Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1987-11-24
1989-09-19
Lee, Lester L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
A61K 3702, C07K 704
Patent
active
048681563
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a pharmaceutical composition containing a dipeptide which reversibly inhibits cell proliferation in squamous epithelia, and a process for preparing such a peptide.
Many skin disorders are characterized by an abnormally fast rate of cell proliferation in the epidermis. In this category of skin diseases, psoriasis is the one which has been best investigated. Here, cell proliferation takes place very rapidly, and the cells do not have sufficient time to mature normally and are shed from the surface while still containing their nucleus. In many other skin diseases the cell proliferation rate is markedly increased, but none of these have been subjected to such extensive studies as has psoriasis. High mitotic activity is also found in most benign and malignant skin tumors of epidermal origin.
Cell division (mitosis) in the normal epidermis is confined to the lowermost cell layer (the basal cell layer) facing the underlying layer of connective tissue (the dermis). After a basal cell has divided into two daughter cells, one of the daughter cells-on average-remains in the basal cell layer, while the other gradually matures (keratinizes) as it migrates through the various layers of the epidermis. It reaches the surface as a fully keratinized cell without a nucleus, and is eventually shed. In the adult epidermis the number of cells lost from the surface in a given time is exactly balanced by the production of new cells in the basal cell layer. It is only in this manner that a constant thickness of the epidermis can be maintained. If a large number of epidermal cells are suddenly lost, e.g. after injury, the rate of cell division in the basal cell layer increases after a short lag time. After a period of time which depends on the degree of cell loss, the epidermis regains its former, normal, thickness. Large series of experiments have indicated that the balance between cell loss and cell renewal in the epidermis is biologically regulated according to the negative feedback principle. In such a system, the maturing cells continuously produce an inhibitor which diffuses down to the basal cell layer where it inhibits the rate of cell proliferation. The concentration of inhibitor in the basal cell layer is dependent on the number of mature, or maturing cells. Thus, when mature cells are lost from the surface, the concentration of inhibitor decreases, allowing the basal cells to divide at a faster rate. This regulatory mechanism seems to be active to a certain extent even in malignant tumors.
We have now discovered that the keratinizing cells produce an inhibitor (or a group of inhibitors) which is of peptide nature. We have also been able to isolate and determine the structure of such compounds. In particular we have purified, identified and chemically synthesized a dipeptide which, when tested for biological activity in vivo, reversibly inhibits the rate of cell proliferation in the basal cell layer, e.g. upon administration to mice. Furthermore, in vitro experiments have demonstrated that cells of an established cell line are inhibited by this dipeptide at very low concentrations. This cell line originates from mouse epidermis treated with a skin carcinogen (DMBA). Continuous treatment in vitro will arrest cell proliferation completely for a period of several days in normal keratinizing epithelial cells, while transformed cells are only partially inhibited. In both cases the inhibition is completely reversible when the treatment is terminated. In vitro experiments have also demonstrated that both normal and transformed cells mature (keratinize) at a faster rate after a 24-hour treatment with one of the new pentapeptides. No toxic effects have been observed either in vivo or in vitro at the concentrations tested.
The dipeptides which have the above described effects, have the formula ##STR2## wherein R is H or CH.sub.3, the pyroglutamic acid moiety (pGlu) being in the L-configuration, and the C-terminal amino acid moiety being in the D-configuration when R is methyl, and the C-terminal car
REFERENCES:
patent: 4053588 (1977-10-01), Konig et al.
patent: 4493828 (1985-07-01), Leung et al.
Yamada et al., Separation and Determination of Peptides by Liquid Chromatography, C.A. 1979, vol. 91, p. 104835w.
Elgjo Kjell
Reichelt Karl-Ludvig
Bio-Tech A/S
Lee Lester L.
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