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Biotech / Medical : Biotechnology Value Fund, L.P. -- Ignore unavailable to you. Want to Upgrade?

To: mike head who wrote (633)	4/29/1999 11:43:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 4974

Thanks, Mike. I don't know what to think of the work. Wells has been accumulating evidence like this for a few years. I was blindly confident that it was the anti-angio properties.

To: mike head who wrote (633)	4/30/1999 11:31:00 AM
From: Biomaven	Respond to of 4974

Here's some commentary from the Lancet (free if you register): Thalidomide's potential for treating cachexia in patients with AIDS or cancer has naturally raised concerns about its teratogenic potential. A study now indicates that teratogenesis could be the result of embryonic DNA oxidation, and could be greatly reduced by the free-radical trapping agent -phenyl-N-t-butylnitrone (PBN). On day 12 of gestation, 30 pregnant rabbits were given 400 mg/kg thalidomide and 40 mg/kg PBN; thalidomide alone; or vehicle. The fetuses were examined for defects on day 29 of gestation. In a second study, embryos from three rabbits per treatment group were tested for DNA oxidation 6 hours after treatment. Compared with control rabbits, DNA oxidation was increased to 380% in the embryos exposed to thalidomide but was reduced to 73% by PBN. Thalidomide also increased fetal resorptions and postpartum fetal death, and decreased fetal bodyweight. Pretreatment with PBN abolished almost all birth defects, and reduced fetal resorptions and weight loss (Nat Med 1999; 5: 582-85 ). Team leader Peter Wells (University of Toronto, Canada) warns that "we still don't know if people share this mechanism", but this finding may indicate what risk factors to look for when trying to identify people susceptible to thalidomide's teratogenic effects, and could suggest strategies for protection. In a commentary, Barbara Hales (McGill University, Montreal, Canada) says that the possibility of protecting against oxidative stress with a free-radical scavenger is an urgent priority. However, William Figg (US National Cancer Institute, Bethesda, MD, USA) notes that "we need to make sure that mopping up free radicals doesn't reduce the effectiveness of thalidomide". Wells agrees, saying that this could be investigated in vitro, although he cautions that the human safety of free-radical trapping agents during pregnancy has yet to be established. T has two desired effects (anti-angiogenesis and anti-TNF) and two undesired side-effects (teratogenesis and neuropathy). They need to find out what PBN does to the other three. BTW, here's a possible explanation of why T is teratogenic in rabbits and humans but not rats: Biochem Pharmacol 1998 Jun 1;55(11):1827-34 Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Bauer KS, Dixon SC, Figg WD Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Thalidomide has been shown to be an inhibitor of angiogenesis in a rabbit cornea micropocket model; however, it has failed to demonstrate this activity in other models. These results suggest that the anti-angiogenic effects of thalidomide may only be observed following metabolic activation of the compound. This activation process may be species specific, similar to the teratogenic properties associated with thalidomide. Using a rat aorta model and human aortic endothelial cells, we co-incubated thalidomide in the presence of either human, rabbit, or rat liver microsomes. These experiments demonstrated that thalidomide inhibited microvessel formation from rat aortas and slowed human aortic endothelial cell proliferation in the presence of human or rabbit microsomes, but not in the presence of rat microsomes. In the absence of microsomes, thalidomide had no effect on either microvessel formation or cell proliferation, thus demonstrating that a metabolite of thalidomide is responsible for its anti-angiogenic effects and that this metabolite can be formed in both humans and rabbits, but not in rodents. BTW, T supposedly has at least 12 metabolites, and perhaps many more (an expert system identified over 130 possible metabolites). Peter