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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: celeryroot.com who wrote (14479)	2/9/1998 9:59:00 AM
From: Henry Niman	Respond to of 32384

Celeryroot, Actually, there were some indications last week of some major activity in Biotechs. In Barron's table of NASDAQ's biggest movers for the week, there were 3 Biotechs (HYSQ, SMTG, KDUS) in the top 10. The Biomed/Genetics index rose 2.1% on Friday (#2 out of 197 industry groups), and the somewhat narrower AMEX Biotech index was up almost 4%. The January effect may just be a month or two late this year.

To: celeryroot.com who wrote (14479)	2/9/1998 10:23:00 AM
From: Henry Niman	Respond to of 32384

Bob Walberg (sp?) of Briefing.com was just on CNBC. When asked for sectors that looked good, he mentioned Biotechs first.

To: celeryroot.com who wrote (14479)	2/9/1998 10:38:00 AM
From: bob zagorin	Respond to of 32384

isip announced earnings.slighter higher revenue, larger losses cause of clinical trials, enough cash, expect first antisense nda this year.

To: celeryroot.com who wrote (14479)	2/10/1998 6:02:00 AM
From: Henry Niman	Respond to of 32384

More positive news from studies targeting IRs: L O N D O N, Feb. 9 - British researchers believe that vitamin D and its derivatives can help to reduce cancer cell growth and could be useful in treating breast cancer. The vitamin, which helps the body absorb calcium and phosphorous, is essential for healthy bones and teeth. Two British studies, funded by the Association for International Cancer Research, have shown it may have a role to play in cancer treatments. "There is evidence that vitamin D can both reduce the growth of certain cancer cells, including breast cancer, and make cells become less cancerous in nature," Professor Barbara Mawer of the Manchester Royal Infirmary in central England said in a statement. "Our present studies are concerned with understanding just how vitamin D influences cell growth." Vitamin D Upped Survival Chances Mawer, who is studying women with advanced breast cancer, found that patients with high levels of the active form of vitamin D in their blood had a better chance of survival than patients with lower levels. "Thirteen women with normal or high levels of active vitamin D survived the six-month test period but, sadly, in those with low levels five out of 13 had died within six months," she said. Despite the seemingly obvious benefits, Mawer warned women not to take large doses of vitamin D unsupervised because it could cause high levels of calcium in the blood and serious side effects such as kidney stones. Researchers have suspected for many years that conventional vitamin D in cultured cells had an anti-proliferative effect on cancerous cells but they were not able to separate the hypercalcemic, or calcium causing, actions that cause the side effects. Pancreatic Cancer Applications? In a separate study at St. George's Hospital Medical School in London, Kay Colston is testing a synthetic form of vitamin D called EB 1089 on patients with pancreatic cancer. Developed by the Danish company Leo Pharmaceuticals, EB 1089 has less hypercalcemic agents and causes fewer unpleasant reactions. "From our laboratory studies with cultured cells we think that this compound is causing the tumors cell to undergo active cells death," Colston said in an interview. Colston and her colleagues do not know how vitamin D affects cancer cells. In the latest trials they are trying to work the signaling pathway, or method, of how it is done. "From the tissue culture studies and animal work some of these compounds seem to be effective in the laboratory but it is very early days to say whether this will translate itself to efficacy in the clinic," she said. In animal studies of malignant breast cells, the drug reduced cancerous tumors by up to 40 percent with no obvious effects on other tissues. The London trial of EB 1089 is expected to last up to 18 months.

To: celeryroot.com who wrote (14479)	2/10/1998 6:19:00 AM
From: Henry Niman	Respond to of 32384

Here's an early paper from Ron Evan's lab which mentions some of the similarities between retinoic acid, thyroid hormone, and Vitamin D3 receptors, including heteroduplex formation with RXRs: Genes Dev 1993 Jul;7(7B):1411-1422 Determinants for selective RAR and TR recognition of direct repeat HREs. Perlmann T, Rangarajan PN, Umesono K, Evans RM Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037. Recently, we have shown that receptors for vitamin D3 (VDR), thyroid hormone (TR), and retinoic acid (RAR) activate preferentially through direct repeats (DRs) spaced by 3, 4, and 5 nucleotides, respectively. In addition, the RAR can activate weakly through DRs spaced by 2 nucleotides. A common feature of RAR, TR, and VDR is their ability to heterodimerize with the retinoid X receptor (RXR) through their ligand-binding domains (LBDs) to form high-affinity DNA-binding complexes that are specific for appropriately spaced repeats. In this paper we demonstrate that selective binding of RAR-RXR and TR-RXR heterodimers to their cognate DRs is a consequence of a novel cooperative dimer interaction within the DNA-binding domains (DBDs). Accordingly, a region in the first zinc finger of the TR and RAR DBDs interacts with the second zinc finger in the RXR DBD to promote selective DNA-binding to DRs spaced by 4 and 5 nucleotides, respectively. The resulting polarity established by this interaction places RXR in the 5' position of the direct repeats. These data provide a mechanism for selective receptor recognition of a restricted set of target sequences in DR DNA and explains the structural basis for physiological specificity. PMID: 8392478, UI: 93321869

To: celeryroot.com who wrote (14479)	2/10/1998 6:32:00 AM
From: Henry Niman	Respond to of 32384

Here's an early paper that not only mentions RXR alpha / Vitamin D3 receptor heterodimerization, but it also shows synergy between Vitamin D and rexinoids (Panretin): Nature 1993 Feb 18;361(6413):657-660 Two nuclear signalling pathways for vitamin D. Carlberg C, Bendik I, Wyss A, Meier E, Sturzenbecker LJ, Grippo JF, Hunziker W Department of Pharma Research New Technologies, F. Hoffmann-La Roche Ltd, Basel, Switzerland. The dihydroxylated form of vitamin D3 (1,25-dihydroxy-D3)mediates a biological response by binding to intracellular receptors which belong to the steroid receptor superfamily. These receptors act as ligand-dependent transcription factors that bind to specific DNA sequences (reviewed in refs 6-9). We have identified two classes of vitamin D response elements that are activated either by the vitamin D receptor (VDR) alone or by heterodimers of VDR and the retinoid-X receptor-alpha (RXR-alpha). The motif GGGTGA arranged as a direct repeat with a spacing of six nucleotides or as a palindrome without spacing, or as an inverted palindrome with a 12-nucleotide spacing, confers vitamin D inducibility mediated by VDR alone. A second class of response elements, composed of directly repeated pairs of motifs (GGTCCA, AGGTCA, or GGGTGA) spaced by three nucleotides, is synergistically activated by RXR and VDR, but only in the presence of both ligands. Thus, the RXR ligand and the nature of the response element determine whether a nuclear receptor is co-regulated by RXR.

To: celeryroot.com who wrote (14479)	2/10/1998 6:39:00 AM
From: Henry Niman	Respond to of 32384

Here's another early paper from another LGND consultant (BW O'Malley) which describes factors influencing VDR/RXR activities: J Biol Chem 1993 Feb 25;268(6):4152-4160 Multiple mechanisms of chicken ovalbumin upstream promoter transcription factor-dependent repression of transactivation by the vitamin D, thyroid hormone, and retinoic acid receptors. Cooney AJ, Leng X, Tsai SY, O'Malley BW, Tsai MJ Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030. The chicken ovalbumin upstream promoter transcription factor (COUP-TF) is a member of the steroid/thyroid hormone receptor superfamily about which little is known of its functional role in the cell. However, it is able to repress hormonal induction of target genes by vitamin D3 receptor (VDR), thyroid hormone receptor (TR), and retinoic acid receptor (RAR). We have shown previously that COUP-TF can bind a wide variety of A/GGGTCA repeats. This promiscuous recognition of response elements correlates with the ability of COUP-TF I to repress other receptors that bind to A/GGGTCA repeats with different spacings between the half-sites. Here we show that repression of transactivation by these receptors is a general phenomenon for the COUP-TF subfamily, as inhibition is also observed with COUP-TF II. This repression is also dose-dependent on COUP-TF. Inhibition of VDR, TR, and RAR activities also occurs through natural physiological response elements found in the osteocalcin, myosin heavy chain, and beta RAR promoters, respectively. In search of the mechanisms of repression by COUP-TF we show that it does not involve the formation of detectable functionally inactive heterodimers between COUP-TF and VDR, TR, and RAR. Instead, we show that the mechanism of repression could occur at three different levels: (a) active silencing of transcription and dual competition for; (b) occupancy of DNA binding sites; and (c), heterodimer formation with retinoid X receptor, the coregulator of VDR, TR, and RAR. The silencing activity was localized to the putative ligand binding domain of COUP-TF. We postulate that COUP-TF may play a master role in regulating transactivation by VDR, TR, and RAR. PMID: 8382695, UI: 93179420

To: celeryroot.com who wrote (14479)	2/10/1998 7:53:00 AM
From: Henry Niman	Respond to of 32384

Here's a more recent abstract that demonstrates synergy between a Vitamin D derivative (CB 1267) and Panretin for treating prostate cancer cells in vitro: 2 UI - 97637577 AU - Elstner E; Campbell MJ; Said J; Reed JC; Binderup L; Koeffler HP TI - Combination of a novel 20-epi-vitamin D3 analog (CB 1267) with 9-cis retinoic acid additively inhibits clonal growth and promotes differentia- tion of prostate cancer cells (Meeting abstract). SO - Proc Annu Meet Am Assoc Cancer Res 1997;38:A577 AD - Cedars-Sinai Medical Center/UCLA, CA 90048 AB - We evaluated the combined effect of CB1267 and 9-cis retinoic acid (9-cis-RA) on clonal growth, differentiation and apoptosis of a human prostate cancer cell line, LNCaP. Combination of both analogs additively inhibited clonal growth of LNCaP cells (more than 95% clonal inhibition at 10(-7) M vs 60% and 30% clonal inhibition by CB1267 and 9-cis-RA, at 5 x 10(-8) M, respectively). LNCaP cultured with one or both analogs (5 x 10(-8) M, 3 days) showed the changes summarized in a table in expression of apoptosis, and cell cycle- related proteins compared to untreated cells as determined by Western blot, immuno-histochemistry and FACS analysis. Wild-type p53 was stimulated to migrate from the cytoplasm to the nucleus by the combination of both analogs. Apoptosis occurred in 37%, 23% and 30% of cells cultured with either CB1267, 9-cis-RA, or both analogs (5 x 10(-8) M x 3 days). Together, the analogs had an additive effect on differentiation of LNCaP cells as measured by morphology and expression of E-cadherin and cytokeratins 8 and 18. Taken together, CB1267 is a promising new vitamin D3 analog which together with 9-cis-RA should be tried in clinical trials of prostate cancer.

To: celeryroot.com who wrote (14479)	2/10/1998 7:55:00 AM
From: tonyt	Respond to of 32384

Wow! You're very popular today :-)

To: celeryroot.com who wrote (14479)	2/10/1998 8:56:00 AM
From: Henry Niman	Respond to of 32384

Here's a recent review on EB 1089: Biochem Pharmacol 1997 Dec 1;54(11):1173-1179 EB 1089, a novel vitamin D analog with strong antiproliferative and differentiation-inducing effects on target cells. Hansen CM, Maenpaa PH Biological Research and Development, Leo Pharmaceutical Products, Ballerup, Denmark. The physiologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3, plays an important role not only in the establishment and maintenance of calcium metabolism, but also in regulating cell growth and differentiation. As the clinical usefulness of 1alpha,25-dihydroxyvitamin D3 is limited by its tendency to cause hypercalcemia, new analogs with a better therapeutic profile have been synthesized. One of these new synthetic vitamin D analogs is EB 1089, which is characterized by an altered side chain structure featuring 26,27-dimethyl groups and two double bonds. This analog has been shown to be more potent than 1,25-dihydroxyvitamin D3 in inhibiting proliferation, stimulating differentiation, and inducing apoptosis in a number of different cell types, including cancer cells. Despite being more potent than 1alpha,25-dihydroxyvitamin D3 with respect to its cell regulatory effects, EB 1089 displays weaker calcemic side-effects. These characteristics make EB 1089 a potentially useful compound for the treatment of a diversity of clinical disorders, including cancer and metabolic bone diseases. 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. Publication Types: Review Review, tutorial PMID: 9416968, UI: 98077450

To: celeryroot.com who wrote (14479)	2/10/1998 8:59:00 AM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

Here's a recent paper showing that EB 1089 (Vitamin D derivative) and Panretin (9-cis retinoic acid) produce additive effects when used to treat human breast cancer cells (MCF-7): J Endocrinol 1997 Sep;154(3):495-504 Vitamin D derivatives inhibit the mitogenic effects of IGF-I on MCF-7 human breast cancer cells. Xie SP, James SY, Colston KW Division of Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK. The effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and four novel synthetic analogues (EB1089, KH1060, KH1230 and CB1093) on IGF-I-stimulated growth of MCF-7 human breast cancer cells have been determined. A significant time- and dose-dependent inhibition of IGF-I-stimulated cell growth was seen with EB1089, such that after 7 days of treatment with 10(-8) M EB1089, the mitogenic effect of IGF-I (30 ng/ml) was negated. Comparison with 1,25(OH)2D3 showed the synthetic analogues to be more potent. The anti-oestrogen ICI 182,780 similarly inhibited IGF-I-stimulated growth of these cells and in combination with EB1089 exerted additional inhibitory effects. Retinoids (all-trans-retinoic acid or the isomer 9-cis-retinoic acid) were less effective in limiting MCF-7 cell responsiveness to IGF-I but, in combination with EB1089, a co-operative effect was achieved. Using radioligand-binding techniques, we observed that 1,25(OH)2D3 and EB1089 down-regulated the levels of 125I-IGF-I binding to MCF-7 cell membranes. Scatchard analysis showed that EB1089 decreased maximal binding approximately 2-fold. Vitamin D derivatives were also demonstrated to reduce IGF-I receptor expression in MCF-7 cells by Western analysis. Our findings demonstrate that vitamin D derivatives limit responsiveness of MCF-7 cells to the mitogenic effects of IGF-I, which may be mediated by reduction of IGF-I receptor expression. PMID: 9379127, UI: 98022033