cholecalciferol and Myelodysplastic-Syndromes

Myelodysplastic syndrome is a hematopoietic stem cell disorder characterized by ineffective hematopoiesis and leukemic progression. Accumulation of various kinds of genetic alterations in oncogene and tumor suppressor gene develops and accelerates the disease. Recently, alpha-catenin gene has been identified as a candidate gene in the 5q- anomaly. Diagnostic criteria have been updated by Valent et al. WHO classification has become popular and WHO classification-based prognostic scoring system will be employed to evaluate prognosis. In our country, clinical studies on vitamin K2+D3 and cyclosporine A were conducted in low-risk patients, and their efficacy and safety have been reported. In US, molecular-targeting therapy with lenalidomide or demethylase is approved by FDA.

Topics: alpha Catenin; Antineoplastic Agents; Azacitidine; Cholecalciferol; Cyclosporine; Decitabine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lenalidomide; Myelodysplastic Syndromes; Prognosis; Thalidomide; Vitamin K 2; World Health Organization

Topics: Blood Transfusion; Bone Marrow Transplantation; Cholecalciferol; Cytarabine; Cytokines; Diagnosis, Differential; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes

Topics: Acetamides; Amifostine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arginine; Azacitidine; Butyrates; Cholecalciferol; Cytarabine; Harringtonines; Hematopoietic Cell Growth Factors; Heme; Homoharringtonine; Humans; Interferons; Myelodysplastic Syndromes; Retinoids

Refractory anemias and the myelodysplastic syndromes are a group of hematopoietic stem cell disorders characterized by ineffective and dysplastic hematopoiesis, leading to persistent peripheral cytopenias. Patients also have an increased risk of transformation to acute myelogenous leukemia. Since defective cellular maturation is the central pathogenetic feature, improved differentiation may result in correction of neutropenia and thrombocytopenia. Clinical trials using retinoic acid and vitamin D3 analogues are not satisfactory and only small numbers of patients may benefit from receiving them. In view of the absence of other effective treatment, future studies should be directed to the combined use of differentiating agents with hematopoietic growth factors and to the identification of new compounds with greater differentiating ability and less toxicity.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Animals; Cholecalciferol; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Tretinoin

Myelodysplastic syndromes (MDS) include hemopoietic cytopenias of different origin, which are usually refractory to treatment. Therefore MDS patients should generally be treated conservatively. Transfusions of packed red cells (given in a strict regimen to minimize the risk for secondary hemochromatosis) may be sufficient to maintain a good quality of life. Indications for cytotoxic treatment include signs of progression of the disease. In patients with symptomatic cytopenias low-dose cytarabine (ara-C) should be tried. It is essential then to monitor each patient individually and to avoid fixed treatment schedules. Standard (high-dose) chemotherapy in MDS, is associated with a high mortality and a low response rate, and should be considered only in younger patients with advanced MDS. Allogeneic bone marrow transplantation (BMT) may be offered to younger MDS patients, when a suitable donor is available. Treatment with differentiation inducers has not met with expectations and should not be used outside clinical trials at the present. The use of recombinant hemopoietic growth factors (GF) seems promising. GF, like GM-CSF, G-CSF, IL-3, and erythropoietin, can be used either alone or in combinations, to support failing peripheral blood values, and decrease the risk for lethal complications. GF can also be given together with chemotherapy, in an effort to make the leukemic clonogenic cells more susceptible to cytotoxic drugs. Other treatments for MDS include: IFN-alpha and etoposide, with responses primarily in chronic myelomonocytic leukemia; hem arginate, whose role is still not clear; and corticosteroids, but only in carefully selected cases.

Topics: Antineoplastic Agents; Cholecalciferol; Chronic Disease; Hematopoietic Cell Growth Factors; Humans; Myelodysplastic Syndromes; Tretinoin

Topics: Bone Transplantation; Cholecalciferol; Colony-Stimulating Factors; Cytarabine; Danazol; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Immunologic Factors; Isotretinoin; Myelodysplastic Syndromes

It is important to make the correct diagnosis of MDS and to exclude very carefully all other disorders that may induce dysplastic features in the bone marrow. In patients without excess of bone marrow blasts, cytogenetics and in vitro bone marrow cultures may aid in making the correct diagnosis. MDS patients without excess of bone marrow blasts or symptomatic cytopenia or cytogenetic abnormalities associated with poor prognosis should be followed on a regular basis with sequential examinations of blood counts and bone marrow specimens. In the absence of obvious disease progression, ie, increasing cytopenia or increasing percentage of marrow blasts, patients should only receive supportive care. An increase in RBC requirements alone is insufficient reason to start cytotoxic therapy. Once progression of the disease has been well documented, cytotoxic treatment is indicated. There is no reason to delay treatment until these patients have progressed to overt AML. In patients over the age of 50, the best available therapy is low-dose cytarabine with a 30% probability of a good response; this therapy requires careful supervision and the availability of intensive supportive care. In patients under 50 years with progressive disease, or with clear evidence of a poor prognosis, allogeneic BMT is the therapy of choice if a HLA-identical sibling can be identified. In those patients who lack a HLA-identical sibling, intensive combination therapy is the treatment of choice and should preferably include high-dose cytarabine. Intensive consolidation therapy will be necessary for a durable remission. Trials with inducers of differentiation remain experimental. Results to date have been disappointing.

Topics: Bone Marrow Transplantation; Cholecalciferol; Combined Modality Therapy; Cytarabine; Hormones; Humans; Myelodysplastic Syndromes; Tretinoin

The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities.

Topics: Anemia, Refractory, with Excess of Blasts; Animals; Antineoplastic Agents; Blood Cell Count; Bone Marrow; Cell Transformation, Neoplastic; Cholecalciferol; Chromosome Aberrations; Chromosome Disorders; Colony-Forming Units Assay; Colony-Stimulating Factors; DNA; Hematopoietic Stem Cells; Humans; Leukemia; Leukemia, Radiation-Induced; Mice; Myelodysplastic Syndromes; Oncogenes; Preleukemia; Rats; Tretinoin

An in vitro synergism between different inducers of AML cell differentiation has been previously observed. Therefore, we treated 53 myelodysplastic (MDS) patients with a low dose combination of cis-retinoic acid (cRA, 20-40 mg/day) and 1,25 alpha (OH)2 cholecalciferol [(OH)2D3, 1-1.5 micrograms/day] +/- intermittent 6-thioguanine (30 mg/m2/day). The latter was reserved for patients with bone marrow (BM) blast excess (> or = 5%). The treatment was well tolerated, without major toxicity. Among 25 patients with BM blasts less than 5%, we observed one complete, eight partial and four minor responses (response rate 52%) with a median response duration of 8 months (2 +/- 24). Median survival, which did not correlate with response, is projected at 76 months. Thirty-one patients with BM blast excess (> or = 5%), including three of the previous group who progressed to refractory anemia with excess of blasts (RAEB), were treated with the three-drug protocol. One complete, 12 partial and six minor responses were obtained (response rate 61%) with a median response duration of 6 months (2-29+). A significant difference in survival (P < 0.005) was observed between the 19 responders (median 25 months) and the 12 non-responders (median 9 months). A reduction in the transfusion need was observed in 41% of the transfusion-dependent patients with blast excess and in 53% of those without blast excess. Therefore, combined differentiating therapy seems more effective than previously reported single agent treatments and should be considered for a larger randomized study to assess its actual impact on survival of MDS patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Blood Transfusion; Bone Marrow Transplantation; Cholecalciferol; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Remission Induction; Survival Analysis; Thioguanine; Tretinoin

Topics: Administration, Oral; Aged; Aged, 80 and over; Cholecalciferol; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life

Vitamin K2 (VK2) effectively induces apoptosis in leukemia cell lines, including HL-60 and U937. However, combined treatment of cells with VK2 plus 1alpha,25-dihydroxy vitamin D3 (VD3) resulted in suppression of VK2-inducing apoptosis and pronounced induction of monocytic differentiation as compared with that by VD3 alone. After achieving monocytic differentiation by pre-exposure to VK2 and VD3, the cells became resistant to various apoptotic stimuli including VK2- and H2O2-treatment and serum deprivation. Accumulation of cytoplasm p21CIP1 along with disappearance of nuclear p21CIP1 was detected in cells in response to 96-h treatment with VK2 plus VD3. A stable transfectant, U937-deltaNLS-p21CIP1, which lacked the nuclear localization signal of p21CIP1 and showed overexpression of cytoplasm p21CIP1 without monocytic differentiation, was resistant to apoptosis. These data suggest that a change of intracellular distribution of p21CIP1 from nucleus to cytoplasm along with differentiation appears to be anti-apoptotic. Clinical benefits of using VK2 for treatment of patients with leukemia and myelodysplastic syndrome (MDS) have been reported. Our data suggest that VK2 plus VD3 may be an effective combination for differentiation-based therapy for leukemia and also MDS whose cytopenias are mediated though apoptosis.

Topics: Apoptosis; Calcitriol; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cytoplasm; Flow Cytometry; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Hydrogen Peroxide; Immunoblotting; Immunoprecipitation; Leukemia; MAP Kinase Kinase 4; Models, Biological; Monocytes; Myelodysplastic Syndromes; Time Factors; Transfection; U937 Cells; Vitamin K 2

It is known that 1 alpha, 25(OH)2D3 is an inducer of nonlymphoid leukemic cell differentiation to monocyte-macrophage-like in vitro. The effects of oral administration of 4.5-15 micrograms/d 1 alpha (OH)D3, which is converted to 1 alpha, 25(OH)2D3 in vivo by liver cells, on leukemic cells were studied in two patients with AML and one with RAEB. In these three cases, 1 alpha (OH)D3 reduced the number of leukemic cells in the bone marrow and aggregated the dispersed chromatin of leukemic cells as heterochromatin. Furthermore, this drug induced atypical lymphocyte-like cells, which were considered to be differentiated from leukemic cells in case 1, and improvement of pancytopenia in case 3. While hypercalcemia developed during 1 alpha (OH)D3 therapy in case 1, it disappeared within three days after discontinuation. We also studied the in vitro effects of 1 alpha, 25 (OH)2D3 on leukemic cells freshly isolated from the bone marrow in these three cases. After incubation with 10(-8) M 1 alpha, 25(OH)2D3 at 37 degrees C for 72 h, the number of adherent cells on the bottom of Petri dishes had increased. These cells were quite similar to monocyte-macrophages. These leukemic cells, after differentiation induced by 1 alpha, 25(OH)2D3, reacted strongly with monoclonal antibodies My-4 and My-7. Both 100 microM D-cis and L-cis diltiazem (calcium channel blocker) enhanced the differentiation of HL-60 cells induced by 1 alpha, 25 (OH)2D3. There was no significant difference between D-cis and L-cis diltiazem with regard to this enhancing effect. The cytoplasmic free Ca2+ concentration in HL-60 cells induced by 1 alpha, 25(OH)2 D3 and/or diltiazem, was increased significantly as compared with that in HL-60 cells incubated without inducers.

Topics: Administration, Oral; Aged; Anemia, Refractory, with Excess of Blasts; Calcium; Cell Differentiation; Cholecalciferol; Diltiazem; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes

Topics: Aged; Androgens; Cholecalciferol; Cytarabine; Drug Therapy, Combination; Erythropoiesis; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes