Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-02
2004-02-03
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S844000, C549S027000, C549S049000, C549S432000, C562S453000, C562S466000, C562S467000
Reexamination Certificate
active
06686386
ABSTRACT:
The present invention relates to the use of specific retinoids in the preparation of a pharmaceutical composition which is intended to increase the rate of apoptosis. These retinoids can also be used in cosmetic compositions which are intended, in particular, to prevent and/or combat photoinduced or chronological ageing of the skin.
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 the 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 a physical trauma, or due 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 result in any inflammation phenomenon. Apoptosis has been reported to be able to take place under various physiological conditions. It is a highly selective form of cell suicide which is characterized by readily observable morphological and biochemical phenomena. Thus, condensation of the chromatin, which is or is not associated with an endonuclease activity, formation of apoptotic bodies and fragmentation of the deoxyribonucleic acid (DNA), by activation of endonucleases, into 180-200 base pair DNA fragments (these fragments can be observed by means of agarose gel electrophoresis) are, in particular, observed.
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 the substances which are able to play a role in the differentiation, growth and maturation of cells are also linked to the phenomenon of apoptosis.
In the medical field, some pathological situations exhibit a modified, if not deregulated, apoptosis mechanism. 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, more specifically diseases linked to cell hyperproliferation, as in the case of cancer, autoimmune diseases and allergies, or, on the other hand, diseases which are linked to cell disappearance, as in the case of the human immunodeficiency virus (HIV) immunodeficiency syndrome, neurodegenerative diseases (Alzheimer's disease) or excessive damage which is induced during myocardial infarction.
Specifically, it has been noted in oncology that a large number of antineoplastic drugs, such as dexamethasone, cyclophosphamide and cisplatin, are able to induce apoptosis.
In the cosmetic field, the signs of cutaneous ageing essentially result from dysfunction of the principal biological mechanisms of the skin which, in particular, bring the mechanism of apoptosis into play. It is possible, therefore, to imagine that any product which induces the mechanism of apoptosis is a product which is suitable for preventing and/or combating the appearance of ageing and the existing signs of ageing such as large and small wrinkles.
In the field of retinoids, it is known that all-trans retinoic acid is a powerful modulator (i.e. an inhibitor or, on the other hand, a stimulator, depending on the nature of the cells which are treated) of the differentiation and proliferation of many normal or transformed cell types. For example, it inhibits the differentiation of epithelial cells such as the keratinocytes of the epidermis. It also inhibits the proliferation of many transformed cells such as melanoma cells. These effects on proliferation and differentiation can affect one and the same type of cell simultaneously, as is the case, for example, for HL-60 human promyelocytic cells; thus, it is known that 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 nucleoreceptors which are termed RARs (retinoic acid receptors) and which are present in the cell nucleus. To date, three subtypes of RAR receptors, termed RAR-&agr;, RAR-&bgr; and RAR-&ggr;, respectively, have been identified. After having bound the ligand (i.e. all-trans retinoic acid), these receptors interact with specific response elements (RARE) in the promoter region of genes which are regulated by retinoic acid. In order to bind to the response elements, the RARs heterodimerize with another type of receptor known as RXR receptors. The natural ligand of the RXRs is 9-cis-retinoic acid. The RXRs are regarded as being master regulatory proteins because they interact with other members of the steroid/thyroid receptor superfamily, such as the receptor for vitamin D3 (VDR), the receptor for triiodothyroxine (TR) and the PPARs (peroxisome proliferator activated receptors), to form heterodimers, as they do with the RARs. Furthermore, the RXRs are able to interact with specific response elements (RXRE) in the form of homodimers. These complex interactions, and the existence of numerous RAR and RXR receptors which are expressed differently depending on the tissue and the cell type, explain the pleiotropic effects of retinoids in virtually all cells.
Large numbers of synthetic structural analogues of all-trans retinoic acid or of 9-cis-retinoic acid, commonly termed “retinoids”, have so far been described in the literature. Some of these molecules are able to bind to, and specifically activate, the RARs or, on the other hand, the RXRs. Furthermore, some analogues are able to bind to, and activate, a particular subtype (&agr;, &bgr; or &ggr;) of RAR receptor. Finally, other analogues do not exhibit any particular selective activity with regard to these different receptors. In this respect, and by way of example, 9-cis-retinoic acid activates both the RARs and the RXRs without any noteworthy selectivity for either of these receptors (nonspecific agonist ligand), whereas all-trans retinoic acid selectively activates the RARs (RAR-specific agonist ligand) without regard to subtype. In a general manner, and qualitatively, a given substance (or ligand) is said to be specific for a given receptor family (or with regard to a particular receptor of this family) when the said substance exhibits an affinity for all the.receptors of this family (or, respectively, for the particular receptor of this family) which is stronger than that which it otherwise exhibits for all the receptors of any other family (or, respectively, for all the other receptors, of this same family or not).
It has been reported that 9-cis-retinoic acid and all-trans retinoic acid are modulators of apoptosis (activator or inhibitor of apoptosis depending, in particular, on the cell type) and that 9-cis-retinoic acid is the more active of these two modulators, with it being possible to explain this observation by the fact that 9-cis-retinoic acid activates both the RARs and the RXRs, contrary to all-trans retinoic acid, which only activates the RARs.
In view of that which has been previously stated, it appears to be of interest to find novel modulators of apoptosis.
In this regard, the Applicant has just discovered that agonist ligands which are specific for receptors of the RAR-&ggr; type are excellent inducers of apoptosis in a variety of cell types, more specifically in thymocytes.
Thus, the present invention relates to the use of at least one agonist ligand which is specific for receptors of the RAR-&ggr; type in the preparation of a pharmaceutical composition which is intended to increase the rate of apoptosis in at least one cell population in which apoptosis can be induced by activating receptors of the RAR-&ggr; type.
The invention also relates to
Fesus Laszlo
Reichert Uwe
Szondy Zsuzsa
Galderma Research & Development S.N.C.
White Everett
Wilson James O.
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