Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-05-25
1998-06-02
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530329, 530330, A61K 3800, C07K 700, C07K 706
Patent
active
057600031
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel peptides which have hemoregulatory activities and can be used to inhibit the myelopoietic system of humans and animals.
BACKGROUND OF THE INVENTION
A variety of regulatory messengers and modifiers such as colony stimulating factors, interferons, and different types of peptides are responsible for the regulation of myelopoiesis. Metcalf, Cell, 43:5 (1985); Baserga R., Foa P., Metcalf D, Polli EE (eds), Biological Regulation of Cell Proliferation (1986); Nicola et al., J. Cell Physiol. 128:501 (1986), Zoumbos et al., Proyr. Hemat. 1:341 and 14:201 (1986); Werner et al., Experientia 42:521 (1986). Over twenty years ago, Rytomaa and Kivieniemi Cell Tissue Kinet 1:329-340 (1968); Rytomaa et al., Control of Cellular Growth in Adult Organisms pp 106-138 (1967) reported that extracts of mature granulocytes (granulocytic chalone) could specifically inhibit rat myelopoietic cell proliferation in cover slip cultures. Later, they demonstrated that the factor, which had a molecular weight less than 3,000 daltons, was able to induce the regression of a transplantable rat granulocytic leukemia, as well as retard the growth of leukemia cells in humans. Paukovits and others extracted a similar factor from rat bone marrow cells and showed that it inhibited the titrated thymidine uptake of bone marrow cells, Paukovits, W. R., Cell Tissue Kinet 4:539-547 (1971); Naturforsch 37:1297 (1982). In 1979, Boll et al., Acta Haematologica 6:130 (1979) demonstrated the inhibitory effects of rat granulocytic extracts on human bone marrow cells in culture and a number of other researchers demonstrated that this crude granulocytic extract inhibited the development of g-CFUC and/or gm-CFUC in vitro from rodent bone marrow cells.
This biological agent was termed a granulocyte chalone which, according to this theoretical concept, should be an endogenous inhibitor of cell proliferation acting in the same tissue as it was secreted. The material obtained from crude extracts was found to be non-species specific but highly tissue specific. Furthermore, it was found to be nontoxic and to have reversible activities.
In 1982, a synthetic hemoregulatory pentapeptide was reported to have a selective inhibitory effect on myelopoietic cells both in vitro and in vivo, where the main effect seems to be on myelopoietic stem cells (CFU-gm), Paukovits et al., Z. Naturforsch 37:1297 (1982) and U.S. Pat. No. 4,499,081. This peptide is believed to be an analogue of a naturally occurring granulopoiesis inhibition factor which has been found in minute quantities in bone marrow extracts.
We have now found certain synthetic peptides which have a selective inhibitory effect on myelopoietic cells in vitro. These peptides, by inhibiting haematopoiesis, and, in particular, granulopoiesis tend to prevent quiescent cells from entering into cell division and so becoming susceptible to attack by cytotoxic anti-cancer drugs. In addition to providing a protective function in therapy using cytotoxic drugs, the peptides may also be used to arrest proliferation of cancer cells related to the myelopoietic system, i.e. myeloid leukemia.
SUMMARY OF THE INVENTION
This invention comprises peptides, hereinafter represented as formula (I), which have hemoregulatory activities and can be used to inhibit haematopoiesis.
The peptides are useful in providing a protective function in therapy using irradiation and/or cytotoxic drugs, and may also be used to arrest proliferation of cancer cells related to the myelopoietic system, for example, in the treatment of myeloid leukemia. The peptides may also be used in many clinical situations where it is desirable to alter hemopoiesis.
These compounds may also be used in combination with the dimers of co-pending U.S. application Ser. No. 071,547,730, incorporated by reference herein, to provide alternating peaks of high and low activity in the bone marrow cells, thus augmenting the natural circadian rhythm of haematopoiesis. In this way, cytostatic therapy can be given at periods
REFERENCES:
patent: 4499081 (1985-02-01), Laerum
Broxmeger, The American Journal of Pediatric Hematology/Oncology, 14(1) pp. 22-30, 1992.
Wlodawer et al, Science, 245, pp. 616-621, 1989.
Reichelt, et al. "Isolation and Structure of an Epidermal Mitosis Inhibiting Pentapeptide", Biochem, and Biophy, Res. Comm. 146: 1493-1501 (1987).
Wlodawer, et al., "Conserved Folding Retroviral Proteases: Crystal Structure of a Synthetic HIV-1 Protease", Science 245: 616-621 (1989).
Paukovits, et al., "Hemoregulatory Peptide pGlu-Glu-Asp-Cys-Lys: A New Synthetic Derivative for Avoiding Dimerization and Loss of Inhibioty Activity", Mol. Pharm. 38: 401-409 (1990).
Paukovits, et al., "Protection from Arabinofuranosylcytosine and n-Mustard-Induced Myelotoxicity Using Hemoregulatory Peptide pGlu-Glu-Asp-Cys-Lys Monomer and Dimer", Blood 77: 1313-1319 (1991).
Bhatnagar Pradip Kumar
Huffman William Francis
Hall Linda E.
Lentz Edward T.
Marshall S. G.
SmithKline Beecham Corporation
Tsang Cecilia J.
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