Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing
Reexamination Certificate
1997-10-28
2004-12-14
McKelvey, Terry (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Reexamination Certificate
active
06831057
ABSTRACT:
BACKGROUND OF THE INVENTION
The inducible transcription factor Nuclear Factor-kappa B (NF-&kgr;B) participates in the regulation of multiple cellular genes, including many involved in the immune and inflammatory processes (for example, GM-CSF, IL-6, IL-8 and IL-2). NF-&kgr;B is a member of the rel family of protein complexes, and is activated by cellular exposure to various factors, including phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), interleukin-1 (IL-1), tumor necrosis alpha (TNF&agr;), and ultraviolet radiation. See Baldwin,
Annu. Rev. Immunol
. 14:649 (1996). NF-&kgr;B has also been implicated in the transcriptional activation of several viruses, including HIV-1 (Nabel et al.,
Nature
326:711 (1987); Kaufman et al.,
Mol. Cell. Biol
., 7:3759 (1987)). The various signaling pathways that can control the activation of NF-&kgr;B are not all clearly understood. It is apparent that different inducers can initiate their pathways through distinct receptors.
The latent cytoplasmic form of NF-&kgr;B is associated with a cytoplasmic inhibitory protein called I&kgr;B. Baeuerle and Baltimore,
Science
242:540 (1988); PCT US92/04073 (WO 92/20795). The release of NF-&kgr;B from I&kgr;B results in the rapid appearance of the active form of NF-&kgr;B in the cell nucleus. Genes regulated by NF-&kgr;B can be transcriptionally activated minutes after exposure of the cell to the appropriate inducer. Activation of NF-&kgr;B after exposure of a cell to an inducer is correlated with the hyperphosphorylation of I&kgr;B&agr; and its subsequent degradation. As I&kgr;B is diminished in the cytoplasm, NF-&kgr;B increases in the nucleus. Phosphorylation of I&kgr;B was once thought to lead to dissociation from NF-&kgr;B and subsequent proteolysis of I&kgr;B. Beg and Baldwin,
Genes Dev
. 7:2064 (1993). More recently, it has been proposed that the proteasome is responsible for signal-mediated degradation of I&kgr;B&agr; and I&kgr;B&bgr;. Baldwin,
Annu. Rev. Immunol
. 14:649 (1996). Phosphorylation of I&kgr;B apparently renders the molecule susceptible to proteolysis.
Activation of NF-&kgr;B has been suggested as playing a pathological role in the development of autoimmune diseases and chronic inflammatory diseases such as rheumatoid arthritis, and in acute situations such as septic shock.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of enhancing the cytotoxic effects of an antineoplastic chemotherapeutic agent. A therapeutically effective amount of NF-&kgr;B inhibitor is administered in conjunction with the chemotherapeutic agent, so that the cytotoxic effect of the chemotherapeutic agent is increased compared to that which occurs in the absence of NF-&kgr;B inhibitor.
A further aspect of the present invention is a method of enhancing chemotherapeutic cytotoxicity in a subject treated with a chemotherapeutic agent. A therapeutically effective amount of NF-&kgr;B inhibitor is administered to a subject in conjunction with a chemotherapeutic agent. The cytotoxic effect of the chemotherapeutic agent is increased compared to that which occurs in the absence of NF-&kgr;B inhibitor.
A further aspect of the present invention is a method of enhancing the cytotoxic effect of TNF&agr;, by administering a therapeutically effective amount of NF-&kgr;B inhibitor in conjunction with TNF&agr;. The cytotoxic effect of TNF&agr; is increased compared to that which occurs in the absence of NF-&kgr;B inhibitor.
A further aspect of the present invention is a method of enhancing chemotherapeutic cytotoxicity in a subject treated with TNF&agr;, by administering a therapeutically effective amount of NF-&kgr;B inhibitor in conjunction with TNF&agr;. The cytotoxic effect of TNF&agr; is increased compared to that which occurs in the absence of NF-&kgr;B inhibitor.
A further aspect of the present invention is a method of screening a compound for the ability to reduce the anti-apoptotic protective effects of an NF-&kgr;B induced anti-apoptotic gene. A population of test cells is exposed to an anticancer treatment and a test compound, and the cell viability following the exposure is assessed. Reduced cell viability, compared to that which occurs in cells treated only with the anticancer treatment, indicates that the test compound reduces the anti-apoptotic effects of an NF-&kgr;B induced anti-apoptotic gene.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth below.
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Wang et al.;TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-&kgr;B, Science, 274: 784-787 (Nov. 1, 1996).
Slater et al.,Constitutive nuclear NF&kgr;B/rel DNA-binding activity of rat thymocytes is increased by stimuli that promote apoptosis, but not inhibited by pyrrolidine dithocarbamate, Biochem J. 312:833-838 (1995).
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Baldwin Albert S.
Cusack James C.
Mayo Marty W.
Wang Cun-Yu
McKelvey Terry
Myers Bigel & Sibley & Sajovec
The University of North Carolina at Chapel Hill
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