Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-05
2003-07-29
Mosher, Mary E. (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S553000, C514S597000, C514S119000, C514S171000, C424S130100
Reexamination Certificate
active
06599912
ABSTRACT:
BACKGROUND OF THE INVENTION
Resistance of tumor cells to cancer therapy, limited efficacy of cancer therapy in metastatic disease, and undesired host toxicity of cancer therapy are three significant challenges in patient management.
A common resistance mechanism to chemotherapy observed in preclinical studies is the overexpression of drug efflux proteins (Lum, B. L. et al. (1993)
Cancer
72, 3502-3514; Barrand, M. A. et al. (1997)
Gen. Pharmacol.
28, 639-645; Fidler, I. J. (1999)
Cancer Chemother. Pharmacol.
43:S3-S10.). However, at least some clinical studies show that inhibition of the drug efflux proteins does not significantly improve the effectiveness of chemotherapy in patients (Ferry, D. R., et al. (1996)
Eur. J. Cancer
32:1070-1081; Broxterman, H. J., et al. (1996)
Eur. J. Cancer.
32:1024-1033), suggesting the existence of other resistance mechanisms.
Cancer therapy, such as chemotherapy and radiation, targets proliferating cells and thereby causes undesired toxicity to normal host tissues that undergo continuous renewal, including the hematopoietic cells, cells in the lining of the gastrointestinal tract, and hair follicles. Bone marrow suppression induced by cancer therapy is, at least in part, overcome by the use of hematopoietic growth factors, including erythropoietin, granulocytes colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor (Gabrilove, J. L. and Goldie, D. W. (1993) In:
Cancer, Principles
&
Practice of Oncology
(eds. DeVita, V. T. et al., J. B. Lippincott Co., Philadelphia). On the other hand, no treatment is available to overcome the gastrointestinal toxicity and alopecia induced by anticancer agents.
Therefore, there exists a need to identify new mechanisms by which tumor and normal cells elude cytotoxicity of anticancer agents, to identify methods and agents to overcome such resistance in tumor cells, and to utilize these resistance mechanisms to protect normal host tissues from the undesired toxicity of cancer therapy.
SUMMARY OF THE INVENTION
The invention is based, at least in part, on the elucidation of the role played by basic Fibroblast Growth Factor (bFGF) in the induction of broad spectrum resistance to anticancer agents in a number of tumors and metastatic lesions, and the role played by acidic FGF (aFGF) in amplifying the bFGF-induced resistance. Inhibitors of aFGF/bFGF enhance the in vitro and in vivo activity of anticancer agents, and result in shrinkage and eradication of human xenograft tumors including lung metastasis and subcutaneous tumors in mice. Methods of the invention use FGF antagonists to potentiate the antitumor effect of anticancer agents. FGF agonists (e.g., aFGF, e.g., bFGF) reduce the cytotoxicity of anticancer agents to normal noncancerous intestinal epithelial cells. Methods of the invention use FGF agonists to protect normal cells from the cytotoxic effects of anticancer agents.
Accordingly, in general, the invention features, a method of inhibiting unwanted cell growth or division, e.g., reducing or inhibiting the proliferation of, or enhancing the killing of, a cell, e.g., a hyperproliferative cell, e.g., a malignant cell or a benign hyperproliferative cell. The method includes: contacting the cell with at least one cytotoxic agent, (e.g., a cytostatic agent, e.g., an agent that causes cell death) and at least one FGF antagonist, in an amount, which together, is effective to reduce or inhibit the proliferation of the cell, or induce cell killing. Preferably, the unwanted cell is the cell of an established tumor.
In another aspect, the invention features a method of improving the efficacy of an agent, e.g., a cytotoxic agent, in a subject. The method includes:
administering to the subject at least one agent, e.g., a cytotoxic agent;
administering to the subject at least one FGF antagonist.
The FGF antagonist enhances the efficacy of the agent, e.g., a cytotoxic agent, relative to the effect of the cytotoxic agent in the absence of the FGF antagonist.
In a preferred embodiment, the FGF antagonist improves the efficacy of the cytotoxic agent against a cancer, e.g., an established tumor.
In another aspect, the invention features, a method of inhibiting unwanted cell growth or division, or inducing the killing of an unwanted cell (e.g., a hyperproliferative cell), e.g., a cell of an established tumor or a benign hyperproliferative cell, in a subject. The method can be used to treat or prevent, in a subject, a disorder characterized by unwanted cell growth or division. The method includes: administering to the subject at least one cytotoxic agent, (e.g., a cytostatic agent, an agent that causes cell death), and at least one FGF antagonist, in an amount, which together, is effective (e.g., therapeutically or prophylactically) to reduce or inhibit the growth or division of, or induce the killing of, the unwanted cell. Preferably, the unwanted cell is the cell of an established tumor.
In a preferred embodiment, the FGF antagonists inhibits or reduces the FGF-induced resistance to a broad spectrum of cytotoxic agents, i.e., agents with diverse structures and mechanisms of action, including but not limited to, antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, intercalating agents, agents capable of interfering with a signal transduction pathway (e.g., protein kinase C inhibitors, e.g., anti-hormones, e.g., antibodies against growth factor receptors), agents that promote apoptosis and/or necrosis, interferons, interleukins, tumor necrosis factors, and radiation.
In a preferred embodiment, the FGF antagonist comprises an inhibitor of bFGF.
In a preferred embodiment, the FGF antagonist comprises an inhibitor of aFGF.
In a preferred embodiment, the FGF antagonist includes at least one bFGF inhibitor and at least one aFGF inhibitor.
In a preferred embodiment, the aFGF inhibitor potentiates the action of the bFGF inhibitor.
In a preferred embodiment, the FGF antagonist acts extracellularly, e.g., inhibits the binding of an FGF molecule to its receptor.
In a preferred embodiment, the FGF antagonist acts intracellularly, e.g., interacts with the intracellular domain of the FGF receptor, inhibits the intracellular effects of FGF.
In a preferred embodiment, the FGF antagonist: is capable of binding to an FGF molecule or an FGF receptor; blocks the binding of FGF to a receptor; blocks the interaction of FGF with molecules that facilitate the binding of FGF to a receptor; and/or down regulates FGF receptor action. Preferably, the FGF molecule is bFGF and/or aFGF.
In a preferred embodiment, the FGF antagonist is other than suramin.
In a preferred embodiment, the FGF antagonist is other than an antibody, e.g., an antibody against FGF or an FGF receptor.
In a preferred embodiment, the FGF antagonist inhibits or reverses the resistance to anticancer drugs induced by FGF (e.g. aFGF and/or bFGF) or conditioned medium of tumor histocultures in cultured tumor cells under in vitro conditions as described in Example II and Example IV. The determination of effect on cultured cells can be determined using the system described in Example XV.
In a preferred embodiment, the FGF antagonist improves the efficacy of an agent, e.g., a cytotoxic agent, in the subject, relative to the effect of the cytotoxic agent in the absence of the FGF antagonist. Preferably, the FGF antagonist improves the efficacy of the cytotoxic agent against an established tumor.
In a preferred embodiment, the FGF antagonist is present in an amount sufficient to block FGF (e.g., bFGF and/or aFGF) action, but is not sufficient to cause one or more of: (i) significant inhibition of cell proliferation; (ii) significant cell death in human and/or animal tumor cells, (iii) a measurable antitumor effect in a subject, e.g., a human subject; and/or (iv) significant cell cycle arrest. The determination of effect on cultured cells can be determined with the system described in Example XV.
In a preferred embodiment, the FGF antagonist is administered at levels such that
Au Jessie L.-S.
Wientjes Guillaume
Mosher Mary E.
Mueller and Smith LPA
Yu Misook
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