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PubMed2002

1,25-dihydroxycholecalciferol: endocrinology meets the immune system.

Previous work has demonstrated that, besides its effects on Ca and bone metabolism, the active form of cholecalciferol, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), possesses pronounced immunomodulatory effects. In non-obese diabetic (NOD) mice primary (before disease onset), secondary (after insulitis but before diabetes onset) as well as tertiary (after transplantation of syngeneic islets) prevention of diabetes was demonstrated with 1,25(OH)2D3 and its chemically-manufactured non-hypercalcaemic analogues. 1,25(OH)2D3 exerts its immune effects both at the level of the T lymphocyte (shift in cytokine profile from T-helper (Th)1 to Th2, enhanced sensitivity to apoptosis-inducing signals) as well as at the level of the antigen-presenting cell (reduced antigen presentation, reduced production of Th1-promoting cytokines, reduced expression of co-stimulatory molecules). Also, physiologically, 1,25(OH)2D3 is believed to have a role in the immune system by serving as a negative feedback signal, limiting the mounted immune reaction. To test the clinical applicability of 1,25(OH)2D3 as treatment for type 1 diabetes in genetically-at-risk young children, we tested whether short-term early-life intervention with cholecalciferol or non-hypercalcaemic analogues of 1,25(OH)2D3 could prevent diabetes in NOD mice. Significant protection of pancreatic beta cells against autoimmune destruction was observed in analogue-treated and especially in cholecalciferol-treated NOD mice as compared with controls (P<0.005). This short-term early-life intervention was, however, not able to protect the mice from developing diabetes during their lifetime. Possible solutions are longer or combined treatments with other immunomodulators that have synergistic effects with 1,25(OH)2D3 and its analogues.

Animals↗

PubMed1976

Studies on the 1alpha, 25-dihydroxycholecalciferol-like activity in a calcinogenic plant. Cestrum diurnum, in the chick.

Cestrum diurnum (day-blooming jessamine) has been proposed to cause calcinosis in horses and cattle in Florida. The present studies investigated some physiological properties of the plant, using the chick as the experimental animal. The inclusion of dried leaf powder in a rachitogenic diet restored intestinal calcium-binding protein synthesis (CaBP) and increased calcium absorption in the cholecalciferol-deficient chick. The estimated level of cholecalciferol-equivalents in the dried leaf was about 30,000 to 35,000 IU/kg. Most of the activity was extractable with methanol:chloroform (2:1), indicating that the major cholecalciferol-like component in C. diurnum was different from the water soluble factor(s) in Solanum malacoxylon. The time course of effect of C. diurnum extract in rachitic chicks was similar to that ot 1,25-dihydroxycholecalciferol but the former had a longer lag time. The strontium fed chick, in which the kidney 25-hydroxycholecalciferol-1alpha-hydroxylase is inhibited, responded to C. diurnum extract, confirming the 1alpha,25-dihydroxycholecalciferol-like character of the Cestrum factor. The extract also appeared to interact with the intestinal 1 alpha,25-dihydroxycholecalciferol cytosol receptor although this observation is preliminary. These findings indicate that the l alpha,25-dihydroxycholecalciferol-like principle in C. diurnum many cause excessive calcium and phosphate absorption leading to calcinosis.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1984

Hydroxylation of carbon-24 of 25-hydroxycholecalciferol is not necessary for normal embryonic development in chickens.

Laying hens fed 25-hydroxycholecalciferol, 24,24-difluoro-25-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol or 24,25-dihydroxycholecalciferol were used to investigate whether hydroxylation of C-24 of cholecalciferol is necessary for normal embryonic development in chickens. Laying hens were fed a rachitogenic diet and 25-hydroxycholecalciferol from hatching until normal egg production, fertility and hatchability were achieved. When the hens were 40 weeks old, 25-hydroxycholecalciferol was withdrawn and egg production ceased in 4 weeks. The hens were divided into 6 groups of 5 and dosed daily for 19 weeks with either 2.0 micrograms of 25-hydroxycholecalciferol, 2.0 micrograms of 24,24-difluoro-25-hydroxycholecalciferol, 0.4 microgram of 1,25-dihydroxycholecalciferol, 2.0 micrograms of 24,25-dihydroxycholecalciferol, both 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol or vehicle only. Egg production during this period was high for all hens fed the cholecalciferol compounds. Egg production of 3% occurred in hens given vehicle only. Fertility was over 90% for all groups of cholecalciferol compound-fed hens. Hatchability of over 90% was achieved with the eggs from hens given 25-hydroxycholecalciferol or 24,24-difluoro-25-hydroxycholecalciferol and 6% with eggs from hens fed both 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol. No eggs from hens fed 1,25-dihydroxycholecalciferol or 24,25-dihydroxycholecalciferol alone hatched (over 140 eggs in each group.

24,25-Dihydroxyvitamin D 3↗

PubMed1985

Dietary calcium and vitamin D: risk factors in the development of atherosclerosis in young goats.

Effects of supplemental dietary calcium and vitamin D on lipid distribution and aortic mineralization were examined in young goats. Twenty-four goats, 2-4 wk of age, were allotted one of four dietary treatments for a 20-wk period and fed a basal milk diet (Basal), a calcium-supplemented diet (Basal + Ca), a cholecalciferol-enriched diet (Basal + D3) or a diet with both calcium and cholecalciferol (Basal + Ca + D3). Goats in the Basal + Ca group had plasma cholesterol concentrations that were 16.6% of those of the Basal group. Percentage absorption and fecal excretion of total lipids were unaffected by dietary treatment. Generally, total lipid and cholesterol concentrations were unaltered in liver, other viscera and carcass tissues. Dietary cholecalciferol increased concentrations of cholesterol and total lipid in aortas, whereas dietary calcium decreased total lipids in aortas. Concentrations of calcium, magnesium and total ash were increased in aortas by dietary treatment, with a marked increase observed in the Basal + Ca + D3 group. Sudan IV and gross calcium staining in aortas revealed both lipid and mineral deposition that confirmed composition data. A high intake of vitamin D accompanied by excessive intake of calcium seems to accelerate the development of atherosclerosis. Supplemental calcium with normal amounts of vitamin D, however, is hypocholesterolemic and seems protective against the atherogenic process.

Animals↗

PubMed1988

Immunochemical evidence for the catalysis of vitamin D3 25-hydroxylation and testosterone 16 alpha-hydroxylation by homologous forms of cytochrome P-450 in rat liver microsomes.

Polyclonal antibody elicited in a rabbit against purified cytochrome P-450cc25, which catalyzes 25-hydroxylation of vitamin D3, inhibited not only 25-hydroxylation of cholecalciferol and 1 alpha-hydroxycholecalciferol, but also 16 alpha- and 2 alpha-hydroxylation of testosterone catalyzed by the purified P-450cc25 preparation. Antibody inhibition experiments with microsomes revealed that most 16 alpha- and 2 alpha-hydroxylation of testosterone and most 25-hydroxylation of cholecalciferol by male rat liver microsomes were catalyzed by P-450cc25. In order to examine the identity of cholecalciferol 25-hydroxylase and testosterone 16 alpha-hydroxylase, monoclonal antibodies recognizing three different epitopes of P-450cc25 were prepared from hybridoma clones produced by fusion of mouse myeloma cells (P3X63Ag8U1) with the spleen cells of immunized BALB/c mouse. All of these monoclonal antibodies inhibited both 25-hydroxylation of 1 alpha-hydroxycholecalciferol and 16 alpha-hydroxylation of testosterone by purified P-450cc25. These observations suggested that immunochemically indistinguishable form(s) of cytochrome P-450 catalyzed both reactions.

Animals↗

PubMed1986

Isolation of a cytochrome P-450 that catalyzes the 25-hydroxylation of vitamin D3 from rat liver microsomes.

A molecular species of cytochrome P-450 that catalyzes the 25-hydroxylation of cholecalciferol (P-450cc25) was purified from rat liver microsomes on the basis of its catalytic activity. The purification procedure consisted of polyethylene glycol fractionation, and column chromatographies on octylamino Sepharose 4B, hydroxylapatite, DEAE-Sepharose CL-6B, and CM-Sepharose CL-6B. The specific cytochrome P-450 content of the final preparation was 17.0 nmol/mg of protein. The enzymatic activity was reconstituted with the purified cytochrome P-450, NADPH-cytochrome P-450 reductase, an NADPH-generating system, and dilauroylglyceryl-3-phosphorylcholine, the specific activity obtained being 3.7 nmol/min/mg of protein, which was 4,000 times as high as that in microsomes. The apparent molecular weight of the P-450cc25 was 50,000, based on the results of sodium dodecyl sulfate polyacrylamide gel electrophoresis. The absorption spectra of the oxidized form of the enzyme showed a Soret band at 416 nm, which is typical of the low spin state of cytochrome P-450, and alpha and beta bands at 570 and 536 nm, respectively. The Soret peak of the reduced cytochrome P-450-CO complex was at 450 nm. The purified enzyme not only catalyzed the 25-hydroxylation of cholecalciferol but also showed hydroxylation activity toward a variety of substrates, i.e. 1 alpha-hydroxycholecalciferol (at 25), testosterone (at 2 alpha and 16 alpha) and dehydroepiandrosterone (at 16 alpha). Amino terminal sequence of the purified cytochrome P-450 was determined by the manual sequence method to be H2N-Met-Asp-Pro-Val-leu-Val-Leu-Val-. The antibody elicited against the purified enzyme in a rabbit inhibited the cholecalciferol 25-hydroxylation activity by more than 90% with a concentration of 2 mg of immunoglobulin per nmol of cytochrome P-450.

Amino Acids↗

PubMed1981

Serum concentrations of metabolites of vitamin D in patients with chronic renal failure (CRF). Consequences for the treatment with 1-alpha-hydroxy-derivatives.

In forty-two patients with chronic renal failure (CRF), serum concentrations of 25-hydroxy-cholecalciferol (25-OHCC), 24,25-dihydroxy-cholecalciferol (24,25-OH2CC) and 1,25-dihydroxy-cholecalciferol (1,25-OH2CC) were measured before and during intermittent haemodialysis (IHD) and in a few cases also after renal transplantation. 25-OHCC and 24,25-OH2CC were measured by means of a competitive protein binding assay after Sephadex LH20 chromatography and 1,25-OH2CC by means of a radioimmunoassay after Sephadex LH20 and high pressure liquid chromatography (HPLC). In our patients serum values for 25-OHCC and 24,25-OH2CC showed a seasonal fluctuation as in normal individuals. The concentrations in the serum of 24,25-OH2CC and 1,25-OH2CC showed a positive correlation with renal function. With regard to 24,25-OH2CC this correlation was only found for the 24,25-OH2CC:25-OHCC ratio which was used to eliminate the seasonal fluctuation. For both dihydroxylated metabolites subnormal concentrations were found when the creatinine clearance was 40-50 ml/min and lower. It appears that the decrease of the plasma level of these metabolites of Vitamin D precedes (or is concomitant with) the changes in the serum values of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) and the diminution of the intestinal absorption of Ca. These findings indicate that patients with CRF should be treated at an early stage of the disease with 1 alpha-hydroxy-derivatives of Vitamin D in order to prevent the development of, or to induce the healing of, bone-lesions of renal osteodystrophy.

24,25-Dihydroxyvitamin D 3↗

PubMed1975

Specific binding of 1alpha,25-dihydroxycholecalciferol to nuclear components of chick intestine.

Specific binding of 1alpha,25-dihydroxycholecalciferol to macromolecular components of small intestinal mucosa nuclei is demonstrated in vitamin D-deficient chicks. The nuclear 1alpha,25-dihydroxycholecalciferol-macromolecule complex was isolated on sucrose density gradients and sediments at 3.7 S in the presence of 0.3 M KCl. Agarose gel filtration of the nuclear component indicated an apparent molecular weight of 47,000. The nuclear receptor complexes could not be distinguished from previously described cytoplasmic 1alpha,25-dihydroxycholecalciferol-binding components by the ultracentrifugation and chromatographic procedures employed. The association of the 3-H-sterol with the nuclear component is thermolabile and is destroyed by treatment with pronase, but not by nucleases; the receptor component is therefore presumed to be a protein. The macromolecular-1alpha,25-dihydroxycholecalciferol complex formed in vivo or in vitro at 25 degrees can be extracted from intestinal nuclei by 0.3 M KCl, but not by low salt buffers. Smaller amounts of the 3.7 S binding component can be detected in isolated purified chromatin or after incubation of 1alpha,25-dihydroxy[3-H]cholecalciferol with reconstituted cytosol-chromatin at 0 degrees. Following incubation of the labeled hormone with reconstituted cytosol-chromatin at 0 degrees, 1alpha,25-dihydroxy[3-H]cholecalciferol is primarily associated with the cytoplasmic receptor, After shifting the incubation temperature to 25 degrees, a progressive increase in the concentration of the nuclear receptor complex and a concomitant decrease in the concentration of the cytoplasmic binding component occur. Thus the 1alpha,25-dihydroxycholecalciferol binding molecules appear to exist primarily in the cytoplasm, where they presumably function to transport the hormone into the nucleus. Experiments employing incubation of 1alpha,25-dihydroxy[3-H]cholecalciferol with reconstituted cytosol-chromatin from nontarget tissues indicate a requirement for both intestinal cytosol and chromatin for maximal formation of the nuclear hormone-receptor complex. These results suggest that the nuclear-binding component arises from hormone-dependent transfer of the cytoplasmic 1alpha,25-dihydroxycholecalciferol receptor to intestinal chromatin acceptor sites.

Animals↗

PubMed1985

Improved radioimmunoassay for vitamin D and its use in assessing vitamin D status.

We describe a faster, more-sensitive radioimmunoassay for vitamin D in plasma. Antibodies were generated in rabbits immunized with a new vitamin D analog, the 23,24,25,26,27-pentanor-C(22)-carboxylic acid of vitamin D, coupled directly with bovine serum albumin. After several months, Rivanol-treated sera from the rabbits contained high-titer antibodies, as determined by their abilities to bind 25-hydroxy-[3H]cholecalciferol. The antibody, used at a 1:15 000 final dilution, cross reacted equally with all cholecalciferol and ergocalciferol metabolites tested except 1,25-dihydroxycalciferol metabolites and the parent calciferols. 25-Hydroxycalciferol and similar forms were efficiently extracted from plasma or serum with acetonitrile. We separated bound from free 25-hydroxy-[3H]cholecalciferol by using a second antibody: goat antiserum to rabbit serum. The detection limit of the assay was 3.0 pg of 25-hydroxycholecalciferol and its equivalents per tube; thus only 1 microL of plasma is needed per assay tube. Results compared well with those from a liquid-chromatographic procedure involving specific ultraviolet detection of 25-hydroxycalciferol in plasma.

Animals↗

PubMed2001

Sustained-release sodium fluoride in the treatment of the elderly with established osteoporosis.

BACKGROUND: We ascertained the safety and efficacy of fluoride in augmenting spinal bone mass and reducing spinal fractures in older women with established osteoporosis. We compared a combination of sustained-release sodium fluoride, calcium citrate, and cholecalciferol (SR-NaF group) with calcium and cholecalciferol alone (control group). METHODS: Eighty-five ambulatory women aged 65 years or older with 1 or more nontraumatic vertebral compression fractures were enrolled in a 42-month randomized, double-blind, placebo-controlled trial. Primary outcome measures were vertebral fracture rate, bone mass, and safety. RESULTS: The vertebral fracture rate determined by means of computer assistance in the SR-NaF group was significantly lower than that in the control group (relative risk [RR], 0.32; 95% confidence interval [CI], 0.14-0.73; P =.007). Results of visual adjudicated inspection also confirmed a significant reduction in fracture rate (RR, 0.40; 95% CI, 0.17-0.95; P =.04). Bone mineral density in L2 through L4 increased significantly from baseline in the SR-NaF group by 5.4% (95% CI, 2.7%-8.2%; P<.001), and by 3.2% in the control group (95% CI, 0.8%-5.6%; P =.01). The between-group differences in bone mineral density were not significant. The femoral neck and total hip bone mineral density remained stable in the SR-NaF group and was not significantly different from that of the control group. There were no significant differences in adverse effects between groups. CONCLUSION: The SR-NaF group significantly decreased the risk for vertebral fractures and increased spinal bone mass without reducing bone mass at the femoral neck and total hip.

Aged↗

PubMed1980

Vitamin D metabolism in patients treated with phenytoin and phenobarbitone.

There are many reports of abnormalities in calcium metabolism and even of frank osteomalacia in patients taking anticonvulsant drugs. Although enzyme induction has been suggested to be the cause of increased requirements for vitamin D leading to these changes, this has still to be proved. We have studied the metabolism of [3H]cholecalciferol and 25-hydroxycholecalciferol in subjects taking anticonvulsant drugs. The rate of removal of cholecalciferol from the plasma was no different from that in control subjects and no abnormality was detected in the production of disappearance of 25-hydroxycholecalciferol. However, plasma concentrations of 25-hydroxycholecalciferol fell more rapidly during the winter in epileptic subjects than in control subjects. Our results do not confirm that these changes are due to enzyme induction.

Calcifediol↗

PubMed2006

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia.

1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D(3) in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D(-) murine myelomonocytic leukemia cells induced by 1 nM 1,25D(3) or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 microM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G0 + G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 microg Ro25-4020 in Balb/c mice bearing WEHI-3B D(-) tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 microg Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia.

Abietanes↗

PubMed1981

Decreased 1,25-dihydroxycholecalciferol and increased 25-hydroxy- and 24,25-dihydroxycholecalciferol in tissues of rats treated with thyroxine.

The effect of thyroxine on the metabolism of vitamin D was investigated in rats. Vitamin D depleted rats were repleted by injections of radiolabelled cholecalciferol or 25-hydroxycholecalciferol (25OHD3). After 3 weeks, a state of hyperthyroidism was induced by daily injections of L-thyroxine for 21 days. The lipid extracts of the Plasma and tissues were analyzed by successive Sephadex LH-20 and high pressure liquid chromatography. The concentrations of 25OHD3 and of 24,25-dihydroxycholecalciferol (24,25 (OH)2D3) were significantly higher and those of cholecalciferol and of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) were significantly lower in the plasma and tissues of animals treated with thyroxine than in controls. The present study suggests that alterations in the metabolism of vitamin D may be involved in the disturbances of calcium metabolism observed in hyperthyroidism.

24,25-Dihydroxyvitamin D 3↗

PubMed2001

[Osteoporosis and multiple pregnancy--a case report with positive outcome].

BACKGROUND: Pregnancy-associated osteoporosis is a rare condition. Due to the rareness of pregnancy-associated osteoporosis, no guidelines concerning an adequate therapy exist. However, since many antiresorptive drugs are potentially teratogenous, the therapeutic approach is limited. CASE REPORT: In a 30-year-old patient, pubic fracture occurred during her first pregnancy. Osteodensitometry revealed a distinct osteoporosis. The bone density improved under therapy with sex hormones, alendronate, 1,000 mg calcium and 1,000 IU cholecalciferol daily, but still remained osteoporotic when the patient again became pregnant 3 years later. During her triplet pregnancy the patient was treated with 3,000 mg calcium and 1,500 IU cholecalciferol daily. After delivery the bone density remained at the same level as immediately before the second pregnancy. CONCLUSION: Regarding the nonoccurrence of the expected considerable bone loss with this treatment the efficacy of this therapeutic approach during pregnancy warrants further study.

Adult↗

PubMed1998

Effect of 5-aza-2'-deoxycytidine and vitamin D3 analogs on growth and differentiation of human myeloid leukemic cells.

PURPOSE: The object of this study was to investigate the antineoplastic action of 5-aza-2'-deoxycytidine (5-AZA) in combination with vitamin D analogs on HL-60 and NB-4 myeloid leukemic cells. The vitamin D analogs chosen for this investigation were 1,25-(OH)2-23-yne-cholecalciferol (23-D) and 1,25-(OH)2-delta16-23-yne-cholecalciferol (16-23-D) since they have the potential to be used clinically owing to their minimal action on calcium metabolism. METHODS: HL-60 and NB-4 leukemic cells were incubated with different concentrations of 5-AZA and either 23-D or 16-23-D and their antineoplastic action determined by inhibition of DNA synthesis and growth, induction of differentiation and colony assay. RESULTS: 5-AZA in combination with either vitamin D analog produced a greater growth inhibition and induction of differentiation than either agent alone. For HL-60 leukemic cells the combination of 5-AZA with either analog produced a synergistic loss of clonogenicity. These effects on clonogenicity correlated with the effects of the combination on inhibition of growth and DNA synthesis. CONCLUSION: These results suggest that vitamin D analogs may enhance the antileukemic action of 5-AZA and that it may be interesting to test these agents in combination in patients with myeloid leukemia.

Antimetabolites, Antineoplastic↗

PubMed1984

Effect of vitamin D and its metabolites on developing myogenic cultures.

Growth, protein synthesis and expression of creatine kinase (CK) by embryonic chick myogenic cells are inhibited by vitamin D and certain of its metabolites. 25-OH cholecalciferol was most active in concentrations of 10(-5) - 10(-6) M, with cholecalciferol and ergocalciferol less active in that order. Ergosterol had no activity of this sort. Inhibition of CK was most marked on the 4th and 5th day of culture and was due to suppression of the appearance of CK-NM and MB. CK-BB was not affected and CK-MB was more affected than CK-BB. Skin fibroblasts by comparison were slightly stimulated in growth at 10(-6) M and much less affected at 10(-5) M than the myogenic cells. It is suggested that vitamin D has a direct effect upon the muscle cell, to cause a selective diminution in the production of certain polypeptides.

Animals↗

PubMed1984

Pain threshold and morphine activity in vitamin D-deficient rats.

In rats, vitamin D-deficiency increases basal pain threshold and the analgesic effect of morphine (hot plate test). Cholecalciferol (1000 I.U./Kg/day s.c.x 5 days) restores pain sensitivity in vitamin D-deficient rats and brings the analgesic effect of morphine back to normal. On the other hand, tolerance to morphine develops faster in vitamin D-deficient rats, this effect too being prevented by cholecalciferol treatment. These data suggest a role for vitamin D status in pain sensitivity and opiate activity.

Animals↗

PubMed1993

Interaction of retinoic acid and vitamin D3 analogs on HL-60 myeloid leukemic cells.

Retinoic acid (RA) is an interesting agent which has been shown to induce differentiation and complete remission in patients with acute promyelocytic leukemia. 1,25-(OH)2-delta 16-23-yne-cholecalciferol (16-23-D3) and 1,25-(OH)2-23-yne-cholecalciferol (23-D3) are vitamin D3 analogs capable of inducing differentiation of myeloid leukemic cells with little effect on either calcium absorption or mobilization. Using HL-60 myeloid leukemic cells as in vitro model for human acute myeloid leukemia we observed an additive to synergistic interaction between RA and 16-23-D3 or 23-D3 with respect to the inhibition of cell growth and DNA synthesis, the induction of differentiation and the loss of cell clonogenicity. In addition, we observed that RA and 16-23-D3 interact additively with respect to the reduction of c-myc mRNA expression. These results suggest that Ra used in combination with 16-23-D3 or 23-D3 may be an interesting chemotherapeutic regimen to evaluate in patients with acute myeloid leukemia.

Cell Division↗