Metabolism of the vitamin D analog EB 1089: Identification of in vivo and in vitro liver metabolites and their biological activities∗

Kissmeyer, Anne-Marie; Binderup, Ernst; Binderup, Lise; Hansen, Christina Mørk; Andersen, Niels Rastrup; Makin, H. L. J.; Schroeder, Neil J.; Shankar, V.; Jones, Glenville

doi:10.1016/s0006-2952(96)00816-7

Cited by 59 publications

(27 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although 1,25-(OH) 2 D 3 induces 24-hydroxylase (the enzyme that converts 1,25-(OH) 2 D 3 into an inactive metabolite) in PC-3 cells and not in LNCaP cells (4,7), this difference alone does not explain the reduced response. We have found that more frequent addition of 1,25-(OH) 2 D 3 or use of an analog (EB1089) that is not 24-hydroxylated in vivo (59) does not substantially alter the responsiveness of PC-3 cells (data not shown).…”

Section: Discussionmentioning

confidence: 91%

p53 Is Required for 1,25-Dihydroxyvitamin D3-Induced G0 Arrest But Is Not Required for G1 Accumulation or Apoptosis of LNCaP Prostate Cancer Cells

et al. 2003

View full text Add to dashboard Cite

1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is an effective agent for inhibiting the growth of prostate cancer cells including LNCaP and PC-3 cell lines. However, the extent of growth inhibition in these cell lines differs because LNCaP cells are much more responsive than PC-3 cells. Previous studies in LNCaP cells have shown that 1,25-(OH)(2)D(3) treatment results in G(0)/G(1) cell cycle accumulation, loss of Ki67 expression, and induction of apoptosis. One difference between the two cell lines is that PC-3 cells lack functional p53, a protein that plays roles both in cell cycle regulation and induction of apoptosis. In this study, the role of p53 in 1,25-(OH)(2)D(3) action was examined using the p53-negative PC-3 cells and a line of LNCaP cells, called LN-56, in which p53 function was shut off using a dominant negative p53 fragment. We found that treatment with 1,25-(OH)(2)D(3) extensively inhibits growth of LN-56 prostate cancer cells lacking p53, but in contrast to the parental LNCaP cells, the LN-56 cells recover rapidly. Moreover, in prostate cancer cells, the synergism between 1,25-(OH)(2)D(3) and 9-cis retinoic acid appears to be dependent on the presence of functional p53; however, 1,25-(OH)(2)D(3)-mediated induction of G(1) cell cycle accumulation and induction of apoptosis is not.

show abstract

Section: Discussionmentioning

confidence: 91%

p53 Is Required for 1,25-Dihydroxyvitamin D3-Induced G0 Arrest But Is Not Required for G1 Accumulation or Apoptosis of LNCaP Prostate Cancer Cells

et al. 2003

View full text Add to dashboard Cite

show abstract

“…One of the most widely studied 1,25(OH) 2 D 3 analogs is 1(S),3(R)-dihydroxy-20(R)-(5Ј-ethyl-5Ј-hydroxy-hepta-1Ј(E),3Ј(E)-dien-1Ј-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene, or EB1089. EB1089 effectively inhibits the growth of LNCaP cells, exhibits greater potency than 1,25(OH) 2 D 3 (Skowronski et al, 1995), and is only 50% as calcemic in vivo (Hansen and Maenpaa, 1997;Kissmeyer et al, 1997). Other analogs, including 16-diene analogs (Schwartz et al, 1994;Hedlund et al, 1997), 1,25 dihydroxy-16-ene-23-yne-vitamin D 3 (Schwartz et al, 1995), 19-nor-hexafluoride D 3 analogs (Campbell et al, 1997), 19-nor-26,27-bishomo-vitamin D 3 analogs (Kubota et al, 1998), 20-cyclopropyl-cholecalciferol vitamin D 3 (Koike et al, 1999), 5,6-trans-16-ene-vitamin D 3 (Hisatake et al, 1999), and some nonsecosteroidal analogs (Boehm et al, 1999) also inhibit the growth of prostate cancer cells in vitro.…”

Section: Vitamin D Analogsmentioning

confidence: 99%

Vitamin D and Prostate Cancer

Polek

Weigel

2002

Journal of Andrology

View full text Add to dashboard Cite

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among American men. It arises primarily from the epithelial secretory cells of the peripheral prostate gland; generally occurs as a multifocal disease within the prostate gland; and then preferentially metastasizes to lymph nodes, bone, lung, and brain. Localized disease can be treated relatively successfully by radical prostatectomy (Catalona and Smith, 1998). In contrast, treatments for metastatic prostate cancer, including androgen ablation, are initially effective, but the majority of patients relapse with androgen independent prostate cancer (Denis, 1998; Leewansangtong and Crawford, 1998). The incidence of prostate cancer and the lack of good, long-term treatments for metastatic disease highlight the need for new chemopreventive and chemotherapeutic treatments. As discussed below, active vitamin D metabolites and analogs of the active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), are candidates for these treatments. Vitamin DVitamin D is best known for its actions in regulating calcium levels and bone remodeling (reviewed in Brown et al, 1999), but recent studies highlight a role for vitamin D in the growth and differentiation of various cell types. It is synthesized in the epidermis by the conversion of its precursor, 7-dehydrocholesterol, into vitamin D 3 , a reaction catalyzed by the ultraviolet rays of sunlight. Subsequent hydroxylation reactions in the liver and kidney produce 1,25(OH) 2 D 3 (Holick, 1984). Levels of 1,25(OH) 2 D 3 are tightly regulated as excess 1,25(OH) 2 D 3 is inactivated by the enzyme 24-hydroxylase (Horst and Reinhardt, 1997).

show abstract

“…The synthetic analogue seocalcitol is 50 -200 times more potent than vitamin D in inhibiting growth and inducing differentiation of cancer cell lines Kissmeyer et al, 1997). In vivo studies in animal models have shown that seocalcitol can cause regression of established tumours, prevent the development of metastases, and prolong survival time in tumour-bearing animals (Colston et al, 1992(Colston et al, , 1997James et al, 1998;Lokeshwar et al, 1999;Nickerson and Huynh, 1999), with significant inhibition of tumour progression achieved at doses that do not cause significant hypercalcaemia (Colston et al, 1992).…”

mentioning

confidence: 99%

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

et al. 2002

View full text Add to dashboard Cite

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo . Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10–15 μg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82–532 days (median=168 days). The time to treatment failure ( n =36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states. British Journal of Cancer (2002) 86 , 680–685. DOI: 10.1038/sj/bjc/6600162 www.bjcancer.com © 2002 Cancer Research UK

show abstract

Metabolism of the vitamin D analog EB 1089: Identification of in vivo and in vitro liver metabolites and their biological activities∗

Cited by 59 publications

References 22 publications

p53 Is Required for 1,25-Dihydroxyvitamin D3-Induced G0 Arrest But Is Not Required for G1 Accumulation or Apoptosis of LNCaP Prostate Cancer Cells

p53 Is Required for 1,25-Dihydroxyvitamin D3-Induced G0 Arrest But Is Not Required for G1 Accumulation or Apoptosis of LNCaP Prostate Cancer Cells

Vitamin D and Prostate Cancer

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

Contact Info

Product

Resources

About