Disease relevance of EB-1089

• The vitamin D analogue EB 1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells [1].
• Here, we report the efficacy of EB 1089, a low calcemic analogue of vitamin D, on the development of osteolytic bone metastases after intracardiac injection of the human breast cancer cell line MDA-MB-231 in nude mice [1].
• We studied the effects of 25-hydroxyvitamin D(3) [25(OH)D(3)], 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and vitamin D analogue, EB 1089, on the growth of a human ovarian cancer cell line, OVCAR-3 [2].
• We tested the efficacy of the 1,25(OH)(2)D(3) analogue, EB 1089, to chemoprevent prostate cancer in these transgenic mice [3].
• Studies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitro [4].

High impact information on EB-1089

• Some analogues of vitamin D3 (EB 1089, MC 903, and KH 1060) that are known to be potent inhibitors of breast cancer cell growth both in vitro and in vivo had similar or more pronounced inducing effects on TGF-beta 1 mRNA levels [5].
• Here we show that the treatment of MCF-7 breast cancer cells with 1,25(OH)(2)D(3) or its chemotherapeutic analog, EB 1089, releases Ca(2+) from the endoplasmic reticulum [6].
• To determine the mechanism for tissue-specific differences in potency, we determined the binding affinity of 1,25(OH)2D3 and EB 1089 for the vitamin D receptor [7].
• EB 1089 was also less effective than 1,25(OH)2D3 in the induction of intestinal but not renal calbindin-D9k mRNA [7].
• PURPOSE: The purpose of this research was to evaluate theinfluence of the combination of the vitamin D(3) analogue EB 1089 with fractionated radiation on growth and apoptosis of MCF-7 tumor xenografts in athymic mice [8].

Chemical compound and disease context of EB-1089

• The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice [8].
• Preclinical activity of ketoconazole in combination with calcitriol or the vitamin D analogue EB 1089 in prostate cancer cells [9].
• Previous studies have demonstrated that pretreatment of MCF-7 breast tumor cells with vitamin D3 or EB 1089 can increase sensitivity to both Adriamycin and irradiation [10].
• Taken together, these data indicate that EB 1089 (and 1alpha, 25 dihydroxycholecalciferol or its analogs) could selectively enhance breast tumor cell sensitivity to radiation through the promotion of cell death, in part through the generation of ceramide and the suppression of polo-like kinase [11].

Biological context of EB-1089

• Loss of cellularity, a marked reduction in the fraction of proliferating cells, and the promotion of apoptosis confirmed that the combination of EB 1089 with radiation was significantly more effective than radiation alone in blocking tumor cell growth and promoting tumor cell death [8].
• CONCLUSIONS: This work demonstrates that EB 1089 can improve local tumor control by fractionated radiation, in part through the promotion of apoptotic cell death [8].
• The 1,25(OH)2D3 analogues EB-1089, KH-1060, Ro 27-0574, and Ro 23-7553 are more potent than 1,25(OH)2D3 in both their antiproliferative actions as well as ER down-regulation [12].
• Vitamin D3 analogue (EB 1089) inhibits in vitro cellular proliferation of human colon cancer cells [13].
• Potent effects of EB 1089 on cell differentiation were also seen in the stimulation of alkaline phosphatase activity, cellular vitamin D receptor mRNA levels, and medium osteocalcin synthesis [14].

Anatomical context of EB-1089

• Conversely, neither 1,25(OH)(2)D(3) nor EB 1089 inhibited the growth of the normal rat prostate basal epithelial cell line NRP-152 [3].
• Our aim was to investigate the possible synergistic effect exerted by CsA in combination with 1,25(OH)2D3 or its nonhypercalcemic analogues, EB 1089 and KH 1060, on the proliferative response of T lymphocytes obtained from active ulcerative colitis patients [15].
• We have investigated the effects on bone resorption of two new potent antiproliferative vitamin D3 analogs, EB 1089 and KH 1060, by studying recruitment of osteoclasts in murine bone marrow cultures and 45Ca release from prelabeled neonatal mouse calvarial bones [4].
• In contrast, EB 1089 failed to enhance the response to radiation (or to promote apoptosis) in normal breast epithelial cells or BJ fibroblast cells [11].
• Studies of c-myc and c-fos expression in MCF-7 cells and of differentiation markers in U937 cells show that growth inhibition by EB 1089 is accompanied by induction of differentiation [16].

Associations of EB-1089 with other chemical compounds

• Addition of vitamin D binding protein to serum-free incubations of neonatal mouse calvarial bones, significantly inhibited the bone resorbing effect of 1 alpha,25(OH)2D3, but did not affect EB 1089 and KH 1060 induced 45Ca release.(ABSTRACT TRUNCATED AT 250 WORDS)[4]
• Both calcitriol and EB 1089 significantly decreased cell growth after 2 days in culture [14].
• The levels of the c-myc encoded protein remarkably decreased after treatment of SH-SY5Y cells for 1, 3, 7 days with 0.1 and 1 microM 9-cis retinoic acid, alone or combined with 10 nM 1,25(OH)(2)D(3) or 10 nM KH 1060 or 10 nM EB 1089 [17].
• The non-hypercalcemic analogs of vitamin D: CB 1093 (CB), EB 1089 (EB) and MC 1288 (MC) were more effective than 1,25D in both age groups in stimulating CK in the absence of DEX [18].
• 1. Seocalcitol (EB 1089), a vitamin D analogue with strong antiproliferative effects in vitro and in vivo, is presently under clinical evaluation for the systemic treatment of various solid tumours [19].

Gene context of EB-1089

• The level of IGFBP-2 was decreased by 42+/-8 and 49+/-7% by 10 nM EB 1089 and CB1093, respectively, compared to controls [20].
• The possibility that the combination of vitamin D(3) compounds with radiation might promote cell death (i.e. through a differentiation stimulus plus DNA damage) was investigated by exposing both TP53 (formerly known as p53) wild-type and TP53 mutated breast tumor cells to 1,25-(OH)(2)-D(3) or EB 1089 for 48 h prior to irradiation [21].
• After the termination of EB 1089 and solvent administration, tumors were irradiated (3 x 5 Gy) over a period of 3 days using a 300 KV Pantax Therapax irradiator [8].
• Our study, therefore, demonstrates a stepwise increase in PTHrP expression when cells progress from normal to malignant phenotype and suggests that EB-1089 should be further evaluated as a therapeutic agent in human melanoma [22].
• During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship [23].

Analytical, diagnostic and therapeutic context of EB-1089

• Despite the complete absence of effector caspase activation, transmission electron microscopy of MCF-7 cells treated with 1,25(OH)(2)D(3) or EB 1089 revealed apoptosis-like morphology characterized by the condensed cytoplasm, nuclei, and chromatin [6].
• RESULTS: A significantly higher rate of decline in tumor volume (7.5% per day) was observed in mice exposed to radiation subsequent to EB 1089 compared with animals treated with radiation alone (5.6% per day) [8].
• All the possible isomers of 26- and 26a-hydroxy EB 1089 were synthesised and these were compared to biologically generated material using HPLC, NMR, and GC-MS techniques [24].
• A promising phase I study with EB 1089 in patients with advanced breast and colon cancer has already been carried out, and more clinical trials evaluating the clinical effectiveness of EB 1089 in other types of cancer are in progress [25].
• Taken together with our previous findings that EB 1089 enhances breast tumor cell sensitivity to ionizing radiation, there studies further support the concept that vitamin D3 analogs could have utility in combination with conventional chemotherapy and/or radiotherapy in the treatment of breast cancer [26].

References