To All The Drugs Companies
tdlaing at nospam.mailhost.dres.dnd.ca
Thu Apr 16 11:15:18 EST 1998
In article <35363087.C8E at mail.tju.edu>, mark <mark.haynes at mail.tju.edu> wrote:
> Now my second question is--I wonder if the effects of thalidomide on
> development are related to an effect in apoptosis? is that the tack of the
> recent studies?
Thalidomide may be anti-angiogenic; it's theorized to affect cellular
migration that occurs when endothelial cells form new vessels
(angiogenesis). If vessels don't form, the dividing cells in the limb
buds can't obtain the necessary nutrients so they slow down/stop growth
and hence limbs are stunted. Thalidomide's teratogenic effects occur in a
narrow time-frame in pregnancy during a critical period of limb
development; the drug has little teratogenic effect when given before or
after this window. However only a few species are susceptible to
thalidomide's teratogenic effect (human, rabbit), and the drug was tested
in non-susceptible species during its workup, which was why it was allowed
on market the first time. (It's also why preclinical drug protocols
require testing at least 2 different animal species.)
A couple of references from Medline:
Med Hypotheses 1997 Aug;49(2):123-131
Thalidomide may impede cell migration in primates by down-regulating integrin
beta-chains: potential therapeutic utility in solid malignancies, proliferative
retinopathy, inflammatory disorders, neointimal hyperplasia, and osteoporosis.
Nutrition 21, San Diego, CA 92109, USA.
A growing number of human inflammatory disorders are reported to respond to
treatment with thalidomide, and recently this drug has been shown to inhibit
angiogenesis in the rabbit, in doses which can elicit teratogenicity in this
species. Studies in marmosets and humans indicate that thalidomide, and a
teratogenic analogue, decrease the expression of beta integrin subunits, most
notably beta 3 and the beta 2 produced by leukocytes. Since integrins are
crucial for cell-matrix interactions, and the beta 2 integrins of leukocytes
mediate adhesion to endothelium, it is reasonable to postulate that thalidomide
inhibits cell migration in susceptible species, and that this accounts for its
anti-inflammatory, anti-angiogenic, and teratogenic activity. This perspective
suggests that thalidomide will show utility in the prevention or treatment of a
wide range of disorders, including solid tumors, proliferative retinopathies,
many inflammatory diseases, neointimal hyperplasia, and osteoporosis. It is
likely that dietary fish oil-as well as selective inhibitors of urokinase, when
and if they become clinically available-will complement the efficacy of
thalidomide in most if not all of these applications.
PMID: 9278924, UI: 97424811
Proc Natl Acad Sci U S A 1994 Apr 26;91(9):4082-4085
Thalidomide is an inhibitor of angiogenesis.
D'Amato RJ, Loughnan MS, Flynn E, Folkman J
Department of Surgery, Children's Hospital, Harvard Medical School, Boston
Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in
humans. We have demonstrated that orally administered thalidomide is an
inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit
cornea micropocket assay. Experiments including the analysis of thalidomide
analogs revealed that the antiangiogenic activity correlated with the
teratogenicity but not with the sedative or the mild immunosuppressive
properties of thalidomide. Electron microscopic examination of the corneal
neovascularization of thalidomide-treated rabbits revealed specific
ultrastructural changes similar to those seen in the deformed limb bud
vasculature of thalidomide-treated embryos. These experiments shed light on the
mechanism of thalidomide's teratogenicity and hold promise for the potential
use of thalidomide as an orally administered drug for the treatment of many
diverse diseases dependent on angiogenesis.
PMID: 7513432, UI: 94224887
(Judah Folkman is a pre-eminent authority on angiogenesis.)
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