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 active form of vitamin D3 [1 alpha, 25-dihydroxyvitamin-D3 (1 alpha, 25(OH)2D3)] modulates the proliferation and differentiation of hematopoietic cells. Analogs of 1 alpha, 25(OH)2D3 that have greater potency may have the potential as adjuvant therapy for high-risk patients in remission for acute myelogenous leukemia (AML) and myelodysplastic syndromes. A new generation of 11 analogs of 1 alpha, 25(OH)2D3 has been synthesized, and we examined their effects on the human leukemic cell line HL-60. This cell line provides a sensitive monitor of activity of the 1 alpha, 25(OH)2D3 analogs. All the compounds were potent, producing a 50% clonal inhibition (ED50) in the range of 10(-8) to 10(-11) mol/L; nine of the 11 analogs had ED50s at concentrations that were at least 10-fold lower than those for the parental 1,25(OH)2D3. The most active compound [cmpd LA, (22R)-1 alpha, 25-(OH)2-16,22,23-triene-D3] had an ED50 of 2 x 10(-11) mol/L; it was also tested on clonogenic cells from patients with AML, and it achieved an ED50 of approximately 6 x 10(-11) mol/L, while 1 alpha, 25(OH)2D3 produced an ED50 of approximately 10(-8) mol/L on the same population of cells. Five different cell surface markers were examined on HL-60 cells exposed to the 1 alpha, 25(OH)2D3 analogs: HLA-DR and CD11b were induced by all of the compounds; CD13 was induced by six of the 12 compounds, including 1,25(OH)2D3; CD14 was strongly induced by all compounds; and CD38 was induced rather weakly by nine of 12 analogs. WAF1/CIP1/p21, a cyclin-dependent kinase inhibitor (CDKI), which is important in blocking the cell cycle, was examined by Western blot and was found to be induced by all of the compounds, suggesting a possible mechanism by which these analogs inhibit leukemic growth. The induction of WAF1 occurred at concentrations of vitamin D analogs as low as 10(-10) mol/L. This structure-function study showed that a new series of 1 alpha, 25(OH)2D3 analogs was active in clonal inhibition, as well as induction of differentiation and WAF1 expression of HL-60 cells. The key structural motifs included C-16 double bond, double and/or triple bonds in the side chain, lengthening of the side chain, 20-epi-conformation of the side chain, replacement of six hydrogens at the end of the side chain with fluorines, and the removal of C-19. Consideration should be given to further in vivo testing of toxicity and efficacy to move toward a clinical trial, especially in a setting of minimal residual disease.
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PMID:A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia. 882 40

We studied the effects of a novel vitamin D analog CB1093, EB1089 (one of the most antileukemic analogs yet) and 1 alpha,25(OH)2D3 both on HL-60 cells and cells from 13 AML patients. Differentiation was measured both by induction of superoxide production and non-specific esterase. Cell proliferation was assessed by colony assay and 3H-thymidine incorporation. The effect on serum calcium was measured in rats. The CB1093 proved to be the most efficient of the analogs tested so far, both in inducing differentiation and in inhibiting proliferation. This, combined with its low hypercalcemic effect shown here, makes it a promising candidate for preclinical animal studies.
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PMID:CB1093, a novel vitamin D analog; effects on differentiation and clonal growth on HL-60 and de novo leukemia cells. 915 Mar 49

The hormonally active form of vitamin D is 1alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3], which is a principal regulator of calcium homeostasis. It also affects hormone secretion, cell differentiation, and proliferation by a mode of action that involves stereospecific interaction with an intracellular vitamin D receptor (VDR). We recently found that retinoids, which are vitamin A derivatives, exert anticoagulant effects by upregulating thrombomodulin (TM) and downregulating tissue factor (TF) expression in acute promyelocytic leukemia cells and monoblastic leukemia cells. Both the VDR and retinoid receptors belong to the same family of receptors. A heterodimer consisting of the retinoid X receptor and the VDR binds to vitamin D responsive elements on genes regulated by vitamin D. To determine whether 1,25(OH)2D3 would exhibit anticoagulant effects similar to retinoids, we measured the antigen level, activity, and mRNA level of TM and TF in human leukemic cells, vascular endothelial cells, and monocytes treated with 1,25(OH)2D3. We found that 1,25(OH)2D3 upregulates antigen expression, activity, and mRNA levels of TM and downregulates antigen expression, activity, and mRNA levels of TF in human monocytic leukemia cells, some acute myelogenous leukemia cells, and monocytes, but not in umbilical vein endothelial cells. Transient transfection studies with reporter plasmids in monocytic leukemia cells and mobility gel-shift assay showed interaction with 1,25(OH)2D3 and functional retinoic acid responsive elements present in the 5'-flanking region of the TM gene. However, auxiliary factors or other elements in the TM gene may contribute to VDR specificity and transactivation of the gene in specific target cells. These findings indicate that 1,25(OH)2D3 resembles the retinoids in its control of the transcription of the TM and TF genes in human monocytic cells. Analogs of 1,25(OH)2D3 with anticoagulant activity may serve as adjunctive antithrombotic agents in monocytic leukemia and atherosclerotic disease.
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PMID:Anticoagulant effects of 1alpha,25-dihydroxyvitamin D3 on human myelogenous leukemia cells and monocytes. 963 12

Vitamin D compounds induce differentiation of human leukemic cells and have potential for the treatment of leukemia. In this review we summarize some of the basic mechanisms underlying the action of vitamin D compounds. A variety of vitamin D analogues were synthesized until now, some of which have enhanced antileukemic activity and a decreased propensity to cause hypercalcemia. Most actions of vitamin D compounds are mediated by nuclear receptors. In vivo, vitamin D binding protein interacts with free vitamin D compounds. Both in normal and leukemic cells, vitamin D compounds cause a differentiation to monocytes and macrophages. A variety of genes are regulated by vitamin D compounds. Recently, the cell cycle inhibitory gene p21/WAF-1/CIP-1 was characterized. The expression de novo of WAF-1 in blasts of acute myelogenous leukemia is an independent factor of unfavorable prognosis. In HL-60 leukemic cells treated with vitamin D analogs, WAF-1 can be induced by nano- or picomolar concentrations of vitamin D analogs and correlates with the induction of a differentiated phenotype. When vitamin D analogs are combined in-vitro with retinoids, an irreversible differentiation is observed. Clinical trials of vitamin D analogs are indicated in the situation of minimal residual disease and in combination with standard chemotherapy.
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PMID:Vitamin D analogs, leukemia and WAF1. 986 91

1. The conventional approach to treatment of acute myeloid leukemia has been the use of chemotherapy, which although being cytotoxic to malignant clones, is also cytodestructive to normal cells. In addition, some leukemia cells develop resistance to chemotherapy and are therefore difficult to eradicate. 2. Differentiation therapy, whereby immature cells are induced to attain a mature phenotype by differentiation agents, has provided an alternative strategy in the treatment of hyperproliferative disorders. This has been highlighted by the use of all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). 3. Another differentiation agent, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), directs monocytic maturation of normal and leukemic cells. Cellular studies have revealed that combinations of vitamin D derivatives and retinoids such as ATRA and 9-cis retinoic acid (9-cis RA) exhibit cooperative effects on differentiation in established leukemia cell lines such as HL-60, U937, and NB4. Furthermore, vitamin D compounds, although not able to induce apoptosis when used alone, potentiate apoptosis induced by 9-cis RA in HL-60 cells and differentially regulate the expression of the apoptosis-related gene products bcl-2 and bax. The molecular mechanisms involved in regulating differentiation and apoptosis by these agents are mediated through the interactions of the nuclear receptors for vitamin D (VDR), ATRA (RAR), and 9-cis RA (RXR), which are able to form homo- or heterodimeric complexes and transcriptionally activate or repress target gene expression. 4. There is evidence to suggest that nitric oxide may also play a role in leukemic cell differentiation and that 1,25(OH)2D3 may influence endogenous nitric oxide production either by directly increasing tumor necrosis factor-alpha (TNF-alpha) or through a secondary mediator such as the C-type lectin CD23.
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PMID:Leukemia cell differentiation: cellular and molecular interactions of retinoids and vitamin D. 988 67

AML2 is a member of the acute myelogenous leukemia, AML family of transcription factors. The biologic functions of AML1 and AML3 have been well characterized; however, the functional role of AML2 remains unknown. In this study, we found that AML2 protein expressed predominantly in cells of hematopoietic origin is a nuclear serine phosphoprotein associated with the nuclear matrix, and its expression is not cell cycle-related. In HL-60 cells AML2 expression can be induced by all three natural retinoids, all-trans-retinoic acid (RA), 13-cis-RA, and 9-cis-RA in a dose-dependent manner. A synthetic retinoic acid derivative, 4HPR, which neither activates RA receptor (RAR) alpha nor retinoic X receptor alpha was unable to induce the expression of AML2. A RAR-selective activator, TTNPB, induced AML2 expression similar to RA. Our study further showed that AGN193109, a potent RARalpha antagonist, suppressed AML2 expression induced by RA and that a retinoic X receptor pan agonist AGN194204 had no effect on its expression. Taken together, these studies conclusively demonstrated that the expression of AML2 in HL-60 cells is regulated through the RARalpha-specific signaling pathway. Our study further showed that after all-trans-retinoic acid priming, AML2 expression could be augmented by vitamin D(3). Based on these studies we hypothesize that AML2 expression is normally regulated by retinoid/vitamin D nuclear receptors mainly through the RARalpha-dependent signaling pathway and that it may play a role in hematopoietic cell differentiation.
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PMID:Regulation of AML2/CBFA3 in hematopoietic cells through the retinoic acid receptor alpha-dependent signaling pathway. 1041 74

Different types of acute myeloid leukemia blast cells were induced to differentiate in vitro with all-trans-retinoic acid (ATRA) and vitamin D3 (VD). M0/M1 leukemic cells are not sensitive to differentiating agents, whereas M3 leukemic cells are induced to undergo granulocytic differentiation after ATRA treatment but are not sensitive to VD. M2 leukemic blast cells behave differently because they undergo monocytic differentiation with both the differentiation inducers. To gain some insight into the maturation of M2-type leukemic cells, we studied the molecular mechanisms underlying monocytic differentiation induced by ATRA and VD in spontaneous M2 blast cells as well as in Kasumi-1 cells (an acute myeloid leukemia M2-type cell line). Our results indicate that ATRA as well as VD efficiently increases the nuclear abundance of VD receptor (VDR) and promotes monocytic differentiation. VDR is functionally active in ATRA-treated Kasumi-1 cells because it efficiently heterodimerizes with retinoid X receptor, binds to a DR3-type vitamin D-responsive element, and activates the transcription of a vitamin D-responsive element-regulated reporter gene. Consistent with these findings, VD-responsive genes are induced by ATRA treatment of Kasumi-1 cells, suggesting that the genetic program underlying monocytic differentiation is activated. The molecular mechanism by which ATRA increases the nuclear abundance of a functional VDR is still unknown, but our data clearly indicate that the M2 leukemic cell context is only permissive of monocytic differentiation.
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PMID:Induction of a functional vitamin D receptor in all-trans-retinoic acid-induced monocytic differentiation of M2-type leukemic blast cells. 1044 99

We encountered 3 patients with erythroleukemia who showed differing outcomes. The first patient was an 11-year-old girl who was treated with an ANLL 91 national protocol followed by bone marrow transplantation from an HLA-identical brother. She is still in complete remission after 6 years. The second patient was a 15-year-old girl. Treatment with low dose Ara-C was effective. She experienced a relapse once, but achieved her second remission with low dose-Ara-C plus vitamin D. Up to the present, she has maintained remission for 5 years. The third patient was a 1-month-old girl who initially presented with an increase of proerythroblasts with infiltration to the liver. Although her response to Ara-C and etoposide was favorable, she died of a generalized fungal infection in the leukopenic phase. Chromosomal analyses of bone marrow cells were normal for patients 1 and 2, but patient 3 had an abnormal complex karyotype. We think the prognosis for erythroleukemia in childhood is not necessarily poor in all cases. Appropriate treatment should be based on the patient's age, the proportion of proerythroblasts, and the presence of chromosomal abnormalities.
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PMID:[Three pediatric cases of erythroleukemia: review of the literature on prognostic factors]. 1077 50

The runt family transcription factor (AML-3/PEBP2alphaA1/Cbfa1/RUNX2) plays a crucial role in formation of the mineralized skeleton during embryogenesis and regulates maturation of the osteoblast phenotype. Because steroid hormones and growth factors significantly influence growth and differentiation properties of osteoblasts, we addressed Cbfa1 as a target gene for regulation by dexamethasone (Dex), 1,25(OH)D(3) (vitamin D(3)), 17beta-estradiol, and transforming growth factor-beta1 (TGF-beta1). The representation of functional protein levels by Western blot analyses and gel mobility shift assays was examined during the growth and mineralization of several conditionally immortalized human osteoblast cell lines HOB 04-T8, 03-CE6, and 03-CE10, each representing different stages of maturation. In situ immunofluorescence demonstrates Cbfa1 is associated with nuclear matrix in punctate domains, some of which are transcriptionally active, colocalizing with phosphorylated RNA polymerase II. Although each of the cell lines exhibited different responses to the steroid hormones and to TGF-beta1, all cell lines showed a similar increase in Cbfa1 protein and DNA binding activity induced only by Dex. On the other hand, Cbfa1 mRNA levels were not altered by Dex treatment. This regulation of Cbfa1 by steroid hormones in human osteoblasts contrasts to modifications in Cbfa1 expression in primary rat calvarial osteoblasts and the mouse MC3T3-E1 osteoblast cell line. Thus, these results reveal multiple levels of regulation of Cbfa1 expression and activity in osteoblasts. Moreover, the data suggest that in committed human osteoblasts, constitutive expression of Cbfa1 may be required to sustain the osteoblast phenotype.
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PMID:Expression and regulation of Runx2/Cbfa1 and osteoblast phenotypic markers during the growth and differentiation of human osteoblasts. 1113 73

The seco-steroid hormone, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits proliferation and induces differentiation of malignant cells including those of the hematopoietic system. The 24-oxo metabolite of 1,25(OH)(2)D(3) also has prominent antiproliferative activities against various cancer cells. We chemically synthesized five novel 24-oxo vitamin D(3) analogues and evaluated their abilities both to inhibit clonal growth and induce differentiation of myeloid leukemia cells and to cause hypercalcemia. The 1alpha,25-dihydroxy-16-ene-D(3) [1,25(OH)(2)-16-ene-D(3)] and 1alpha,25-dihydroxy-16-ene-19-nor-D(3) [1,25(OH)(2)-16-ene-19-nor-D(3)] and their 24-oxo metabolites showed greater potency than 1,25(OH)(2)D(3) in their abilities to inhibit clonal proliferation of HL-60, NB4, and U937 leukemic cell lines as measured by methylcellulose soft-gel assay. Their inhibition of clonal growth was irreversible as analyzed by pulse exposure studies. The synthetic analogues also had greater potency than 1,25(OH)(2)D(3) to induce differentiation of HL-60 and NB4 cells as measured by generation of superoxide, nonspecific esterase production, and induction of CD11b and CD14 cell surface antigens and to increase the proportion of these cells in the G(0)-G(1) phase of the cell cycle. For most assays, the 24-oxo metabolite was slightly more potent than the unmodified analogue, and 50% activity was usually found in the nanomolar range. These analogues and their 24-oxo metabolites also inhibited fresh leukemic cell clonal proliferation. Expression of p27(KIP1), a cyclin-dependent kinase inhibitor that plays an important role in blocking the cell cycle, was found by Western blot analysis to be induced by the analogues and their 24-oxo metabolites in both HL-60 and U937 cells, suggesting a possible mechanism by which these analogues inhibit leukemic growth. Notably, the calcemic activity tested by injections of 1alpha,25-dihydroxy-16-ene-24-oxo-19-nor-D(3) in mice was at least 12-fold less than 1alpha,25(OH)(2)-16-ene-19-nor-D(3). Taken together, chemically synthesized 24-oxo metabolites of 1alpha,25(OH)(2)-16-ene-D(3) and 1alpha,25(OH)(2)-16-ene-19-nor-D(3) irreversibly inhibited proliferation and induced differentiation of acute myeloid leukemia cells with minimal toxicity; these compounds may have a role in the maintenance phase of therapy for acute myeloid leukemia.
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PMID:24-Oxo metabolites of vitamin D3 analogues: disassociation of their prominent antileukemic effects from their lack of calcium modulation. 1130 93


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