Pentapeptides with cell growth regulatory effects and a process

Details Pentapeptides with cell growth regulatory effects and a process Pentapeptides with cell growth regulatory effects and a process

1987-02-18

1988-12-27

Phillips, Delbert R.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

C07K 706

Patent

active

047941693

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new pentapeptides which reversibly inhibit cell proliferation in squamous epithelia, and a process for preparing such pentapeptides.
Many skin detectors 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 still containing the cell 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 decrease, 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 sunthesized pentapeptides which, when tested for biological activity in vivo, reversibly inhibit 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 these pentapeptides at very low concentrations. This cell line originates from mouse epidermis treated with a skin carcinogen (DMBA=dimethylbenzathracene). 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 vitro or in vitro at the concentrations tested.
According to the invention there is provided a pentapeptide of the formula ##STR2## wherein X.sup.1 and X.sup.2 are the same or different and are OH or NH.sub.2, the C-terminal amino acid unit is in the D-configuration when Z.sup.2 is methyl, amide form, and cation complexes and salts

REFERENCES:
Elgjo et al., Cell Biology International Reports, vol. 8, No. 5, pp. 379-382 (5/1984).
Elgjo et al., Chem. Abstr. vol. 101, No. 66833j (1984).
Elgjo et al., Chem. Abstr. vol. 106, No. 79315v (1987) (Abstract of Serono Symp. Publ. Raven Press 34 pp. 259.gamma., 1986).
Elgjo et al., Chem. Abstr. vol. 105, No. 219705d (1986) (Abstract of J. Invest. Dermatol. 87(5), pp. 555-8, 1986).

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