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To: Russian Bear who wrote (176)	10/26/1998 5:45:00 PM
From: nigel bates	Respond to of 1073

Certainly fascinates me. >>Burnham is discussing licensing of the technology with a number of drug companies, he said. The institute has a patent on the phage library technology and a patent pending on this usage of it. << Any chance of your posting us as & when they choose a partner ? nig

To: Russian Bear who wrote (176)	10/27/1998 1:37:00 PM
From: scaram(o)uche	Respond to of 1073

RB: Good stuff, huh? That's why I'm interested in any company that both targets budding endothelial cells and a hypoxic environment. Jason, thanks for jumping in. I'm not nuts about subset analysis..... it's almost always a ploy for bait and switch. Ruoslahti has been up to his eyeballs in biotech since its inception. He was co-founder of Telios Pharmaceuticals, a well-conceived bet on integrins and wound healing. They went belly up and some "band-aid equivalents" and the patents were picked up for a song by Integra Life Sciences. The Telios connection to Burnham (then La Jolla Cancer Research Institute) was terminated, and Ruoslahti is now free-lancing it on a project-by-project basis. Burnham is a hot spot for both integrins and apoptosis. Integrin research in La Jolla is characterized as much by animosity and guarded secrets as it is by collaboration. Scripps is right across the street from Burnham, and the endothelial targeting work of Ruoslahti is largely derived from observations, using anti-integrin MAbs, of Dave Cherish. This work is licensed to Ixsys (a private company, given that their planned IPO is '97 didn't float) and the anti-integrin "Vitaxin" is in phase I trials. Rick

To: Russian Bear who wrote (176)	10/27/1998 2:23:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 1073

RB: Damn website hasn't been updated much in the last year....... oxigene.com We should follow Landuyt closely. There's always the chance that a detailed publication will show up that the company chooses not to publicize. I'm a bit less enthusiastic now that I see that Combretastuff is a tubulin inhibitor. BTW.... a medline search on G. Pettit will make MOGN fans drool....... "Combretastatin A-4, a naturally-occurring substance, was identified and isolated by Dr. George R. Pettit, Regents Professor of Chemistry, and his colleagues at ASU, from the South African tree Combretum caffrum."............ Br J Cancer 1996 Jul;74 Suppl 27:S86-8 Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents. Chaplin DJ, Pettit GR, Parkins CS, Hill SA Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex. [Medline record in process] We have assessed the vascular effects of vinblastine and four other tubulin binding agents (dolastatin 10, dolastatin 15, combretastatin A1 and combretastatin A4), which are awaiting clinical evaluation. All five agents induce a reduction in tumour blood flow as measured by uptake of RbCI 24 h post drug administration. The degree of reduction ranged from 50% with combretastatin A1 to 90% with dolastatin 10. These reductions were similar to that seen with flavone acetic acid (FAA) and indicate that antivascular effects are a common feature of tubulin binding agents. We subsequently evaluated whether the blood flow reductions, induced by FAA and vinblastine, could be used to enhance the activity of the bioreductive drug tirapazamine. Since the kinetics and extent of blood flow reductions induced by the agents is comparable, similar therapeutic response was expected. Potentiation was only evident with FAA, indicating that this effect is not directly related to killing of hypoxic tumour cells induced as a consequence of blood flow reduction. Cancer Res 1997 May 15;57(10):1829-34 Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Dark GG, Hill SA, Prise VE, Tozer GM, Pettit GR, Chaplin DJ Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom. Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4 prodrug induces vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. In vitro studies indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms responsible for the antivascular effects of combretastatin A-4.