Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical observations of bone pain, abnormal gait, and unusual fractures during remission of leukemia led us to assess mineral status in a cohort of 16 children with acute lymphoblastic leukemia treated with intensive chemotherapy. During maintenance and 6 months after the completion of therapy, blood and urine were analyzed for calcium and magnesium and blood for osteocalcin, vitamin D, and parathyroid hormone. Bone mineral content and bone width of the distal one third of the radius of the nondominant arm was measured by single-photon absorptiometry. During therapy, mild ionic hypocalcemia (less than 1.19 mmol/L) and hypomagnesemia (less than 0.77 mmol/L) were demonstrated in 9 and 8 of 16 children, respectively; hypercalciuria (8/16) and hypomagnesiuria (12/16) were also observed. Plasma osteocalcin values correlated with plasma magnesium levels (r = 0.54; p less than 0.05). Oral magnesium supplements normalized plasma magnesium, calcium, and osteocalcin levels, all of which were normal at the postchemotherapy study. Plasma 1,25-dihydroxyvitamin D levels were nondetectable (less than 8 ng/ml) in 12 of 13 patients receiving therapy and in 7 of 14 patients not receiving therapy; alkaline phosphatase activity increased significantly after therapy (179 +/- 86 to 340 +/- 101 units/L), and parathyroid hormone levels were normal in both studies. Bone mineral content/bone width ratio was less than 1 SD below the mean for age- and sex-related population standards in 70% of patients. These data indicate that alterations in magnesium, calcium, and vitamin D metabolism in children treated for acute lymphoblastic leukemia may be instrumental in inducing or sustaining altered bone turnover during chemotherapy.
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PMID:Mineral homeostasis and bone mass in children treated for acute lymphoblastic leukemia. 278 92

Four analogues of vitamin D3 with an oxygen atom in the side chain skeleton were synthesized to determine whether their differentiation-inducing activity could be separated structurally from their activity to induce hypercalcemia. The order of the in vitro potency to reduce nitroblue tetrazolium in human myeloid leukemia cells (HL-60) was 22-oxa-1 alpha, 25-(OH)2D3 greater than 1 alpha, 25-(OH)2D3 greater than 20-oxa-1 alpha, 25-(OH)2D3 not equal to 22-oxa-1 alpha-(OH)D3 greater than 1 alpha-(OH)D3 greater than 20-oxa-1 alpha-(OH)D3. 22-Oxa-1 alpha, 25-(OH)2D3 was also about 10-times more potent than 1 alpha, 25-(OH)2D3 in suppressing proliferation and inducing differentiation of mouse myelomonocytic leukemia cells (WEHI-3), but the former was much weaker than the latter in inducing the release of 45Ca from prelabeled fetal mouse calvaria. These results suggest that the differentiation-inducing activity of vitamin D compounds can be separated structurally from their activity to induce hypercalcemia.
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PMID:Synthetic analogues of vitamin D3 with an oxygen atom in the side chain skeleton. A trial of the development of vitamin D compounds which exhibit potent differentiation-inducing activity without inducing hypercalcemia. 282 55

Production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] by human T-lymphotropic virus-I (HTLV-I)-infected lymphocytes may be the cause of the hypercalcemia frequently found in HTLV-I-associated adult T-cell lymphoma/leukemia. We examined three HTLV-I-transformed lymphocyte cell lines, two HTLV-II-transformed lymphocyte cell lines, and six HTLV-negative B and T-lymphocyte leukemia cell lines for metabolism of 25-hydroxyvitamin D3 (25OHD3). One HTLV-I-positive cell line, designated S-LB1, converted the substrate 25OH-[3H]D3 to several more polar metabolites, which were identified by high performance liquid chromatographic analysis as putative 1,25-(OH)2D3, 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], and 1,24,25-trihydroxyvitamin D3 [1,24,25-(OH)3D3]. The other cell lines gave no evidence of 25OH-[3H]D3 metabolism. Likewise, phytohemagglutinin-stimulated normal human lymphocytes did not metabolize 25OH-[3H]D3. The characteristics of 25OHD3 metabolism by S-LB1 cells were investigated in more detail. Kinetic studies revealed average Km values of 92 and 383 nM for 25OHD3 1-hydroxylase and 24-hydroxylase, respectively. Time-course studies showed that both 1,25-(OH)2-[3H]D3 and 24,25-(OH)2-[3H]D3 were further metabolized by S-LB1 cells to more polar compounds [primarily 1,24,25-(OH)3D3] and to compounds from which part of the side-chain had been cleaved. Exogenous 1,25-(OH)2D3 (1) inhibited endogenous 1,25-(OH)2D3 production, (2) stimulated 24,25-(OH)2D3 production, and (3) stimulated production of compounds more polar than 1,25-(OH)2D3. Bovine PTH-(1-34) had no effect on 25OH-[3H]D3 metabolism by S-LB1 cells. Our results indicate that the 25OH-[3H]D3-metabolizing system of cultured HTLV-I-transformed S-LB1 lymphocytes is similar but not identical to that of kidney cell culture systems. It appears, however, that infection of lymphocytes with HTLV does not uniformly result in acquisition of the competence to metabolize 25OHD3.
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PMID:25-Hydroxyvitamin D3 metabolism by human T-lymphotropic virus-transformed lymphocytes. 288 83

Cultured human macrophages from normal donors were examined for their capability to metabolize 25-hydroxyvitamin D3 (25-(OH)D3). Upon exposure to recombinant human interferon-gamma (IFN-gamma) both bone marrow-derived macrophages (BMM) and pulmonary alveolar macrophages (PAM) produced a polar 25-(OH)D3 metabolite which was purified from conditioned media and unequivocally identified as 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) by UV-absorbance spectrophotometry and mass spectrometry. The BMM and PAM also synthesized a second 25-(OH)D3 metabolite which was structurally identified as 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3). The time course of 25-(OH)D3 metabolism by macrophages suggested that the production of 24,25-(OH)2D3 was stimulated by high intracellular levels of 1,25-(OH)2D3 and not by IFN-gamma. The 1,25-(OH)2D3 obtained from BMM and PAM promoted macrophage-like differentiation of promyelocytic HL-60 leukemia cells and inhibited IFN-gamma production by normal human lymphocytes. Our data suggest that locally high levels of 1,25-(OH)2D3 in the microenvironment of IFN-gamma-stimulated BMM and PAM may modulate the function of hormone-responsive cells.
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PMID:Synthesis in vitro of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 by interferon-gamma-stimulated normal human bone marrow and alveolar macrophages. 311 52

Human acute myelogenous leukemia often arises from a transformation at the stem cell level leading to a block in differentiation. The malignant cell, therefore, remains in the proliferative pool and rapidly accumulates. In preleukemia, also known as myelodysplastic syndromes, the malignant clone is already established, leading to disturbed hematopoiesis. One therapeutic approach, therefore, might be to overcome this block in differentiation and thus shift the cell from the proliferative into the differentiating pool. For several years now research in leukemia has focused on study of the proliferation and differentiation of normal and leukemic hematopoietic cells. Numerous substances have been identified which are able to trigger differentiation in myeloid cells, including the retinoids, vitamin D, tumor necrosis factor and hematopoietic hormones. The possible role of these agents in the treatment of preleukemia and acute myelogenous leukemias is discussed.
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PMID:[Induction of myelogenous differentiation: a therapeutic possibility for preleukemia and acute leukemia?]. 329 Nov 4

24-Oxa-vitamin D3 (24-oxa-D3) and 24-oxa-1 alpha-hydroxyvitamin D3 were designed as possible inhibitors of the vitamin D metabolic activation pathway. Their affinity for the vitamin D receptor (from pig intestine) and human vitamin binding protein were reduced, and their potency to induce cell differentiation of human leukemia cells (HL 60) or osteosarcoma cells (MG 63) was markedly reduced (19% and 3%, respectively), in comparison with calcitriol. A single or chronic injection of 24-oxa-D3 had no biological activity, whereas chronic administration of 24-oxa-1 alpha-hydroxy-D3 showed weak agonist activity in rachitic chicks. When the 24-oxa-D3 was given prior to a single injection of vitamin D3, lower values of serum calcium (64% of the value obtained in vitamin D-treated animals), osteocalcin (52%), 25-(OH)D3 (45%) and duodenal calbindin-D 28K (9.4%) were found. When given chronically in a 100-fold more excess no clear antagonistic effects were observed. 24-Oxa-D3 is thus a new metabolic weak antagonist of vitamin D3, but adding a hydroxyl group at C-1 creates a weak agonist.
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PMID:Antagonistic activity of 24-oxa-analogs of vitamin D. 767 83

The retinoid receptors belong to a large superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid hormone receptors, the peroxisome proliferator-activated receptor, the insect edysteroid receptor, and a number of orphan receptors whose ligands are unknown. All nuclear receptors have several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand binding domain at the carboxyl terminus of the receptor. The RAR and RXR classes of nuclear retinoic acid receptors are each composed of alpha, beta and gamma subtypes with more than one isoform for each receptor subtype. Data from many investigators suggest there are RAR- and RXR-dependent gene pathways, and that the individual receptor subtypes may control distinct gene expression patterns. In addition, RXR has been found to heterodimerize with other nuclear receptors to form active transcriptional complexes, which influence the activity of a variety of gene pathways important in growth and differentiation. As a result, retinoids have been useful clinical agents in Dermatology and Oncology. However, upon prolonged exposure to retinoic acid, resistance to retinoids has often been encountered both in the clinical setting and in long-term cell culture (HL60R and RAC65 cells). In the latter case, retinoid resistance has been associated with a mutation in the RAR gene which transcribes a RAR receptor truncated at the C-terminal end. These mutated RAR receptors exhibit a reduced affinity for retinoic acid while retaining the ability to bind to a retinoic acid response element on DNA. As a result, these mutant receptors exhibit dominant-negative activity by binding to the DNA without activating transcription and by competing with other receptors for sites on the response element. In fact, dominant-negative activity may be very important in the development of many neoplastic diseases, including acute promyelocytic leukemia (APL), where a t(15;17) chromosomal translocation fuses the PML gene to the RAR gene, to produce a PML-RAR fusion protein in large excess in the cell. However, retinoid resistance in the patient is most probably the result of pharmacokinetic problems, whereby, with continuous retinoid treatment, the plasma levels of retinoic acid gradually decrease to below that required to maintain differentiation of leukemic cells in vivo. A major challenge for drug discovery is to design a drug which circumvents these pharmacokinetic problems either by designing novel drug delivery systems or by employing retinoids which do not bind to CRABP, such as 9-c-RA.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994
PMID:The retinoid receptors. 780 17

The retinoid receptors belong to a large superfamily of ligand-inducible transcription factors that include the steroid, vitamin D and thyroid hormone receptors, the peroxisome proliferator-activated receptor, the insect edysteroid receptor, and a number of orphan receptors whose ligands are unknown. All nuclear receptors have several well-characterized structural domains, including a conserved DNA-binding domain, and a ligand binding domain at the carboxyl terminus of the receptor. The RAR and RXR classes of nuclear retinoic acid receptors are each composed of alpha, beta and gamma subtypes with more than one isoform for each receptor subtype. Data from many investigators suggest there are RAR- and RXR-dependent gene pathways, and that the individual receptor subtypes may control distinct gene expression patterns. In addition, RXR has been found to heterodimerize with other nuclear receptors to form active transcriptional complexes, which influence the activity of a variety of gene pathways important in growth and differentiation. As a result, retinoids have been useful clinical agents in Dermatology and Oncology. However, upon prolonged exposure to retinoic acid, resistance to retinoids has often been encountered both in the clinical setting and in long-term cell culture (HL60R and RAC65 cells). In the latter case, retinoid resistance has been associated with a mutation in the RAR gene which transcribes a RAR receptor truncated at the C-terminal end. These mutated RAR receptors exhibit a reduced affinity for retinoic acid while retaining the ability to bind to a retinoic acid response element on DNA. As a result, these mutant receptors exhibit dominant-negative activity by binding to the DNA without activating transcription and by competing with other receptors for sites on the response element. In fact, dominant-negative activity may be very important in the development of many neoplastic diseases, including acute promyelocytic leukemia (APL), where a t(15;17) chromosomal translocation fuses the PML gene to the RAR gene, to produce a PML-RAR fusion protein in large excess in the cell. However, retinoid resistance in the patient is most probably the result of pharmacokinetic problems, whereby, with continuous retinoid treatment, the plasma levels of retinoic acid gradually decrease to below that required to maintain differentiation of leukemic cells in vivo. A major challenge for drug discovery is to design a drug which circumvents these pharmacokinetic problems either by designing novel drug delivery systems or by employing retinoids which do not bind to CRABP, such as 9-c-RA.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994 Nov
PMID:The retinoid receptors. 796 25

Hypercalcemia in adult T-cell leukemia has been attributed to increased levels of 1,25-dihydroxyvitamin D (1,25(OH)2D), whereas in other types of leukemia, hypercalcemia has been blamed on direct skeletal invasion by malignant cells, ectopic parathyroid hormone (PTH) production or bone-resorbing cytokines. A 51-year-old man was studied who presented with back pain, circulating myeloblasts, and hypercalcemia. The bone marrow revealed acute myeloblastic leukemia. While the ionized calcium concentration was 8.17 mg/dL (normal, 4.73 to 5.21 mg/dL), the levels of PTH, PTH-related peptide, vitamin D, and thyroxine were normal or subnormal. Bone histomorphometry showed a decreased cortical width with intracortical erosion cavities dissecting into the marrow space. In cancellous bone, the osteoid area, osteoblast perimeter, and tetracycline fluorescence were sparse, whereas the osteoclast perimeter was increased. Persistent marrow fat, the general absence of trabecular narrowing, and the prompt response to calcitonin suggest that the osteoclasts caused the hypercalcemia and lytic lesions, rather than pressure atrophy or osteolysis by leukemic infiltration. Osteoclast activation and subsequent hypercalcemia may have been due to a locally produced cytokine, such as interleukin-1 beta or tumor necrosis factor.
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PMID:Case report: hypercalcemia in acute myeloblastic leukemia is caused by osteoclast activation. 812 79

Vitamin D3 and its hydroxylated metabolites are normally in thermal equilibrium with their previtamin D isomers. To evaluate the biologic activity of 1 alpha, 25-dihydroxyprevitamin D3, we synthesized 19-nor analogs of 1 alpha, 25-dihydroxy(pre)vitamin D3 because the absence of a C19 methylene group prevents the isomerization of these analogs. The affinity of 1 alpha, 25-(OH)2D3-19-nor-D3 for the intestinal vitamin D receptor and plasma vitamin D binding protein was mildly decreased [30 and 20% of the affinity of 1 alpha, 25-(OH)2D3, respectively], but the affinity of 1 alpha, 25-(OH)2-19-nor-previtamin D3 was only 1 and 6% of that of 1 alpha, 25-(OH)2D3 for the receptor and DBP, respectively. The in vitro effects on human promyeloid leukemia (HL-60 cell) differentiation and osteocalcin secretion by human osteosarcoma (MG-63) cells by 1 alpha, 25-(OH)2-19-nor-D3 were nearly identical to those of 1 alpha-25-(OH)2D3, whereas 19-nor-previtamin D3 showed poor activity (2%). The in vivo calcemic effects of both analogs, studied in vitamin D-deficient chicks treated for 10 consecutive days with the analogs, showed no activity of the previtamin D3 analog and reduced calcemic effects (< or = 10%) of 1 alpha, 25-(OH)2-19-nor-D3. We conclude that the previtamin D form of 1 alpha, 25-(OH)2D3 has lost most of its biologic activity in vitro and in vivo.
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PMID:Biologic activity of dihydroxylated 19-nor-(pre)vitamin D3. 821 51


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