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)

The occurence of hypercalcemia appears to be unusual in leukemia. The mechanisms are numerous: secretion of PTH of PTH like substance, prostaglandin E2 or vitamin D like sterols. The reported case is one of lymphoblastic acute leukemia and hypercalcemia associated with osteoclast activating factor secreted by leukemic cells. In this patient the serum levels calcium closely paralleled the course of acute leukemia.
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PMID:[Hypercalcemia and osteoclast activating factor (OAF) associated with acute lymphoblastic leukemia (author's transl)]. 22 85

The pathogenesis of hypercalcemia and mode of action of glucocorticoid therapy was examined in a patient with lymphosarcoma cell leukemia. Circulating neoplastic cells were cultured in vitro and secreted a bone-resorbing factor. The bone-resorbing factor was partially purified with the use of a bioassay for bone resorption, and was found to be chromatographically and pharmacologically similar to osteoclast activiating factor (OAF), which is produced by normal mitogen-activated peripheral blood lymphocytes. Other factors which stimulate bone resorption, such as parathyroid hormone, prostaglandins and the vitamin D metabolites, were excluded by criteria which included dose-response curves, radioimmunoassays, extraction in organic solvents and failure of glucocorticoids to inhibit bone-resorbing activity. The patient's hypercalcemia responded rapidly to prednisone therapy. The effects of the bone-resorbing factor secreted by the neoplastic cells on bone cultures to which cortisol was added were examined. Cortisol inhibited bone resorption directly at low doses (10(-8) M), which suggests that prednisone may have lowered the serum calcium in this patient by direct inhibition of bone resorption.
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PMID:Pathogenesis of hypercalcemia in lymphosarcoma cell leukemia. Role of an osteoclast activating factor-like substance and a mechanism of action for glucocorticoid therapy. 70 20

There is mounting evidence that essentially all fungi, plants and animals living on earth produce provitamin D. It is likely that once exposed to sunlight, these provitamins are converted to previtamin D. It is unclear why fungi, phytoplankton, zooplankton and plants have the capacity to produce such large quantities of provitamin D. It is likely, however, that provitamin D and possibly vitamin D play an important biologic role in these organisms. Buchala and Schmid found, for example, that vitamin D3 promoted adventitious root development. It may be that provitamin D has a more fundamental function in lower life forms. Provitamin D and its photoproducts have UV absorption spectra that overlap with the ultraviolet absorption spectra from ultraviolet radiation-sensitive macromolecules including DNA, RNA and proteins. Thus, provitamin D and photoisomers could serve as a photon sink, and therefore, act as a natural sunscreen to protect lower life forms from the damaging effects of the high energy ultraviolet radiation that they are exposed to. It is more clear, however, that amphibians, reptiles, birds, mammals and humans all require vitamin D and that the vitamin D must be metabolized to 1,25(OH)2D3 before it can carry-out its physiologic functions on calcium and bone metabolism. The intense research activities during the past decade on the antiproliferative and differentiation activities of 1,25(OH)2D3 has opened a new chapter for this vitamin/hormone. 1,25(OH)2D3 and its analogs are being developed for the treatment of psoriasis, breast cancer, and leukemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evolutionary biology and pathology of vitamin D. 129 27

Interleukin-3 (IL-3), retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (calcitriol) (vitamin D) have achieved objective responses in phase I/II clinical trials in myeloid leukaemia and preleukaemia patients. In an effort to explore any additive or synergistic interactions between these biological agents which could provide the basis for improved therapeutic regimens for myeloid leukaemia patients, we have investigated the effects of IL-3 on both RA- and vitamin D-induced actions in HL-60 human myeloid leukaemia cells, which have receptors for these three agents, in both clonogenic microassays and liquid suspension cultures. The proliferative stimulus of IL-3 overrode and reversed the antiproliferative actions of both RA and vitamin D, the latter being more sensitive to the counter-acting effect of IL-3. Whereas only high concentrations of IL-3: 1000 or more U/ml were able to oppose the antiproliferative effect of RA, all concentrations of IL-3 including the low concentration of 10 U/ml, significantly counteracted the anti-proliferative action of vitamin D. RA restrained the proliferative stimulus of IL-3 partly at low physiological concentrations and almost completely at high pharmacological concentrations. The same results were reproduced in liquid suspension culture. Whereas RA restrained the proliferative stimulus of IL-3, vitamin D failed to restrain it. However, IL-3 did not induce differentiation or affect RA- or vitamin D-induced differentiation of HL-60 cells. The present results suggest that the clinical use of the combination of low concentration of IL-3 with RA and not with vitamin D might restrain the progression of myeloid leukaemia incurred during the treatment with IL-3 in some preleukaemic patients.
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PMID:Recombinant human interleukin-3 opposes the effects of vitamins A and D on HL-60 human myeloid leukaemia cells. 162 41

1.25 (OH)2D3 is a potent inducer of differentiation of leukaemic cells into a monocytic direction. However, therapeutic application is difficult because of the development of hypercalcaemia. We examined a novel vitamin D analogue, MC 903, which is at least 100 times less effective on calcium metabolism in rats than 1.25 (OH)2D3. Using the HL-60 cell line, differentiation was measured with a comprehensive panel of qualitative and quantitative parameters. Development of monocytic cells was shown morphologically, immunophenotypically and functionally by increased capability of reducing NBT (vs cultures without MC 903, p less than 0.0001) and by qualitatively and quantitatively increased non-specific esterase activity. Furthermore, a concomitant decreased activity of myeloperoxidase and lactate dehydrogenase was noticed. In conclusion, MC 903 is a potent inducer of monocytic differentiation, comparable with 1.25 (OH)2D3 and will therefore be an interesting and potential therapeutic agent for studies in human acute leukaemia.
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PMID:Monocytic differentiation induction of HL-60 cells by MC 903, a novel vitamin D analogue. 162 69

During the process of enhancing monocytic differentiation of the human leukemia line HL-60, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) also "primes" the cell for respiratory burst by increasing the uptake of Ca2+ across the plasma membrane (Hruska, K.A., Bar-Shavit, Z., Malone, J.D., and Teitelbaum, S.L. (1988) J. Biol. Chem. 263, 16039-16044). The present study asked if the maturational effect of vitamin D is dependent upon this "priming" phenomenon. To this end, we exposed HL-60 to either 1,25(OH)2D3 or its synthetic analogue (1 alpha, 3 beta, 5Z, 7E)-9-10-Secocholesta-5,7,10(19)-triene-1, 3, 25-triol (22-oxa). We found that 22-oxa induced HL-60 maturation as effectively as does the natural steroid. As expected, 48 h of 1,25(OH)2D3 exposure more than doubles (p less than 0.005) HL-60 basal cytosolic Ca2+ and increases inositol triphosphate-sensitive Ca2+ stores approximately 4-fold (p less than 0.01). 22-oxa in contrast alters neither Ca(2+)- nor inositol triphosphate-mobilizable deposits. Moreover, 1,25(OH)2D3 treatment prompts a transient Ca2+ "spike" in response to formyl-methionyl-leucyl-phenylalanine (fMLP) and a marked increase in superoxide (O-2) generation when exposed to the chemotactic peptide (p less than 0.01) or phorbol ester (p less than 0.02). Treatment with 22-oxa does not enable HL-60 to respond to fMLP with a Ca2+ spike or prime the cell for respiratory burst unless it is co-incubated with the Ca2+ ionophore, ionomycin. Similarly, phorbol ester impacts more profoundly on O-2 generation by 1,25(OH)2D3 than 22-oxa preincubated cells (p less than 0.02), unless the latter is added with ionomycin. Our findings indicate that the maturational effects of vitamin D sterols are independent of their capacity to prime cells for respiratory burst and that the Ca2+ ionophoretic effects of 1,25(OH)2D3 play a major role in such priming.
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PMID:Disassociation of the macrophage-maturational effects of vitamin D from respiratory burst priming. 164 14

22-Oxacalcitriol (OCT), a synthetic vitamin D analog, can mimic the ability of 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] to differentiate leukemia and skin cells, to enhance the immune response and to suppress PTH secretion, but has much less calcemic activity. The mechanism for this selective action is not understood. OCT has been shown to have a diminished ability to mobilize calcium from bone in vivo, but in vitro findings are contradictory. Little is known about the effect of OCT on bone forming cells. Therefore, the present studies were designed to investigate the actions of OCT at the molecular level in the osteoblast-like cell line, ROS 17/2.8. 3H-OCT was bound to the vitamin D receptor (VDR) in intact cells at the same rate as 3H-1,25-(OH)2D3. As previously found for 1,25-(OH)2D3, the time course of specific binding of OCT was biphasic, with an initial plateau at 1 h and a further increase from 2-8 h. Scatchard analysis demonstrated that exposure to 3H-1,25-(OH)2D3 increased VDR from 24 fmol/mg protein at 2 h to 85 fmol/mg protein at 8 h. Exposure to 3H-OCT increased VDR from 22 to 76 fmol/mg protein, indicating that OCT is also capable of up-regulating the VDR in ROS 17/2.8 cells. In contrast to the lower affinity of OCT for VDR reported for chick intestine and HL-60 cells, the Kd for OCT in intact ROS 17/2.8 cells was identical to that for 1,25-(OH)2D3. The effect of OCT on osteocalcin secretion and alkaline phosphatase (ALP) activity in ROS 17/2.8 cells was also determined. Pretreatment for 24 h with either 1,25-(OH)2D3 or OCT resulted in a dose-dependent enhancement of osteocalcin secretion. A 2-fold stimulation by both compounds was observed with 10(-7)M. ALP activity was measured after a 72-h incubation with 10(-7)M 1,25-(OH)2D3 or OCT. Both compounds increased ALP activity to the same extent. Stimulation by OCT of VDR levels, ALP activity, and osteocalcin secretion were inhibited by the addition of 5 microM cycloheximide, indicating that these actions of OCT require new protein synthesis. Thus, OCT, like 1,25-(OH)2D3, up-regulates the vitamin D receptor, stimulates osteocalcin secretion, and increases ALP activity in ROS 17/2.8 cells, suggesting that the analog may be as active as 1,25-(OH)2D3 in stimulating bone formation in vivo. The low activity of OCT in mobilizing calcium from bone in vivo does not appear to be due to an inability of this compound to act on osteoblasts.
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PMID:The activity of 22-oxacalcitriol in osteoblast-like (ROS 17/2.8) cells. 164 45

Biological activity of 24-epi-1 alpha,25-dihydroxyvitamin D-2 (24-epi-1,25(OH)2D2) and 1 alpha,25-dihydroxyvitamin D-7 (1,25(OH)2D7), the 22,23-dihydro derivative of the former compound, was investigated. Both of the vitamin D derivatives stimulated intestinal calcium transport and calcium mobilization from bones in rats; however, the effect was about 50% of that of 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)2D3). On the other hand, 24-epi-1,25(OH)2D2 and 1,25(OH)2D7 inducement of HL-60 human leukemia cell differentiation was comparable to that of 1,25(OH)2D3. Accordingly, the differentiation-inducing activity of 24-epi-1,25(OH)2D2 and 1,25(OH)2D7 was much greater than their ability to stimulate calcium metabolism. In contrast to 1,25(OH)2D3, 24-epi-1,25(OH)2D2 and 1,25(OH)2D7 exerted little hypercalcemic activity in mice. These results suggest that both vitamin D derivatives will be useful as anti-tumor agents.
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PMID:Biological activity of 1 alpha, 25-dihydroxyvitamin D derivatives--24-epi-1 alpha, 25-dihydroxyvitamin D-2 and 1 alpha,25-dihydroxyvitamin D-7. 199 78

Myeloid leukemia cells of human and murine origin can be induced to differentiate into more mature forms which lose their neoplastic properties. The hormonal form of vitamin D is a powerful inducer of monocytic differentiation, but its therapeutic use is limited by hypercalcemia. It was recently reported that a novel derivative of vitamin D, 1,25-dihydroxy-16-ene-23-yne-vitamin D3, is an exceptionally potent inducer of monocytic differentiation, and prolongs survival of mice bearing leukemia cells. We now show that this compound is also a most potent inhibitor of erythrodifferentiation. This finding has important implications for the control of hematopoiesis.
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PMID:Vitamin D analogs inhibit erythroid differentiation and induce monocytic differentiation of leukemic cells with the same relative potency. 203 Oct 57

The hormonally active form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], is an efficient stimulator of intestinal calcium absorption (ICA) and bone calcium mobilization (BCM) in humans and experimental animals and, as well, has been shown to be effective in inducing differentiation and inhibiting proliferation of leukemia cells. Thus, it has been proposed that analogues of 1,25(OH)2D3 could be synthesized which might allow for separation of biological functions, i.e., promote a differentiation of leukemia cells without a significant stimulation of ICA or BCM, both biological effects which can cause hypercalcemia in humans. Here we report the results of an evaluation of four analogues of the previously studied (Zhou et al., Blood, 74:82-92, 1989) 1 alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 [1,25(OH)2-16-ene-23-yne-D3]; these analogues allowed evaluation of the consequences of (a) the presence or absence of six deuterium atoms on carbons 26 and 27 of the side chain and (b) the deletion or substitution by a fluorine atom of the 1 alpha-hydroxyl group on the A-ring. The 1,25(OH)2-16-ene-23-yne-D3 analogue was found to be 7-fold more potent than the parent 1,25(OH)2D3 with respect to (a) inhibition of clonal proliferation of HL-60 cells as well as (b) induction of differentiation of HL-60 promyelocytes. Variants of this analogue which possessed the six deuterium atoms on carbons 26 and 27 were slightly less active than the 1,25(OH)2-16-ene-yne-D3. However, replacement of the 1 alpha-hydroxyl group by a 1-fluoro group, or the absence of the 1-hydroxyl group, resulted in analogues that were somewhat less effective than the parent 1,25(OH)2D3 in achieving these biological responses but more potent as inhibitors of the renal mitochondrial 25-OH-D3-1 alpha-hydroxylase, the site of endogenous production of 1,25(OH)2D3. ICA and BCM were assessed in vivo in vitamin D-deficient chickens, and each of the analogues was markedly less potent than the standard 1,25(OH)2D3. The analogue 1,25(OH)2-16-ene-23-yne-D3 had 2% of the ICA and 3% of the BCM activity of the parent 1,25(OH)2D3. Absence of the 1 alpha-hydroxyl group or substitution of the 1-fluoro group for the 1-hydroxyl group significantly diminished both the ICA and BCM activity in comparison to 1,25(OH)2-16-ene-23-yne-D3. Receptor binding studies indicated that 1,25(OH)2-16-ene-23-yne-D3 competed about 75% as effectively as 1,25(OH)2D3 for 1,25(OH)2D3 receptors present in both chick intestinal cells and HL-60 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Structure-function studies on analogues of 1 alpha,25-dihydroxyvitamin D3: differential effects on leukemic cell growth, differentiation, and intestinal calcium absorption. 220 53


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