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 development of a rapid rate of regeneration of osteomalacic bone in a patient treated for acute granulocytic leukemia has been demonstrated for the first time. This positive bone balance was most intense at the time of maximal depletion of leukemic tissue. The authors postulate that new formation of osteomalcic bone is due to inability to maintain the rate of calcification parallel to that of bone formation. A similar abnormality occurs in egg-laying birds, in rapidly growing children on a diet suboptimal in vitamin D who have rickets, and in some patients with osteoblastic metastases.
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PMID:Osteomalacic new bone formation during chemotherapy of acute granulocytic leukemia. 28 69

The active metabolite of vitamin D known as 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is a major physiologic regulator of mineral metabolism in man. The compound is also a potent inducer of differentiation of a human promyelocytic leukemia cell line known as HL-60. The induction of differentiation of myeloid leukemia cells to functional end cells offers an appealing therapeutic prospect. We investigated the ability of 1,25(OH)2D3 both to induce in vitro the differentiation of blast cells taken from patients with acute myelogenous leukemia and to improve hematopoiesis in vivo in patients with the myelodysplastic syndromes (preleukemia). We found that high concentrations (10-6 M) of 1,25(OH)2D3 significantly induced the in vitro differentiation of blast cells as measured by morphology, phagocytosis, and superoxide production. A concentration of 10-9 M 1,25(OH)2D3 had no effect on blast cell differentiation. We gave 2 microgram/day of 1,25(OH)2D3 to 18 patients with myelodysplastic syndrome (preleukemia) in an attempt to improve their hematopoiesis. During therapy, their peak peripheral blood granulocyte, platelet, and macrophage concentrations were slightly elevated as compared to their baseline, starting levels. Eight patients had a partial or minor peripheral blood response to the compound during the administration of 1,25(OH)2D3. However, no patient showed significant improvement of peripheral blood cell or marrow blast cell counts by the end of the study (greater than or equal to 12 weeks) as compared to their starting levels. Seven of the patients developed leukemia before or by 12 weeks of treatment. Nine of the 18 patients developed hypercalcemia. Taken together, the study shows that high concentrations (10-6M) of 1,25(OH)2D3 can induce differentiation of leukemia blast cells in vitro, but the administration of 1,25(OH)2D3 to patients with the myelodysplastic syndromes (preleukemia) does not have an enduring therapeutic effect. Hypercalcemia prevented administering greater amounts of 1,25(OH)2D3. In the future, the use of new vitamin D analogs that induce hematopoietic cell differentiation without inducing hypercalcemia might allow the achievement of higher blood levels of the inducing compound and might be medically useful for selected preleukemic and leukemic patients.
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PMID:1,25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells. 241 38

The expression of the myeloperoxidase (MPO) gene was studied, by means of Northern blot analysis in 14 cases of acute myeloid leukemia (AML), 11 cases of chronic myeloid leukemia (CML), and 6 cases of CML blast crisis, and in HL60 cells before and after induction of terminal differentiation with retinoic acid (RA), phorbol esters (TPA), or vitamin D. The expression of a panel of cell cycle-related genes, namely C-MYC, histone H3, ornithine decarboxylase, P53, vimentin, and calcyclin, was also studied in the same cell populations. Our results indicate that: (a) MPO gene expression (steady state mRNA levels) is strictly confined to the first stages of myeloid differentiation, reaching its peak at the promyelocyte stage and becoming undetectable in mature granulocytes and monocytes; (b) cells devoid of any detectable MPO enzymatic activity such as leukemic basophils have a high content of MPO mRNA; and (c) MPO gene expression is not related to the growth activity of the cell population. Finally, our results show that the pattern of expression of growth-regulated genes in the neoplastic myeloid disorders AML, CML, and CML blast crisis is remarkably different.
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PMID:Expression of the myeloperoxidase gene in acute and chronic myeloid leukemias: relationship to the expression of cell cycle-related genes. 254

Several new cytostatic drugs have entered clinical Phase I-II studies for treatment of leukemia: most promising are pyrimidine analogues such as 5-Azacytosine arabinoside, 5-Aza-2-deoxycytidine, 5-Azacytidine, cyclocytidine, and 2'-2'-difluorodeoxycytidine. They act on different biochemical levels towards DNA-synthesis. Fludarabine is a purin analogue and seems very active in treating CLL. Tiazofurin is an antimetabolite counter-acting nicotinic acid with most promising activity in CML blast crisis. Other substances include deoxycoformycin, an adenosine analogue for treatment of T-cell neoplasias, 1, 25-dihydroxy vitamin D 3 as differentiation inducer, and homoharringtonine, an alkylating agent widely used for treating de novo AML in China. New anthracyclines are THP-adriamycin, fluoroadriamycin, and 4-demethoxydaunorubicin. Amsacrine (mAMSA) finally, is a synthetic aminoacridine with DNA-intercalating properties. The intact acridine ring appears essential for antitumor activity. The plasma clearance of both total amsacrine and unchanged parent species is biphasic. There is a considerable influence of hepatic and renal impairment on plasma clearance. Clinical toxicities include marked myelosuppression, gastrointestinal symptomes, phlebitis, mucocutaneous lesions, occasionally alopecia and neurotoxities. It is a very active drug, particularly in treating AML. Studies using mAMSA alone or in combination revealed comparable results to the anthracyclines. The E.O.R.T.C. Leukemia Cooperative Group has used successfully mAMSA in several trials: relapsed and refractory AML, intensive maintenance treatment during first remission in AML, and, still on-going, during intensive consolidation randomized against BMT in AML-patients under the age of 45 years, and randomized against standard consolidation between the age of 45 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New drugs in the treatment of acute and chronic leukaemia: current role of mAMSA. 269 2

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

The capacity of retinoic acid (RA) and vitamin D to induce differentiation of HL-60 cells in an agar gel system that permits a high cloning efficiency was studied in the presence or absence of leukocyte-conditioned medium (LCM). Vitamin D was about 10 times more effective in inducing differentiation than RA. LCM significantly increased the differentiation-inductive capacity of both vitamins, although LCM did not have an effect of its own. During the first days of culture, the number of cells per clone increased with either vitamin or LCM alone as compared to control cultures. This suggests that cellular proliferation may be important in the initial phase of the differentiation induction. No synergy in this respect was found between RA and vitamin D in the presence or absence of LCM. Thus it is doubtful whether RA and vitamin D have a true synergistic effect on individual HL-60 cell differentiation as previously described in liquid cultures. Furthermore, the findings suggest that the process of differentiation induction regarding the growing cells in agar gel involves an all-or-none process. The data may also help elucide the observed relationship between the in vitro production of colony stimulating activity and favorable prognosis of AML.
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PMID:Clonal analysis of the response of HL-60 cells to retinoic acid and vitamin D in the presence or absence of leukocyte-conditioned medium. 340 89

We have identified a cDNA whose sequence is preferentially expressed when quiescent fibroblasts are stimulated to proliferate. The steady-state levels of the mRNA corresponding to this clone, called 2A9, are increased by serum, platelet-derived growth factor, and epidermal growth factor, but not by insulin or platelet-poor plasma. mRNA levels of 2A9 are also increased in human acute myeloid leukemia. The 2A9 cDNA has been molecularly cloned from an Okayama-Berg library, and its complete nucleotide sequence has been determined. It has an open reading frame of 270 nucleotides, which has a 55% homology with the coding sequence of the beta-subunit of the S-100 protein, a calcium-binding protein that belongs (like calmodulin and the vitamin D-dependent intestinal calcium-binding protein) to the family of calcium-modulated proteins and is found in abundance in several human tumors, including melanoma. The S-100 protein and the deduced aminoacid sequence of 2A9 are also partially homologous to the small subunit of a protein complex that serves as a cellular substrate to tyrosine kinase. The partial homology of 2A9 (whose RNA is inducible by growth factors and is overexpressed in human acute myeloid leukemias) to the S-100 protein, other calcium-modulated proteins, and the subunit of a substrate for tyrosine kinase, is particularly interesting in view of the role attributed to calcium and tyrosine kinases in the regulation of cell proliferation.
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PMID:Molecular cloning of the cDNA for a growth factor-inducible gene with strong homology to S-100, a calcium-binding protein. 375 24

This study shows for the first time that 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] and two fluorinated analogues of 1,25-(OH)2D3 [24,24-F2-1,25-(OH)2D3 and 26, 26, 26, 27, 27, 27-F6-1,25-(OH)2D3] induce macrophage differentiation of human normal and leukemic myeloid stem cells. The addition of either 1,25-(OH)2D3 or one of the two fluorinated analogues of 1,25-(OH)2D3 at concentrations as low as 10(-9) M to culture plates containing normal human marrow cells stimulated myeloid stem cells to preferentially differentiate to colonies of monocytes and macrophages. Over 80% of the normal human myeloid colonies were composed of only monocytes and macrophages in culture plates containing 10(-7) M 1,25-(OH)2D3 or one of the fluorinated analogues. In contrast, control plates not containing 1,25-(OH)2D3 had less than 35% macrophage colonies. Likewise, 1,25-(OH)2D3 and the two vitamin D analogues induced macrophage differentiation of leukemic colony-forming cells taken from patients. In plates containing 10(-7) M 1,25-(OH)2D3 or one of the analogues at 10(-8) M, 80% of chronic myelogenous leukemia and approximately 50% of acute nonlymphocytic leukemia colony-forming cells differentiated to macrophage-like cells. In contrast, control plates had about 30 and 20% macrophage colonies in cultures from chronic myelogenous leukemia and acute nonlymphocytic leukemia patients, respectively. Our findings suggest that 1,25-(OH)2D3 may play a role in hematopoiesis and that the compound or a related analogue may possibly have a therapeutic role in some leukemias.
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PMID:Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25-dihydroxyvitamin D3 and its fluorinated analogues. 659 94

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

We have used the vitamin D analogue, 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (Ro24-5531), for inhibition of mammary carcinogenesis induced by N-nitroso-N-methylurea (NMU) in Sprague-Dawley rats. Rats were first treated with a single dose of either 15 or 50 mg/kg body weight NMU and then fed Ro24-5531 (2.5 or 1.25 nmol/kg of diet) for 5-7 months. Ro24-5531 significantly extended tumor latency and lessened tumor incidence as well as tumor number in rats treated with the lower dose of NMU. In rats treated with the higher dose of NMU, Ro24-5531 was fed in combination with tamoxifen; in these experiments, Ro24-5531 significantly enhanced the ability of tamoxifen to reduce total tumor burden, as well as to increase the probability that an animal would be tumor free at the end of the experiment. In vitro, Ro24-5531 was 10-100 times more potent than 1,25-dihydroxyvitamin D3 for inhibition of proliferation of human breast cancer cell lines as well as primary cultures of cells from 2 patients with acute myelogenous leukemia. When fed chronically, Ro24-5531 did not elevate serum calcium in the present studies. We propose the new term, "deltanoids," for the set of molecules composed of vitamin D and its synthetic analogues, in a manner similar to the naming of "retinoids" for the corresponding set of molecules related to vitamin A.
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PMID:1 alpha,25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), a new deltanoid (vitamin D analogue) for prevention of breast cancer in the rat. 813 76


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