Vitamin D3 analogs: Effect on leukemic clonal growth and differentiation, and on serum calcium levels

Pakkala, Seppo; Vos, Sven de; Elstner, E; Rude, Robert K.; Uskoković, Milan R.; Binderup, Lise; Koeffler, H. Phillip

doi:10.1016/0145-2126(94)00065-i

Cited by 67 publications

(48 citation statements)

References 23 publications

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“…It is about 3,000 times more potent than 1,25(OH) 2 D 3 as a proliferation inhibitor and about 14,000-fold more potent than 1,25(OH) 2 D 3 in inhibiting the clonal growth of the monoblastic cell line U937 (24). However, KH 1060 has the same receptor binding affinity as 1,25(OH) 2 D 3 (24). EB 1089 is characterized by having two double bonds in the side chain, which makes it less susceptible to metabolic degradation.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Effect of Vitamin D Derivatives and Retinoids on C2C12 Skeletal Muscle Cells

2002

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Section: Introductionmentioning

confidence: 99%

Synergistic Effect of Vitamin D Derivatives and Retinoids on C2C12 Skeletal Muscle Cells

2002

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“…In contrast to these 'traditional' immunosuppressive drugs, vitamin D analogs have also demonstrated anti-leukemic effects in vivo and in vitro. 8,9,17 However, different vitamin D analogs vary significantly in their immunosuppressive, anti-leukemic, and calcemic properties, 10 and therefore, further studies are required to assess the most suitable analog for clinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…8 The major obstacle in using natural vitamin D or its early analogs for treatment has been hypercalcemia before therapeutic concentrations could be reached. 9,10 This problem has now been solved with novel analogs with lesser calcemic activity. 7,8 MC 1288 is a 20-epi-1,25(OH) 2 D 3 , differing from 1,25(OH) 2 D 3 by altered stereochemistry of the methyl group at carbon 20 in the side chain of the molecule ( Figure 1).…”

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confidence: 99%

MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation

Pakkala

Taskinen

Pakkala

et al. 2001

Bone Marrow Transplant

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Summary:The major obstacle to successful bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Vitamin D analogs have shown their efficacy in solid organ transplantation. The purpose of this study was to investigate the suitability of a novel vitamin D analog, MC1288, in the prevention of acute GVHD in a rat BMT model. Allogeneic BMT were performed from Lewis to BN rats (n = 18). The animals were divided into four groups: an untreated control group, MC1288, cyclosporin A (CsA), and MC1288 + CsA-treated groups. Rats were harvested for histology and immunohistochemistry on day 20 after BMT. Histological changes for GVHD in liver, skin, and spleen were thickening associated with transplant arteriosclerosis, or chronic rejection, in a rat aortic transplant model. 7 In addition to their immunosuppressive effects, we and others have shown that vitamin D analogs have anti-leukemic effects both in vitro and on de novo patient samples. 8 The major obstacle in using natural vitamin D or its early analogs for treatment has been hypercalcemia before therapeutic concentrations could be reached. 9,10 This problem has now been solved with novel analogs with lesser calcemic activity. 7,8 MC 1288 is a 20-epi-1,25(OH) 2 D 3 , differing from 1,25(OH) 2 D 3 by altered stereochemistry of the methyl group at carbon 20 in the side chain of the molecule (Figure 1). We have previously shown that MC1288 is well tolerated in rats in vivo. It did not induce hypercalcemia during the first month of treatment although in 3 months, the serum calcium level increased by 30%. 7 The purpose of this study was to investigate the suitability of MC1288 in the prevention of acute graft-versushost disease (GVHD) in a rat bone marrow transplantation (BMT) model. Here, we studied the effects of MC1288 on the clinical course and histological manifestations of acute GVHD after allogeneic BMT. Materials and methods Bone marrow transplantation (BMT)Allogeneic bone marrow transplantations were performed using adult Brown Norway (BN; RT1 l ) rats as recipients and 10-week-old Lewis (LEW; RT1 n ) rats as bone marrow cell donors. The cells were collected by flushing the femurs with saline. The recipient animals were irradiated with 960 rad (Varian Climac 600c, 6 MV photon irradiation, distance 120 cm, field size 40 × 40 cm 2 ) prior to BMT. After 24 h, 60-80 × 10 6 mononuclear bone marrow cells from LEW rats were injected into BN recipients.

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“…Unfortunately, this analogue also causes hypercalcaemia at high doses (Pakkala et al, 1995). In a preliminary study to enhance the action of this compound, we investigated combinations of LH with various naturally occurring and receptor-selective retinoids that transactivate through either RARE or RXRE (Campbell et al, 1998b) and demonstrated that the capacity for synergistic effects was reduced with increased cellular transformation.…”

mentioning

confidence: 99%

“…Vitamin D 3 is limited to topical application, most notably for the treatment of psoriasis, and although retinoids have achieved remarkable success in the treatment of acute promyelocytic leukaemia (APL) and the prevention of secondary lesions in individuals with head and neck cancers (Huang et al, 1988;Hong et al, 1990), both vitamin analogues have toxicities. For example, many potent vitamin D 3 analogues when injected into mice at doses that are active in vitro produce lethal hypercalcaemia (Pakkala et al, 1995). ATRA can produce skin, mucous membrane and hepatic toxicities as well as a high teratogenicity (Morosetti and Koeffler, 1996).…”

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confidence: 99%

Synergistic inhibition of prostate cancer cell lines by a 19- nor hexafluoride vitamin D3 analogue and anti-activator protein 1 retinoid

et al. 1998

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The secosteroid hormones, all- trans - and 9- cis -retinoic acid and vitamin D 3 , have demonstrated significant capacity to control proliferation in itro of many solid tumour cell lines. Cooperative synergistic effects by these two ligands have been reported, and it is, therefore, possible that greater therapeutic effects could be achieved if these compounds were administered together. The role of retinoid-dependent anti-activator protein 1 (anti-AP-1) effects in controlling cancer cell proliferation appears significant. We have utilized an anti- AP-1 retinoid [2-(4,4-dimethyl-3,4-dihydro-2H-1 benzopyran-6-yl)carbonyl-2-(4-carboxyphenyl)-1,3,-dithiane; SR11238], which does not transactivate through a retinoic acid response element (RARE), and a potent vitamin D 3 analogue [1α,25(OH) 2 -16-ene-23-yne-26,27-F 6 -19- nor -D 3 , code name LH] together at low, physiologically safer doses against a panel of prostate cancer cell lines that represent progressively more transformed phenotypes. The LNCaP (least transformed) and PC-3 (intermediately transformed) cell lines were synergistically inhibited in their clonal growth by the combination of LH and SR11238, whereas SR11238 alone was essentially inactive. DU-145 cells (most transformed) were completely insensitive to these analogues. LNCaP cells, but neither PC-3 nor DU-145, underwent apoptosis in the presence of LH and SR11238. Transactivation of the human osteocalcin vitamin D response element (VDRE) by LH was not enhanced in the presence of SR11238, although the expression of E-cadherin in these cells was additively up-regulated in the presence of both compounds. These data suggest the anti-AP-1 retinoid and the vitamin D 3 analogue may naturally act synergistically to control cell proliferation, a process that is interrupted during transformation, and that this combination may form the basis for treatment of some androgen-independent prostate cancer. © 1999 Cancer Research Campaign

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Vitamin D3 analogs: Effect on leukemic clonal growth and differentiation, and on serum calcium levels

Cited by 67 publications

References 23 publications

Synergistic Effect of Vitamin D Derivatives and Retinoids on C2C12 Skeletal Muscle Cells

Synergistic Effect of Vitamin D Derivatives and Retinoids on C2C12 Skeletal Muscle Cells

MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation

Synergistic inhibition of prostate cancer cell lines by a 19- nor hexafluoride vitamin D3 analogue and anti-activator protein 1 retinoid

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