Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-03-20
1999-11-09
Mertz, Prema
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514 8, 514885, 530350, C07K 1447, A61K 3804
Patent
active
059814837
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to methods and compositions for treating conditions requiring modulation of cytokines of the TGF-.beta. superfamily, and methods for screening for compounds useful in treating such conditions.
BACKGROUND OF THE INVENTION
The transforming growth factor beta (TGF-.beta.) superfamily is a group of cytokines that regulate many aspects of cellular function. The structural prototype for the gene superfamily is TGF-.beta.. TGF-.beta. is produced as a precursor and the precursor structure is shared by most of the members of the TGF-.beta. superfamily. The superfamily includes the TGF-.beta. family, the inhibin family, the DPP/VGl family and the Mullerian Inhibiting Substance Family.
The TGF-.beta. family includes five members, termed TGF-.beta.1 through TGF-.beta.5, all of which form homodimers of about 25 kd (reviewed in Massague, Annu. Review Cell Biol. 6:597, 1990). The family also includes TGF-.beta.1.2 which is a heterodimer containing a .beta.1 and a .beta.2 subunit linked by disulfide bonds. The five TGF-.beta. genes are highly conserved over great evolutionary distances. The mature processed cytokines produced from the members of the gene family show almost 100% amino acid identity between species, and the five peptides as a group show about 60-80% identity.
All forms of TGF-.beta. have been found to reversibly inhibit growth activity in normal, epithelial, endothelial, fibroblast, neuronal, lymphoid, and hematopoietic cell types (For review see Massague, 1990, Annu. Review Cell Biol. 6:597). In tissue culture, TGF-.beta. has been shown to inhibit cell growth by blocking both cdk-4/cyclinD activation and cdk2/cyclinE activity, events required for G1 to S phase transition (M. E. Ewen, H. K. Sluss, L. L. Whitehouse, D. M. Livingston, Cell 74, 1009 (1993) and A. Koff, M. Ohtsuki, K. Polyak, J. M. Roberts, J. Massague, Science 260, 536 (1993)). The antiproliferative action of TGF-.beta. has also been demonstrated in vivo (Silberstein and Daniel, 1987, Science 237:291-93; and Russell et al, 1988, Proc. Natl. Acad. Sci. U.S.A. 85:5126-30).
TGF-.beta. can also stimulate cell proliferation although the effect may be secondary to other cellular responses. For example, TGF-.beta.1 has been shown to promote the anchorage independent growth of normal rat kidney fibroblasts (Roberts et al., PNAS U.S.A. 78:5339, 1981; Roberts et al, Nature 295:417, 1982 and Twardzik et al., 1985, J. Cell. Biochem. 28:289, 1985) and it induces colony formation of AKR-2B fibroblasts (Tucker et al. Science 226:705, 1984). The inhibitory/stimulatory actions of TGF-.beta. may depend on the cell type and the physiological state of the cells.
TGF-.beta. is involved in mediation of cell adhesion. TGF-.beta. action on normal mesenchymal, epithelial and lymphoid cells, and some tumor cell lines generally results in the up-regulation of cell adhesion. This up-regulation is mediated by enhanced synthesis and deposition of extracellular matrix components, decreased pericellular proteolysis, and modification of cell adhesion receptors (Massague, 1990).
Cellular differentiation processes of many cell lineages can be positively or negatively effected by TGF-.beta.. TGF-.beta. has been shown to exert positive effects on chondrocyte and osteogenic cell types (Massague, 1990).
The biological actions of TGF-.beta. described above suggest a broad role for TGF-.beta. in the physiologic setting. The ability of TGF-.beta. to modulate DNA replication, cell differentiation, cell adhesion and extracellular matrix layout indicate a role for TGF-.beta. in the generation and modification of signals that guide morphogenic events of embryogenesis. The activity of TGF-.beta. as a promoter of extracellular matrix formation and a regulator of cell migration and development, is a major influence in inflammation and tissue repair processes. In fact, the administration of TGF-.beta.1 into wound chambers or to incisional wounds has been shown to accelerate the wound healing response in general (Sporn et al., 1983, Scie
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Demetriou Michael
Dennis James W.
Mertz Prema
Mount Sinai Hospital Corporation
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