Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four patients with acute myeloid leukemia (AML) and three with myelodysplastic syndrome (MDS) were given low dose cytosine arabinoside (Ara-C) therapy. One patient with de novo AML and two patients having refractory anemia with excess of blasts (RAEB) achieved responses. Although the responses lasted for only a short duration (2-3 months), the therapy was well tolerated and not accompanied by severe complications, while severe cytopenia was a frequent side effect with transfusions being necessary in most patients. This therapy could be clinically effective for certain types of AML and MDS (especially RAEB and RAEB in transformation).
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PMID:Low dose cytosine arabinoside therapy in myelodysplastic syndrome and acute myeloid leukemia. 347 89

The effect of a small dose of aclacinomycin-A (ACR) was examined in two patients with refractory anemia (RA) and two with refractory anemia with excess of blasts in transformation (RAEB-t). ACR (7 or 14 mg/m2) was given for 10 days in a 2-h per day drip infusion. Clinical symptoms and laboratory data improved in 3 of these 4 patients. In a patient with RA, marked increase in reticulocytes and elevation of the hemoglobin level from 6 to 9 g/dl was observed after two courses of ACR therapy. In two with RAEB-t, Auer's rod bearing cells disappeared in the bone marrow and megaloblastic change of the erythroblasts was diminished in one patient. Hemoglobin levels rose from 4.7 to 10 g/dl in one, and platelets and WBC increased in another. No effect was seen in a patient with RA. The cytoreductive effect of ACR was minor compared to the therapy with small dose of cytosine arabinoside (Ara-C). Therefore, ACR warrants further consideration for the treatment of patients with MDS.
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PMID:Treatment of four patients with myelodysplastic syndrome with a small dose of aclacinomycin-A. 347 62

Twenty-one patients with refractory acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndrome were treated with low-dose cytosine arabinoside (LDARC). LDARC was administered by subcutaneous injection every 12 hours at a dose of 10 mg/m2 (regimen A) or at a dose of 20 mg/m2 by continuous intravenous infusion (CIV) or continuous subcutaneous injection (CSC) (regimen B). Among 22 courses, two elderly patients with ANLL (M4 and M5) and one M4 patient with myelofibrosis obtained complete remission (CR) and three elderly patients with ANLL (one M1 and two M2) and one patient with ANLL developed from RAEB in transformation obtained partial remission (PR). The overall remission rate (CR + PR) was 31.8%. The CR durations were 2.5, 5 and 2 months, respectively. The plasma concentration of Ara-C determined in regimen B was 8.26 +/- 4.12 ng/ml. There was no difference in the plasma concentration of Ara-C between CIV and CSC. We consider that the major mode of action of LDARC lies in its cytotoxic effect, since all patients who obtained remission exhibited pancytopenia and bone marrow hypoplasia. However, in several patients, we observed transient monocytosis and granulocytosis which were considered to be suggestive evidence of differentiation of leukemia cells.
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PMID:[The clinical effect of low-dose Ara-C in patients with refractory acute nonlymphocytic leukemia and myelodysplastic syndrome]. 356 2

Low-dose Ara-C (10 mg/m2 subcutaneously bid) has been used as an alternative therapy for acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndromes. We sought to define its therapeutic mechanism by assessing clinical and cytogenetic responses to treatment in conjunction with careful in vitro study of both morphologic and functional characteristics of bone marrow cells cultured with Ara-C. Sixteen patients (12 ANLL, four myelodysplastic syndrome) were treated. All developed pancytopenia and 11 of 12 had bone marrow hypoplasia during treatment. Four had a meaningful clinical response while five more showed in vivo leukemic cell sensitivity to low-dose Ara-C. Seven showed no response. Cells with cytogenetic abnormalities were either decreased in number or eradicated during clinical improvement. Liquid culture of marrow mononuclear cells with Ara-C (.033-.333 micrograms/ml X 7 days) produced little evidence of morphologic or functional differentiation (ten of 11 studied). No functional maturation was observed in cells from clinically responding patients. We conclude that low-dose Ara-C is modestly effective for some patients with ANLL or myelodysplasia. However, no evidence for in vivo leukemic differentiation is suggested by either in vitro culture studies or cytogenetic correlates of clinical response. In vitro marrow culture studies failed to predict clinical response to Ara-C.
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PMID:In vitro correlates of low dose ara-C efficacy: clinical, cytogenetic, and bone marrow culture analysis. 357 63

CFU-GM clonal growth was examined in bone marrow from patients with myelodysplastic syndrome (MDS) in the presence of Ara-C at 10(-8) M and 4 X 10(-8) M and the response compared to the effect on progenitors from normal subjects. Seventy-three percent of marrow cultures from patients with MDS showed colony growth below the 95% confidence limits for normal subjects in the presence of 10(-8) M Ara-C. At 4 X 10(-8) M Ara-C 43% of marrow cultures had subnormal colony growth. These results suggest that CFU-GM from patients with MDS may have a greater than normal sensitivity to Ara-C.
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PMID:The effect of cytosine arabinoside on CFU-GM from patients with myelodysplastic syndrome. 358 13

N4-Palmitoyl-1-beta-D-arabinofuranosylcytosine (PLAC) was administered PO to 76 patients with acute leukemia, myelodysplastic syndromes (MDSs), and myeloproliferative disorders (MPDs). Of 20 patients with acute myelogenous leukemia, 2 achieved complete remission, and the only patient with acute lymphoblastic leukemia achieved partial remission. Remission was reached with PLAC 100-300 mg/day 25-66 days after the start of therapy. Among 22 patients with MDS, 1 patient achieved a good response and 8 achieved partial response. Responses were reached with PLAC 50-200 mg/day 7-153 days (median, 33 days) after the start of therapy. Improvement of polycythemia was observed in all 5 patients with polycythemia vera, and reduction of thrombocytosis was observed in 5 out of 6 patients with essential thrombocythemia and myelofibrosis. An antileukemia effect was noted in 1 of 5 with chronic myelogenous leukemia. Major side effects were gastrointestinal toxicities and myelosuppression. In spite of the disadvantages, such as unpredictable absorption and a lower response rate to acute leukemia compared with its parent compound, this antileukemia Ara-C analogue that is administrable PO will be useful in the treatment of MDSs and MPDs, which do not necessarily require admission to hospital, and in the treatment of acute leukemia of the aged, a condition for which intensive chemotherapy is not appropriate.
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PMID:Treatment of leukemia and myelodysplastic syndromes with orally administered N4-palmitoyl-1-beta-D-arabinofuranosylcytosine. 371 96

Twenty-two patients with either a myelodysplastic syndrome or acute nonlymphocytic leukemia were treated with 10-21 days of subcutaneous cytosine arabinoside (Ara-C) (5-10 mg/m2 every 12 hours). There were two complete remissions and ten partial responses. Clinically significant improvements in peripheral blood counts persisted for periods of 8 weeks to greater than 21 weeks. Responses were seen even in patients who had previously proven refractory to conventional induction regimens or high-dose Ara-C. The toxicity, however, was considerable. Nearly all patients developed significant thrombocytopenia. Platelet and red cell transfusion support was required in many cases. The response to low-dose Ara-C therapy seen in patients with the leukemic and myelodysplastic disorders may be mediated by the induction of cell differentiation or a direct cytotoxic effect on a sensitive population of cells. Low-dose Ara-C may provide an alternative therapy in the selected patient with acute nonlymphocytic leukemia or a myelodysplastic syndrome.
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PMID:Low-dose cytosine arabinoside (Ara-C) therapy in the myelodysplastic syndromes and acute leukemia. 385 62

Although the mechanism of action responsible for the effects of low-dose ara-C remains unclear, certain insights are available concerning the interaction of this agent with DNA. Ara-C incorporates into DNA, and the extent of (ara-C)DNA formation correlates significantly with loss of clonogenic survival. The inhibition of DNA replication by ara-C also results in DNA fragmentation and terminal differentiation of leukemic cells. Other studies have demonstrated that inhibition of DNA replication by ara-C results in an aberrant form of DNA synthesis with certain segments of DNA being replicated more than once within a single cell cycle. The additional copies of certain segments of DNA could lead to the accumulation of DNA fragments and alterations in gene expression. It is of interest that other inhibitors of S-phase DNA replication such as aphidicolin and hydroxyurea can also induce similar phenotypic changes in HL-60 and K562 leukemia cells. Although the in vitro data support the concept that ara-C is capable of inducing leukemic cell differentiation, there is no evidence to suggest that this agent induces differentiation of human leukemic cells in vivo. Drug levels achieved by administration of low-dose ara-C (42-64 nmol/L) result in the incorporation of ara-C into bone marrow mononuclear preparations from patients with preleukemia syndromes. This concentration of ara-C (5 X 10(-8) mol/L) slows DNA replication of human leukemic cells in vitro. Thus, the clinical use of low doses of ara-C that achieve plasma concentrations of 10(-8) to 10(-7) mol/L could theoretically induce maturational effects by partially inhibiting DNA synthesis. At the present time we have no available data to support this contention. On the basis of chromosomal analyses, low-dose ara-C apparently maintains sufficient drug levels to suppress more "malignant" clones, but even "clonal" selection may represent elimination of leukemic cells by either cytotoxicity or induction of terminal differentiation. Further studies will be necessary to define the mechanism of action of low-dose ara-C in preleukemia.
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PMID:Cellular and clinical pharmacology of low-dose ara-C. 392 58

Expression of P-glycoprotein (PGP), the product of the multi-drug resistance mdr1 gene was studied by immunocytochemistry on bone marrow slides using JSB1 monoclonal antibody and the alkaline phosphatase-antialkaline phosphatase (APAAP) and avidin-biotin-peroxidase (ABC) techniques in 82 cases of untreated myelodysplastic syndromes (MDS), of whom ten had evolved to AML (MDS-AML). The relationship between PGP expression, myeloperoxidase activity and immunophenotype of blast cells, karyotype and outcome was also analyzed. PGP expression was found in the blasts of 34 of the 82 patients (41%), the majority of blasts being stained in positive cases. PGP positivity was rare in 'low risk' MDS (RA and RARS: 2/12 cases) as opposed to 'high risk' MDS (RAEB, RAEB-T, CMML: 25/60 cases) and MDS-AML (7/10 cases) (p = 0.04). PGP expression was positively correlated to the presence of myeloperoxidase activity in less than 3% of blasts (p = 0.025), and CD34 antigen expression (p = 0.04), whereas CD33 antigen expression had borderline significance (p = 0.07), demonstrating that PGP expression predominated in blasts with an immature phenotype. An abnormal karyotype, and especially the presence of monosomy 7, was not correlated to a higher incidence of PGP expression, however. There was a trend for more frequent progression to AML and for shorter survival in PGP-positive cases, but differences with PGP-negative cases were not significant. Twenty patients received intensive anthracycline-Ara-C chemotherapy and ten (50%) achieved complete response, including 9/13 (69%) PGP-negative cases and 1/7 (14%) PGP-positive cases (p = 0.03). Twenty other patients were treated with low-dose Ara-C and ten (50%) responded (complete or partial response). PGP-positivity did not negatively affect response to low-dose Ara-C: 4/11 responses in PGP-negative, and 6/9 responses in PGP-positive patients (p = 0.18). Because the treatment choice in advanced MDS (especially between anthracycline-Ara-C or low-dose Ara-C, chemotherapy) is difficult, our preliminary therapeutic results suggest that the analysis of PGP expression could have practical importance in MDS. These findings however, will have to be confirmed on larger numbers of patients. Clinical trials using drugs potentially reverting mdr, activity could also be warranted in MDS.
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PMID:Expression of the multidrug resistance P-glycoprotein and its relationship to hematological characteristics and response to treatment in myelodysplastic syndromes. 751 32

Twenty-one patients with myelodysplastic syndrome (MDS) or overt leukemia resulting from MDS were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and cytosine arabinoside (Ara-C). Ara-C was administered in a dose of 20 mg/m2 every 12 h for 5 days and after 2 days 125 micrograms of rhG-CSF was administered for 10 days. After recovery of the leukocyte count the therapy was repeated, doubling the dose of Ara-C serially when possible. Of 13 patients with MDS, four achieved complete remission (CR), two good response (GR), two minor response (MR), and five no response (NR). Of eight patients with overt leukemia from MDS, only one with hyperplastic bone marrow achieved a partial response (PR) and the remaining seven achieved NR. The efficacy of the combination of rhG-CSF and Ara-C in the treatment of MDS and its leukemic phase is discussed, including at which time rhG-CSF should be administered: before, after or concomitantly with Ara-C. Multicenter randomized studies are needed in the evaluation of this combination therapy.
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PMID:Treatment with cytosine arabinoside and granulocyte colony-stimulating factor in patients with myelodysplastic syndrome and its leukemic phase. 753 31


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