Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1989-03-17
1992-05-19
Lee, Lester L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 19, 530330, C07K 510, A16K 3702
Patent
active
051149265
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a novel tetrapeptide acting as an inhibitor of entry into cycle of hemopoietic stem cells as well as its usual derivatives in the field of peptides with biological activity.
The invention also relates to a process for the extraction of this tetrapeptide from biological substances, particularly from fetal calf marrow and a process for its synthesis, as well as of its substitution derivatives, by the chemical route.
It also relates to the uses of this peptide and of its substitution derivatives in biology and in medicine, particularly in the protection of bone marrow in the course of anti-cancer treatments by chemotherapy.
The use of medicines in the treatment of cancers is limited by their toxic effects on healthy tissues, and in particular, on the hemopoietic tissue. The repeated use of these drugs results in a large number of cases either in lethal marrow aplasia, or a secondary leukaemia, or less serious hematological sequelae.
As the majority of anti-cancer medicines only act on proliferating cells, Applicants have thought that it would be possible to prevent hematological damages by protecting pluripotent stem cells by proliferation inhibitors.
Studies carried out by Applicants and previously published [see particularly E. Frindel and M. Guigon, Exp. Hemat., 5 (1977), 74-76, M. Guigon and E. Frindel, Bull. Cancer 68(2), (1981), 15-153, J. Wdzieczak-Bakala, M. Lenfant and M. Guigon, IRCS Med. Sci. 12 (1984) 868-869, J. Wdzieczak-Bakala, M. Guigon, M. Lenfant and E. Frindel, Biomed. Pharm. 37(1983), 467-471 and M. Guigon, J. Wdzieczak-Bakala, J. Y. Mary and M. Lenfant, Cell Tissue Kinet. 17(1984), 49-55] have shown that it was possible to reduce significantly, by administration of a specific inhibitor of stem cells, the lethality observed in animals in the course of treatments with cytosine arabinoside (Ara-C), a drug currently used for chemotherapy of cancer, whose use is limited by its injurious effect on bone marrow. That specific inhibitor which is extracted from certain biological substances, particularly from fetal calf bone marrow or fetal calf liver, protects the stem cells which are at the origin of all blood lines.
In fact, biological studies carried out show that the increase in survival observed can be attributed to a protection of the hemopoietic stem cells, CFU-S (Colony Forming U nits in the Spleen) that is to say pluripotent stem cells capable of giving rise to clones in the spleen of mice irradiated at a lethal dose, this protection being due to the maintenance of said cells outside of the cellular cycle, by the inhibitor.
Published documents describe techniques enabling more or less purified extracts containing the specific inhibitor to be obtained, but in all cases the product finally obtained is not homogeneous and the yields are unsatisfactory. It has therefore not been possible up to now to isolate the active principle and to establish its structure.
Now, Applicants have now developed a novel extraction process which enables a homogeneous active fraction to be obtained from a biological material, particularly from fetal calf marrow.
This process comprises essentially the steps consisting of: presence of a sulphur-containing reducing reagent, particularly dithioerythritol or preferably mercaptoethanol, exclusion limit close to 10,000 daltons, sieve of the polyacrylamide gel type, with elution by a dilute solution of acetic acid, phase support of silica grafted with aliphatic residues, particularly with 18C, repeating this step preferably at least once; and chromatography on a reverse phase column of silica grafted with aliphatic residues, particularly with 18C, to obtain a homogeneous active fraction.
The "active fraction" is identified by biological tests, particularly as described in the experimental part which follows.
A detailed example, which is not limiting, of the practice of this extraction process is given in the experimental part of the present specification.
The combination of different analysis techniques, particularly NMR, mass spectrometry and a
Bakala Johanna
Frindel Emilia
Guigon Martine
Lenfant Maryse
Institut Gustave Roussy
Institut National de la Sante et de la Recherche Medicale
Kraus E. J.
Lee Lester L.
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