Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-07-15
2000-05-16
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514510, 514511, 514533, 514534, 514535, 514537, 514562, 514563, 514564, 514566, 514567, 514569, 514570, 514574, 514577, 514878, 514893, 514903, A01N 3712
Patent
active
060637978
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of particular retinoids in the preparation of a pharmaceutical composition intended to decrease the rate of apoptosis.
Two types of mechanism are involved in the death of cells. The first, which is the classical type, is termed necrosis. Morphologically, necrosis is characterized by swelling of the mitochondria and the cytoplasm and by nuclear distortion, followed by destruction of the cell and its autolysis, with this latter being accompanied by an inflammation phenomenon. Necrosis occurs in a passive and incidental manner. Tissue necrosis is generally due to the cells being subjected to physical trauma or to a chemical poison, for example.
The other form of cell death is termed apoptosis [Kerr, J. F. R. and Wyllie, A. H., Br. J. Cancer, 265, 239 (1972)]; however, contrary to necrosis, apoptosis does not give rise to any inflammation phenomenon. Apoptosis has been reported to be able to take place under a variety of physiological conditions. Apoptosis is a highly selective form of cell suicide which is characterized by readily observable morphological and biochemical phenomena. Thus, events which are observed, in particular, are condensation of the chromatin, which may or may not be associated with endonuclease activity, the formation of apoptotic bodies, and fragmentation of the deoxyribonucleic acid (DNA), due to endonuclease activation, into 180-200 base pair DNA fragments (these fragments can be observed by agarose gel electrophoresis).
Apoptosis can be regarded as being a programmed cell death which is involved in tissue development, differentiation and renewal. It is also thought that the differentiation, growth and maturation of cells are closely linked to apoptosis and that substances which are able to play a role in the differentiation, growth and maturation of cells are also linked to the phenomenon of apoptosis. Thus, in a human being who is in good health, all these phenomena are in equilibrium.
In the medical field, some pathological situations exhibit a modified, if not deregulated, mechanism of apoptosis or a mechanism of apoptosis which does not provide for a deregulation of another biological phenomenon in order to achieve equilibrium. Thus, it has been reported that deliberate modulation of apoptosis, by inducing it or suppressing it, can make it possible to treat a large number of diseases such as diseases which are linked to an inadequate rate of apoptosis, as in the case of cancer, or to autoimmune diseases or allergies, or, on the contrary, diseases which are linked to an excessive rate of apoptosis, as in the cases of the human immunodeficiency virus (HIV) immunodeficiency syndrome, neurodegenerative diseases (Alzheimer's disease) or excessive damage which is induced during myocardial infarction.
To be specific, a large number of inhibitors of apoptosis, such as cycloheximide, cyclosporin and certain interleukins, have already been described.
In the retinoid field, it is known that all-trans retinoic acid is a powerful modulator (i.e. an inhibitor or, on the contrary, a stimulator, depending on the nature of the treated cells) of the differentiation and proliferation of many normal or transformed cell types. For example, retinoic acid inhibits the differentiation of epithelial cells such as epidermal keratinocytes. It also inhibits the proliferation of many transformed cells such as melanoma cells. These effects on proliferation and differentiation can affect one single cell type simultaneously, as in the case, for example, of human promyelocytic cells which are classified as HL-60 cells; thus, it is known that the proliferation of these cells is inhibited by all-trans retinoic acid and that, at the same time, their differentiation into granulocytes and their apoptosis are induced.
It is known, in a general manner, that all-trans retinoic acid acts on the differentiation and proliferation of cells by interacting with nuclear receptors which are termed RARs (Retinoic Acid Receptors) and which are present in the cell nucleus. To date, three sub
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J. Biol. Chem., vol. 270, No. 11, 1995, pp. 6022-6029, XP000574946, L. Zhang et al., "Evidence for the involvement of retinoic acid receptor RAR alpha-dependent signalling pathway in the induction of tissue transglutaminase and apoptosis by retinoids."
Leukemia, vol. 8, No. SPL.3, 1994, pp. S83-S84, XP000575616, P.S. Gill et al, "Solid tumor treatment workshop summary".
Fesus Laszlo
Reichert Uwe
Szondy Zsuzsa
C.I.R.D. Galderma
Krass Frederick
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