Use of phosphotyrosine phosphatase inhibitors or phosphotyrosine

Details Use of phosphotyrosine phosphatase inhibitors or phosphotyrosine Use of phosphotyrosine phosphatase inhibitors or phosphotyrosine

1996-06-18

1998-12-08

Achutamurthy, Ponnathapura

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

556 1, 556 42, 556 44, 435184, 435326, 424617, 424646, A01N 5502, A01N 5916, C12N 999, C07F 5300

Patent

active

058469982

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention is directed to the use of phosphotyrosine phosphatase inhibitors and phosphotyrosine kinase activators for controlling cellular proliferation, particularly proliferation of lymphocytes.
Tyrosine phosphorylation is known to play an essential role in the control of lymphocyte function. This control is exerted by a network of tyrosine kinases and phosphotyrosine phosphatases.
Apoptosis is a pattern of programmed cell death that involves a breakup of the cellular DNA and can be recognized by electrophoresis. Apoptosis is an important lymphocyte response believed to play a prominent role in T and B lymphocyte maturation in the thymus (T cells) and in germinal centers (B cells), an example being the process of negative selection of self-reactive cells (J. J. Cohen et al., "Apoptosis and Programmed Cell Death in Immunity," Annu. Rev. Immunol. 10:267-293 (1992); D. R. Green et al., "Activation-Induced Apoptosis in Lymphoid Systems," Sem. Immunol. 4:379-388 (1992)).
Three different means of inducing apoptosis in lymphocytes all appear to require tyrosine phosphorylation. First, stimulation of the antigen receptor can lead to lymphocyte apoptosis. In the case of B cells, treatment of immature B cell lymphomas, but not mature B cells, with soluble anti-Ig antibodies often induces apoptosis (L. E. Benhamou et al., "Anti-Immunoglobulins Induce Death by Apoptosis in WEHI-231 B Lymphoma Cells," Eur. J. Immunol. 20:1405-1407 (1990); J. Hasbold & G. G. B. Klaus, "Anti-Immunoglobulin Antibodies Induce Apoptosis in Immature B Cell Lymphomas," Eur. J. Immunol. 20:1685-1690 (1990)). Signaling by anti-Ig antibodies requires tyrosine phosphorylation as an early and essential step (A. L. DeFranco, "Structure and Function of the B Cell Antigen Receptor," Annu. Rev. Cell Biol. 9:377-410 (1993)).
In immature B cells, stimulation of sIgM (surface immunoglobulin M) by either antigen or anti-immunoglobulin antibodies activates the cells (G. J. V. Nossal, Annu. Rev. Immunol. 1:33-62 (1983)). Stimulation of sIg (surface immunoglobulin) in B cells induces tyrosine phosphorylation (M. R. Gold et al., Nature 345:810-813 (1990); M. A. Campbell & B. M. Sefton, EMBO J. 9:2125-2131 (1990), which is essential for productive sIg signaling (P. J. L. Lane et al., J. Immunol. 146:715-722 (1991)).
Furthermore, specific tyrosine kinases appear to be involved in the B cell signaling that leads to apoptosis or growth arrest. For example, as a result of sIg stimulation, Src family kinases are activated (A. L. Burkhardt et al., Proc. Natl. Acad. Sci. USA 88:7410-7414 (1991)). Additionally, expression of the Src family tyrosine kinase Blk was found to be essential in B cell lymphomas where sIgM stimulation leads to growth arrest in apoptosis (X. R. Yao & D. W. Scott, "Expression of Protein Tyrosine Kinases in the Ig Complex of Anti-.mu.-Sensitive and Anti-.mu.-Resistant B Cell Lymphomas: Role of the p55.sup.blk Kinase in Signaling Growth Arrest and Apoptosis," Immunol. Rev. 132:163-186 (1993)). Similarly, the expression of the Blk tyrosine kinase has been found to be necessary for antigen receptor induced apoptosis in CH31 lymphoma cells (X. R. Yao & D. W. Scott, "Antisense Oligodeoxynucleotides to the blk Tyrosine Kinase Prevent Anti-.mu.-Chain-Mediated Growth Inhibition and Apoptosis in a B Cell Lymphoma," Proc. Natl. Acad. Sci. USA 90:7946-7950 (1993)), wherein the Lyn tyrosine kinase has been shown to be necessary for antigen receptor induced growth arrest in both human and murine B cell lymphoma lines (R. H. Scheuermann et al., "Lyn Tyrosine Kinase Signals Cell Cycle Arrest but Not Apoptosis in B-Lineage Lymphoma Cells," Proc. Natl. Acad. Sci. USA 91:4048-4052 (1994)).
Thus, on sIgM stimulation, tyrosine kinases such as Blk phosphorylate one or more proteins on tyrosine residues, and once phosphorylated, these proteins are then able to induce apoptosis. However, it has also been shown that the abundant phosphotyrosine phosphatase CD45 is required for sIg signal transduction (L. B. Justement et al., Science 2

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