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Thalidomide and Other Angiogenesis Inhibitors: Drugs for MD? |
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by Philip Filner, Ph. D.
ANGIOGENESIS
Angiogenesis is the formation of new blood vessels as outgrowths from pre-existing blood vessels. It is a
normal aspect of embryonic development, and a response to wounding. Cancers also stimulate angiogenesis, apparently in response to the high demand of rapidly multiplying cancer cells
for oxygen and nourishment, which reach the cancer cells via the blood system. In recent years, numerous researchers have been looking for inhibitors of angiogenesis because they can
inhibit the growth of cancers. Because angiogenesis inhibitors are thought to have the potential to revolutionize cancer chemotherapy, large amounts of money are being invested in
this type of research.
MACULAR DEGENERATION
In the more severe, wet form of macular degeneration, angiogenesis (also called neovascularization) occurs in the blood vessels behind the macula. Leakage from the proliferating blood
vessels is thought to cause damage to the light-sensing cells of the macula, thereby reducing central vision. Compounds which inhibit angiogenesis therefore should be considered
candidates for being inhibitors of wet form macular degeneration.
THALIDOMIDE
Thalidomide is a drug developed in Germany which was marketed in the 1950's as a sleep aid and reliever of morning sickness, until it was
realized that thalidomide inhibited limb development during the first trimester of pregnancy.
Although a widely feared drug, thalidomide is currently used as an
antiinflammatory agent, particularly to treat some symptoms of leprosy. It has also been reported to be beneficial as a treatment of skin lesions and some diseases associated with
AIDS.
THALIDOMIDE INHIBITS ANGIOGENESIS
In
1994, R. J. D'Amato et al hypothesized that thalidomide inhibited limb development by inhibiting angiogenesis. D'Amato was working with Judah Folkman, who had long thought that it
might be possible to inhibit cancers by inhibiting angiogenesis - the development of new blood vessels which deliver nourishment to cancers. Realizing that inhibition of menstruation
might be an indication of inhibition of angiogenesis, D'Amato searched the literature for inhibitors of menstruation, and came upon a number of compounds, including thalidomide. He
realized that if thalidomide inhibited angiogenesis, that could account for its inhibition of embryonic limb development, a process which involves angiogenesis.
D'Amato et al.
published results showing that although thalidomide did not inhibit angiogenesis in the chorioallantoic membrane of the embryonic chick, it did indeed inhibit angiogenesis in another
model system: angiogenesis stimulated in rabbit cornea by Basic Fibroblast Growth Factor (b-FBF). b-FBF, a protein known to promote angiogenesis, was embedded in minute pellets which
were placed in micropockets in rabbit cornea. The thalidomide was administered orally to the rabbit, in order to make possible a metabolic transformation of thalidomide thought
necessary for its activity. In the discussion portion of the paper, D'Amato et al. suggested that thalidomide should be tested as a possible inhibitor of the neovascularization
leading to macular degeneration.
A study looking for beneficial effects of thalidomide on wet form macular degeneration was begun with 60 patients in February, 1996 at the
Sheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Health Center, Philadelphia. No results are available yet. The study is planned to run two years.
OTHER INHIBITORS OF ANGIOGENESIS:
About
twenty-five other compounds have been reported to be inhibitors of angiogenesis. Some are listed in the following table:
Inhibitors of Angiogenesis
Compound
Angiostatin Entremed, 1996
Aptamer antogonist of VEGF NeXstar, 1996
Batimastat Taraboletti et al., 1995
Captopril Volpert et al, 1996
Cartilage Derived Inhibitor (CDI) Moses et al., 1990
Genistein Fotsis et al, 1993
Endostatin Entremed, 1996
Interleukin 12 Voest et al., 1995
Lavendustin A Hu & Fan, 1995
Medroxypregesterone Acetate Oikawa et al., 1988
Recombinant human platelet
factor 4(rPF4) Maione et al., 1990
Taxol Oktaba et al., 1995
Tecogalan(=SP-PG, DS-4152) Nakamura et al., 1992
Thalidomide D'Amato, et al, 1994
Thrombospondin Frazier
TNP-470 (=AGM-1470) Ingber et al., 1990
CAVEATS
While it is nice to see a lengthy list of angiogenesis inhibitors,
thereby expanding the list of potential candidates for treatment of wet form macular degeneration, it should be kept in mind that a sort of first rule of biological research is that
enough of anything will inhibit anything. It is therefore important to establish specificity of an agent's action, i.e. an absence or minimum of side effects. Other factors which must
be considered are duration of effectiveness, prerequisites for effectiveness, accessibility of modes of delivery to the target tissue, availability of the compound, cost of
manufacture, satisfying safety and efficacy criteria of FDA, etc.
It also should be kept in mind that while angiogenesis is believed to be in the sequence of events leading to
wet form macular degeneration, we do not know the primary cause, i.e. what ultimately stimulates the damaging angiogenesis.
Posted January 21, 1997
References
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Volpert, O. V., Ward, W. F., Lingen, M. W., Chesler, L., Solt, D. B., Johnson, M. D., Molteni, A.,
Polverini, P. J., and Bouck, N. P. Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J. Clin. Invest. 98: 671-679,1996.
Crown, E. Common high
blood pressure drug is also an anti-cancer agent e-crown@nwu.edu
Endostatin, Newly Discovered Angiogenic Inhibitor Licensed http://www.pslgroup.com:80/dg/e7fa.htm
Fotsis, T., Pepper, M., Adlercreutz, H., and others. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc. Nat Acad. Sci. U.S. 90:2690-2694, 1993
Oktaba,
A.M.C., Hunter, W.L. and Arsenault, A.L. Taxol: A potent inhibitor of normal and tumor-induced angiogenesis. Proceeedings of the American Association of Cancer Research Eighty Sixth
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Hu, D.-E. and Fan, T-P.D. Suppression of VEGF-induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A. Br.
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inhibitor of matrix metalloproteinases J. Natl Cancer Inst. 87:293-298, 1995
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Nakamura, S., Sakurada, S., Salahuddin, S.Z., and
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Ingber, D., Fujita, T., Kishimoto, S. and
others Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 348:555-557,1990.
Maione, T.E., Gray, G. S., Petro, J., and others
Inhibition of angiogenesis by recombinant human platelet factior-4 and related peptides. Science 347:77-79, 1990.
Aptemer Stops Angiogenesis, Tumor Growth NeXstar
Pharmaceuticals, Inc http://pslgroup.com/dg/d44e.htm
Voest, E.E., Kenyon, B. M., O'Reilly, M.S., Truitt,G., D'Amato, R. J., Folkman, J.. Inhibition of angiogenesis in
vivo by interleukin 12 J. Natl Cancer Inst 87:581-586, 1995
Oikawa,, T. et al. Angiogenic activity of rat mammary carcinoma induced by 7,12 dimethylben(a)anthracene and its
inhibition by medroxypregesterone acetate: possible involvement of antiangiogenic action of medroxypregesterone acetate in its tumor growth inhibition. Cancer Lett. 43:85, 1988.
D'Amato, R. J., Loughnan, M.S., Flynn,E., and Folkman, J. Thalidomide is an inhibitor of angiogenesis Proc. Nat. Acad. Sci. U.S. 91:4082-4085, 1994. |
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