptosis responses to therapeutic agents may be frequently attenuated in AML. Certain cytogenetic abnormalities common in AML may affect apoptosis, as acute promyelocytic leukemia (APL) samples with t(15;17) karyotypes showed consistently low levels of spontaneous and treatment-associated apoptosis. Apoptosis assays may provide unique functional subtyping of AMLs, as other common cytogenetic subsets showed variable apoptosis. Altered function of two well-characterized regulators of apoptosis, BCL-2 and p53, was not entirely responsible for this variability. A genomic p53 mutation was found in only one AML sample. All samples that demonstrated the highest BCL-2-positive cell fractions showed low apoptosis, but reduced apoptosis was seen in both the presence and absence of BCL-2 overexpression. Finally, data from matched diagnosis and relapse sample pairs suggest that neither further reduced apoptosis nor additional BCL-2 overexpression is necessarily associated with disease progression.
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PMID:Measurement of spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. 897 98

Low-dose ARA-C (10 mg/m2 subcutaneous injection twice/day for 20 days with 10 days rest) was prescribed in 8 cases of newly diagnosed ANLL. Only one case attained complete remission in 2 courses and lasted for one and a half years without maintenance therapy. She was 63 years of age. The drug could be tolerated well and no serious side effect was observed.
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PMID:Low dose cytosine arabinoside in the treatment of acute non-lymphoblastic leukemia. 899 85

A five-year-old girl, initially diagnosed as having acute lymphoblastic leukemia (ALL; FAB-L1) relapsed with ALL 4 months after completion of chemotherapy (BFM 83). The initial ALL presentation and subsequent ALL relapse were analyzed using conventional morphology, cytochemistry, cytogenetics and immunophenotyping. The results were consistent with a diagnosis of B-lymphocyte precursor ALL. Bone marrow leukemic cells revealed a 46, XX karyotype at diagnosis and a 46, XX, del(7) (q22; qter) when the girl first relapsed. The case was managed with a BFM REZ-ALL 90 protocol. Upon completion of the first cycle of the protocol, severe myelosuppression developed. This was treated with GM-CSF. Three days later, however, GM-CSF was stopped because the WBC reached 1.1 x 10(9) per liter with 60% of blasts in peripheral blood. Laboratory characteristics were typical of AML. Cytogenetic analysis revealed 46, XX, del(7) (q22; qter) karyotype as before. The bcr-abl fusion gene was not detected. Myeloid blasts were placed in a culture and maintained at 37 degrees C and 7.5% CO2 for two weeks. During this period, formation of hemopoietic colonies was observed and subsequently analyzed using histology and electron microscopy. This showed that the colonies consisted of differentiating erythroid, megakaryocytic and myeloid cells. Further, the chemosensitivity of leukemic cells was examined in both "lymphoid" and "myeloid" relapse instances. While the "lymphoid" phenotype was characterized by good sensitivity to corticosteroids, a typical feature of the "myeloid" phenotype was a high resistance to corticosteroids with marginally increased sensitivity to ARA-C.
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PMID:Differential chemosensitivity of leukemic cells in the myeloid and lymphoid phases of stem cell leukemia (a case report). 920 Dec 94

Cell cycle checkpoints establish the timing and strength of arrest, repair and apoptosis responses to damaging treatments. We designed flow cytometric assays to measure cell cycle arrest and apoptosis in acute myeloid leukemia (AML) samples treated in vitro with relevant therapeutic agents so as to functionally characterize checkpoints in these samples and to ask if checkpoint abnormalities are common in AML and contribute to therapeutic failures. We show here that cell cycle responses to daunomycin (DNR), cytosine arabinoside (ARA-C) and gamma irradiation (RAD) were reproducibly treatment agent- and dose-dependent and distinct in different myeloid cell lines. DNR treatments differentially induced cell accumulations in the gap 2 and mitosis (G2/M) phases of the cell cycle and/or in the gap 1 (G1) phase, as did RAD, while ARA-C induced accumulations in the DNA synthesis (S) phase or in the G1 phase. Flow cytometric gates were devised to exclude lymphocytes and mature neutrophils in analyses of primary myeloid cell samples. Cell subsets in bone marrow samples from normal donors were thus enriched for myeloid constituents and used as normal myeloid cell controls. Proliferating cell nuclear antigen (PCNA) immunostaining was used to further identify actively dividing cell subpopulations in primary cell samples. AML samples were similarly analyzed and the majority showed lower DNA synthesis cell cycle phase (S) fractions and lower PCNA-positive fractions than normal myeloid cells, suggesting that AMLs are generally less proliferative in these culture conditions. Exceptional AML samples with high S phase fractions had cytogenetic abnormalities associated with poor prognosis. Most AML samples mounted weak cell cycle responses relative to normal myeloid cells, while a minority showed robust, agent-specific cell cycle arrests. This non-responsiveness was not simply associated with lower cycling indices-neither the response patterns nor the degrees of response were correlated with untreated S phase fractions or with PCNA-positive fractions. Cell cycle responses were also not associated with clinical parameters including patient age, FAB class, or white blood cell count, nor with immunophenotypic features including CD34 status, nor with specific cytogenetic markers. This suggests that functional cell cycle response assays could provide unique diagnostic information in AML. These assays might also have prognostic value as ARA-C induced G1 arrests and DNR-specific G2/M arrests tended to be associated with failure to achieve clinical remission. In addition, G1 arrests after ARA-C and G2/M accumulations after DNR treatments tended to be more robust in samples that had previously been shown to be more highly immunopositive for bcl-2 expression. This data suggests that the association of bcl-2 expression with particular cell cycle responses to therapeutic agents may contribute to the association of bcl-2 with poor clinical responses in AML. These data provide the basis for further laboratory studies aimed at examining specific cell cycle arrests as mechanisms of therapeutic resistance and prospective studies aimed at rigorously assessing the prognostic utility of in vitro assays of checkpoint function.
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PMID:Cell cycle perturbations in acute myeloid leukemia samples following in vitro exposures to therapeutic agents. 961 14


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