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Biotech / Medical : Biotech Valuation -- Ignore unavailable to you. Want to Upgrade?

To: Biomaven who wrote (1985)	11/7/2000 9:21:08 AM
From: tom pope	Read Replies (1) \| Respond to of 52153

Re: ONYX looking for the IMGN presentation in the thicket of AACR presentations, I found this re ONXX: 520 Activity of ONYX-015 in combination with chemotherapeutic agents against human tumor cells lines. Davidson Karen1, Cerna Cesaer1, Lawrence Richard A.1, Von Hoff Daniel D1, Kirn David2, Heise Carla2, Izbicka Elzbieta1. 1Institute for Drug Development, CTRC, San Antonio TX and 2Onyx Pharmaceuticals, Richmond, CA. An attenuated adenovirus ONYX-015 destroys tumor cells lacking a functional p53 gene. We tested ONYX-015 in combination with standard chemotherapeutic agents to determine the effect of the combination on virus replication, cell growth, and apoptosis in four human tumor cell lines: two colon carcinomas with different p53 expression status, three ovarian carcinomas differing in sensitivity to chemotherapy, a pancreatic carcinoma with a mutated p53, and a head and neck carcinoma with a non-functional p53. The studies were performed at predetermined time points in cells infected with the virus. ONYX-015 induced cytopathic effects in p53-deficient cell lines at low concentration (0.01 pfu/cell). At 10 pfu/cell, ONYX-015 induced apoptosis in p53 wild-type and p53-deficient colon cancer cell lines. In the parent drug-sensitive ovarian carcinoma, ONYX-015 infection significantly increased apoptosis. Apoptosis was also increased in adriamycin- or cisplatin-resistant ovarian carcinoma lines at lower concentrations of ONYX-015 compared to the parent cell line. In adriamycin- or cisplatin-resistant ovarian carcinomas, the chemotherapeutic agents had no effect on apoptosis, while the combination of the drugs and ONYX-015 increased apoptosis more than ONYX-015 alone. Apoptosis was only moderately increased in a pancreatic carcinoma infected by ONYX-015, but the drug combination was more effective. The head and neck carcinoma cells were very resistant to apoptosis induction, and co-infection with chemotherapeutic agents and ONYX-015 did not further increase apoptosis. In all cancer cell lines responsive to the virus, the combination of chemotherapeutic agents plus ONYX-015 increased the level of apoptosis compared to chemotherapy alone. ONYX-015 infection apparently reversed the resistance to adriamycin and cisplatin in ovarian cancer cell lines. The results of this study warrant future clinical trials that include combination studies, especially in drug resistant ovarian tumors. Supported by Onyx Pharmaceuticals

To: Biomaven who wrote (1985)	11/7/2000 9:25:09 AM
From: Biomaven	Read Replies (1) \| Respond to of 52153

The endostatin Phase I results looked no better than OK. Good safety and reasonable PK, and a few responses. Looks like they haven't hit the higher dose levels yet, so maybe there is still room for improvement (and of course the drug would likely do better in less sick patients). No mention of any dose-response curve though, which may mean higher doses won't help. There's also a mouse model abstract which suggests you can use a 10x smaller daily dose if you give it via continuous infusion instead of bolus. Hard to know how the market will react - right now it's slightly up in premarket compared to yesterday's close. People may be waiting to see if there is any update when the presentations are actually made later this week. I'm probably not going to play this one either way. Bottom line though is that it doesn't seem like the spectacular mice results are being replicated in humans. Maybe they still haven't got the structure quite right? I came across the following abstract (not at this conference) which raises this issue: Authors Hohenester E, Sasaki T, Mann K, Timpl R. Author e-mail Address e.hohenester@ic.ac.uk Title Variable zinc coordination in endostatin Source Journal of Molecular Biology. 297(1):1-6, 2000 Mar 17. Abbreviated Source J. Mol. Biol. 297(1):1-6, 2000 Mar 17. Copyright Publisher ACADEMIC PRESS LTD, 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND. URL: apnet.com ISSN 0022-2836 Author Keywords Angiogenesis, Tumour growth, Collagen, Metal binding, Mutagenesis. KeyWords Plus® by ISI® Angiogenesis inhibitor endostatin, Molscript, Binding, Program. Abstract Endostatin is a proteolytic fragment of collagen XVIII that potently inhibits angiogenesis and tumour growth. Human endostatin contains a zinc ion, bound near the N terminus, which was not observed in the original structure of mouse endostatin at pH 5. Controversial data exist on the role of this zinc ion in the anti-tumour activity. We report two new crystal structures of mouse endostatin at pH 8.5 with bound zinc. One crystal form shows a metal ion coordination similar to that in human endostatin (His132, His134, His142, Asp207), but the conformation of the N-terminal segment is different. In the other crystal form, Asp136 replaces His132 as a zinc ligand. Site-directed mutagenesis of zinc-binding residues demonstrates that both coordination geometries occur in solution. The large degree of structural heterogeneity of the zinc-binding site has implications for endostatin function. We conclude that zinc is likely to play a structural rather than a critical functional role in endostatin. (C) 2000 Academic Press. [References: 23] Peter