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)

Retinoic acid (RA) is a potent morphogen that has been shown to increase differentiation in some leukemic cell populations. RA has been used in treatment of some patients with acute myeloblastic leukemia (AML) and myelodysplastic syndromes. In previous experiments we had observed that RA may decrease the self-renewal of blast cells in established cell lines, and in our clinic RA has been tested as maintenance treatment in association with chemotherapeutic drugs. Accordingly, we asked if exposure of AML blast cells to RA affected their subsequent response to ara-C. We found that brief exposure to RA regularly increased the ara-C sensitivity of cells from two established AML cell lines. A similar, though less marked, effect was seen when the blast cells from one patient were tested directly; in a second instance, highly ara-C resistant blasts did not become sensitive when exposed to RA. Experiments using high specific activity tritiated thymidine did not disclose any changes in the proportion of AML cells in the DNA synthesis phase of the cycle at times when their responses to ara-C were changing. We interpret our findings as support for continuing efforts to integrate RA in the management of AML patients and suggest that the mechanism of ara-C sensitization may not depend on changes in the cell cycle.
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PMID:Interaction between retinoic acid and cytosine arabinoside affecting the blast cells of acute myeloblastic leukemia. 281 79

Clinical effects of a low dose of behenoyl ara-C (LD-BHAC) and K-18, an IgG-melphalan conjugate, were studied in hypoplastic leukemia (HL). Among 8 cases of HL treated with LD-BHAC regimen, in which 50 mg BHAC was administered daily by one-hour drip infusion for 14 days, 4 achieved complete remission (CR) and 2, partial remission (PR). The response rate (CR + PR) was 75%. Hematological toxicities were observed in most of the cases. The peak level of serum ara-C concentration, 3.62-18.9 ng/ml (mean: 11.74 ng/ml), was observed at cessation of infusion, and an ara-C level of 2.75-48.9 ng/ml (mean: 3.45 ng/ml) was still present in the blood 6 hours after cessation of infusion. Six cases of HL were treated with K-18. Eight tablets of K-18, containing 30 mg per tablet, were given daily. Two of 6 cases achieved CR with little hematological toxicities. LD-BHAC and K-18 can be expected in the treatment of hypoplastic leukemia and its related diseases such as hypoplastic preleukemia in the aged.
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PMID:[Chemotherapeutic effects in hypoplastic leukemia]. 326 89

62 evaluable patients with myelodysplastic syndromes (MDS) or acute leukemia were treated with different combinations of low dose ara-C, alpha-interferon (IFN), 1 alpha-hydroxyvitamin D3 (vit D3) and retinoic acid. The aim was to study the efficacy and toxicity of each combination. The overall rate was 44%. Of these, 50% responded favorably to the combination of IFN, vit D3 and retinoic acid (IDR), which was comparable to the response rate of 43% for low-dose ara-C. The results of the IDR treatment may be explained by additive or synergistic effects between the separate drugs in the combination. Ara-C and IDR treatment was generally well-tolerated but interferon gave more side effects than any other drug used in the study. Evaluation of the full combination of ara-C, IFN, vit D3 and retinoic acid was not possible because of toxicity. Marrow hypoplasia was infrequent (5/27 patients) in cases responding favorably to treatment. Complete remissions were not longer than partial remissions or significant responses.
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PMID:Therapeutic effects of low-dose cytosine arabinoside, alpha-interferon, 1 alpha-hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes. 337 98

A phase II clinical trial on MDS was conducted in a cooperative study with orally administrable ara-C analogue, PLAC, which is resistant to cytidine deaminase and had shown an anti-tumor activity on various experimental tumors by oral route. Fifty MDS (3 RA, 18 RAEB, 11 RAEB-T, 18 RAEB-blast crisis (BC) were treated orally with 100 to 400mg/body of daily PLAC. One good response (GR) and 3 partial responses (PR) were obtained in 18 RAEB, and 2 complete remissions, 1 GR and 1 PR were noted in 11 RAEB-T, while 3 PR were seen in 18 RAEB-BC. Overall CR rates were 4%, GR rates 4% and PR rates 14%. Thus, 22% of MDS responded to oral PLAC. No clear daily dose-response was noted. Response, however, was dependent on the treatment period and was obtained in cases which had been treated for more than 20 days. Besides myelosuppression, side effects were mainly gastrointestinal, and anorexia (32%), nausea/vomiting (30%) and diarrhea (8%) were observed. Oral PLAC seems to be active on MDS which does not necessarily require admission to hospital.
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PMID:[Treatment of myelodysplastic syndromes (MDS) with oral administration of N4-palmitoyl-1-beta-D-arabinofuranosyl cytosine (PLAC)]. 338 95

The available data fail to support a standard therapy for MDS. Any therapy should therefore, include participation in a well designed clinical trial. The MDS include patients with a variety of prognoses. Since most studies show that death from infection and bleeding are more likely than progression to frank leukaemia, attention to supportive care is crucial for all patients with MDS. Some patients with MDS may be successfully supported with transfusions and observation for prolonged periods. Patients with significant comorbid disease or patients without increased marrow myeloblasts are good candidates for this conservative approach. Conversely, young patients have a better likelihood of benefit from aggressive therapy, and intensive chemotherapy or allogenic bone marrow transplantation should be considered. Patients with preleukaemia related to prior cytotoxic therapy are another poor prognosis group for whom aggressive therapy may be the best alternative. Therapy with low-dose ara-C or other differentiating agents should be considered investigational and unproven until comparative trials can demonstrate a definitive survival advantage. In addition to comparative trials, innovative clinical studies are needed to address differentiation as an in vivo mechanism of action and its importance in MDS therapy.
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PMID:The treatment of myelodysplastic syndromes. 355 48

Low dose ara-C has been widely used in the treatment of preleukemia and leukemia. These studies have generally utilized either a twice daily, subcutaneous bolus schedule or a continuous intravenous infusion schedule. In order to surmount the logistical problems of long term intravenous infusion while providing prolonged ara-C exposure, we have studied the pharmacology of administering ara-C (20 mg/M2/d) by continuous subcutaneous infusion. The results obtained in eight patients demonstrate that steady state plasma ara-C levels achieved during continuous subcutaneous infusion (24.6-65.6 nM) are not significantly different than those obtained during intravenous infusions (26.2-61.5 nM). Subcutaneous infusions result in prolonged myelosuppression similar to that seen with continuous intravenous infusions. The continuous infusion of low dose ara-C by the subcutaneous route provides a treatment option for some outpatients and offers advantages over intravenous infusions which often require placement of venous catheters or hospitalization.
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PMID:Low dose ara-C administered by continuous subcutaneous infusion: a pharmacologic evaluation. 377 5

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

Twenty-eight patients with poor prognosis acute myeloid leukemia (AML) received therapy with two courses of fludarabine 30 mg/m2/day + ara-C 2 g/m2/day (days 1-5) and G-CSF 5 mg/kg/day (FLAG) (from day 0 to polymorphonuclear recovery). Eighteen patients were considered 'refractory' (eight primarily resistant, five relapsing within 6 months of initial remission, or at a second relapse; five relapsing after an autologous bone marrow transplantation procedure. Ten cases were defined 'secondary' AML (diagnosis of AML made after a preexisting diagnosis of: myelodysplastic syndrome: five cases; myelodysplastic syndrome after therapy for breast cancer: one case; previously untreated, and concomitant, non-Hodgkin's lymphoma: two cases; Hodgkin's disease treated with chemoradiotherapy: one case). Overall, 15 patients (58%) achieved a complete remission (CR). Two patients died of infection during induction, and 11 had resistant disease. Analyzing the data in relation to selected host and disease characteristics, the response varied widely. The highest CR rates (89%) were obtained in secondary AML; in particular, two cases of 'second-primary' (concomitant with low-grade non-Hodgkin's lymphoma) AML obtained CR for both diseases. Refractory AML differed widely for response: high CR rate (75%), although with short mean CR duration for primary resistance AML, and very poor response (11% CR) for relapsed (early, second, after ABMT) cases. Interestingly, a slow kinetic of leukemic growth in vivo before FLAG administration was significantly related to the response and outcome (p = 0.0002). Hematological and nonhematological toxicities were acceptable. In conclusion, the FLAG regimen has significant antileukemic activity and acceptable toxicity especially in secondary AML, both with and without coexisting lymphoid malignancy.
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PMID:FLAG (fludarabine + high-dose cytarabine + G-CSF): an effective and tolerable protocol for the treatment of 'poor risk' acute myeloid leukemias. 752 88

The major clinical experience with fludarabine has been obtained in patients with chronic lymphocytic leukemia (CLL). In the initial studies in previously treated patients with CLL, the complete and partial response rate (CR + PR) was over 50%, and in previously untreated patients with CLL, a CR + PR rate of 75-80% was noted with or without the addition of prednisone. Subsequent clinical trials have also demonstrated major activity with fludarabine in Waldenstrom's macroglobulinemia. Fludarabine was noted to be an active agent in indolent lymphoma in phase I/II studies. Approximately 60% of patients with follicular lymphoma respond to fludarabine when it is administered as a single agent. Many of these remissions are complete remissions despite patients having received extensive prior therapy. Combination programs are being developed for application in CLL and indolent lymphoma. Because of the activity of fludarabine in inhibiting DNA repair, it has been combined with cisplatinum and cytosine arabinoside and plans are in place to explore the radiation sensitizing effect of fludarabine in clinical trials. A combination of fludarabine plus ara-C is now being used in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) and a combination of fludarabine, ara-C, and G-CSF (FLAG) has been combined with idarubicin for the management of these conditions. Many of these activities of fludarabine are associated with its interaction with many enzymes which are important in DNA and RNA metabolism and in DNA repair. It is anticipated that these actions will be explored in a wider range of studies subsequently.
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PMID:The expanding role of fludarabine in hematologic malignancies. 753 76

The ability of induction of differentiation of leukemia cells was first proved by cultured leukemia cells, and such ability has been also confirmed clinically as a result of observation of the dramatic effect of all-trans retinoic acid on acute promyelocytic leukemia and the usefulness of low-dose of ara-C therapy for acute myeloid leukemia. We studied differentiation induction of primary cultured bone marrow cells from myelodysplastic syndrome (MDS) patients by ara-C and VP16 with or without addition of G-CSF. We also studied clinical efficacy of differentiation therapy in 56 patients with MDS. Differentiation induction effects were observed in 3 of 14 patients treated with G-CSF in combination with low-dose of ara-C or low-dose of VP16. In addition, high-dose methylprednisolone therapy, GM-CSF and anabolic steroid therapy also showed similar effect on refractory anemia, even in a few patients. Since these results suggested the usefulness of differentiation therapy of MDS, it is earnestly hoped that more effective therapy, including a concomitant use of cytokine, might be established as soon as possible.
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PMID:[Differentiation therapy for myelodysplastic syndrome]. 768 64


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