Polynucleotides for inhibiting metastasis and tumor cell growth

Details Polynucleotides for inhibiting metastasis and tumor cell growth Polynucleotides for inhibiting metastasis and tumor cell growth

2000-01-07

2001-07-31

Hauda, Karen M. (Department: 1632)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S023500, C536S024500, C536S023100

Reexamination Certificate

active

06268350

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to novel methods and compositions for anticancer therapy of certain tumor types in humans. More particularly, the present invention is related to the methods for impairing or inhibiting metastasis and tumor cell growth with polynucleotides.
BACKGROUND OF THE INVENTION
Apoptosis is a characteristic form of cell death involving activation of one or more internally controlled pathways leading to autodigestion. Apoptosis can be induced by the binding and cross-linking of a cell surface receptor known as Fas. Human Fas (also known as APO-1 and CD95) is a cell surface protein consisting of 325 amino acids with a signal sequence at the NH
2
-terminus and a membrane spanning region in the middle of the molecule. Fas appears to be constitutively expressed on cells of a varied, but limited, number of normal tissues, including skeletal muscle, liver, skin, heart, lung, kidney, reproductive tissues, neutrophils and macrophages. Malignant cells of hematologic or non-hematologic origin have also been demonstrated to express Fas (see, e.g., Leithauser et al., 1993,
Laboratory Invest.
69:415).
Fas-mediated apoptosis (also known as Fas-mediated cytotoxicity) requires cross-linking of Fas with either agonistic anti-Fas antibody, with cell bound FasL (Fas-ligand), or with soluble FasL (see, e.g. Alderson et al., 1995,
J. Exp. Med.
181: 71-77). FasL is a type II transmembrane protein of the tumor necrosis factor family. Depending on the tumor type, FasL cell surface expression is variable; e.g., detectable in some tumors and absent in others. For those tumors expressing FasL, it has been suggested that such expression provides a mechanism of immune privilege of the tumors; i.e. a means by which the tumor evades immune-induced tumor cell depletion (Walker et al., 1997
J. Immunol.
158:4521-4). For example, FasL+ hepatocellular carcinomas were shown to kill Fas+ T lymphocytic cells in coculture (Strand et al., 1996,
Nat. Med.
2:1361-6); FasL+ human colonic adenocarcinoma cell lines induced apoptosis of Fas+ T lymphocytic cells in coculture (SW480, Shiraki et al., 1997,
Proc. Natl. Acad. Sci. USA
94:6420-5; SW620, O'Connell et al., 1996,
J. Exp. Med.
184:1075-82); FasL+ human lung carcinoma cell lines killed Fas+ T lymphocytic cells in coculture (Niehans et al., 1997,
Cancer Res.
57:1361-6); and FasL+ melanoma cells induced apoptosis of Fas+ target cells in coculture (Hahne et al., 1996,
Science
274:1363-6). These data suggest that FasL expression by tumor cells enhances tumorigenesis by killing Fas expressing immune effector cells (e.g., activated or tumor-reactive T cells) and surrounding Fas expressing tissue cells (e.g., hepatocytes; see Shiraki et al., 1997, supra). Further, cancer cells found to be FasL+ and Fas+ fail to undergo Fas-mediated apoptosis after treatment with agonistic anti-Fas antibody (O'Connell et al., 1996, supra) suggesting that tumor-expressed Fas did not transmit an apoptotic signal. Resistance to Fas-mediated apoptosis after anti-Fas antibody treatment has also been observed in nonhematopoietic tumors (Owen-Schaub et al., 1994,
Cancer Res.
54:1580-1586), human hepatoma cells (Ni et al., 1994,
Exp. Cell Res.
215:332-7), breast carcinoma (Keane et al., 1996,
Cancer Res.
56:4791-8). Thus, that tumor cells (e.g., from breast, colon, testis, and liver) expressing Fas appear to have lost their sensitivity to anti-Fas mediated cytotoxicity, suggests that tumor cells escape the normal induction of apoptosis that occurs in these tissues (Micheau et al., 1997,
J. Natl. Cancer Inst.
89:783-789).
A need still exists for a method to impair or inhibit metastasis and tumor cell growth, and with less systemic toxicity than the current standard treatments comprising chemotherapy and/or radiation therapy.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a composition comprising one or more polynucleotides for treating individuals having solid, nonlymphoid tumor.
It is another primary object of the present invention to provide methods for treating individuals having solid, nonlymphoid tumor by administering a composition comprising a therapeutically effective amount of one or more polynucleotides.
It is another primary object of the present invention to provide compositions comprising polynucleotides for treating individuals having solid, nonlymphoid tumor; wherein the compositions comprise antisense to FasL, one or more sense polynucleotides encoding FasL, or a combination thereof.
It is another primary object of the present invention to provide methods for treating individuals having solid, nonlymphoid tumor by administering a therapeutically effective amount of a composition comprising one or more polynucleotides; wherein the composition comprises an antisense to FasL, one or more sense polynucleotides encoding FasL, or a combination thereof.
It is another object of the present invention to provide methods for treating an individual having solid, nonlymphoid tumor comprising FasL(−) tumors by administering a therapeutically effective amount of sense polynucleotide encoding FasL in inducing the expression of Fas ligand (FasL) in FasL(−) tumor cells, which can impair or inhibit metastasis and tumor cell growth.
It is another object of the present invention to provide a method for treating individuals having FasL(−) tumors, wherein the method comprises administering a therapeutically effective amount of sense polynucleotide encoding FasL in inducing FasL expression in nonadherent FasL(−) tumor.
It is another object of the present invention to provide a method for impairing metastasis in individuals having FasL(−) tumors by administering a therapeutically effective amount of sense polynucleotide encoding FasL in inducing FasL expression in nonadherent tumor cells, and wherein the method is facilitated, at least in part, by Fas-mediated cytotoxicity of the tumor and by Fas-mediated cytotoxicity of tumor promoting B cells local or regional to the tumor.
It is another object of the present invention to provide a method for impairing tumor growth and/or metastasis in individuals having solid, nonlymphoid tumor, wherein the method is facilitated, at least in part, by inhibiting FasL expression in FasL-expressing cells local or regional to the tumor.
The foregoing objects are based on the novel discoveries that metastatic cells and nonadherent tumor cells (under non-anchorage conditions) which are Fas-expressing (“Fas+”) can be induced to apoptosis by contact with FasL+ tumor cells; and that inducing FasL expression on FasL(−) tumor cells does not confer immune privilege to these cells in vivo, but instead targets the tumor cells for destruction. Additionally, as disclosed by the present inventor (see, e.g., Barbera-Guillem et al., 2000,
Cancer Immunol. Immunother.
48:541-549, herein incorporated by reference), B lymphocytes exposed to shed tumor antigen can promote tumor progression. FasL+ tumors can contact and induce cytotoxicity of these Fas+ tumor-promoting B cells. Also disclosed herein is the discovery that by introducing a therapeutically effective amount of a composition comprising polynucleotide comprising FasL anti-sense in an area local or regional to a tumor, tumor growth and/or metastasis is inhibited. Additionally, disclosed herein is the discovery that administration of a therapeutically effective amount of a composition comprising one or more polynucleotides in an area local or regional to a tumor can effect an inhibition of tumor growth and/or metastasis. For example, such a composition comprises a combination of one or more polynucleotides comprising antisense to FasL, and one or more sense polynucleotides encoding FasL.
These and further features and advantages of the invention will be better understood from the description of the preferred embodiments when considered in relation to the figures in which:


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patent: 5858990 (19

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