Novel antiproliferative factor and methods of use

Abstract

A novel antiproliferative factor comprising a glycopeptide is disclosed. In specific embodiments, the novel antiproliferative factor is associated with the bladder. Compositions, diagnostic kits and reagents, and methods of using the compounds for identifying and / or treating interstitial cystitis and cancer are disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application Ser. No. 60 / 484,010, filed Jul. 1, 2003; U.S. Provisional Patent Application Ser. No. 60 / 515,850, filed Oct. 29, 2003; and U.S. Provisional Patent Application Ser. No. 60 / 569,363, filed May 7, 2004, all of which are incorporated by reference herein in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] The present invention was generated at least in part with funds from National Institutes of Health NIH, NIDDK DK52596; the Veterans Administration (VA Merit Review Funding); and intramural National Cancer Institute funds. The United States Government may have certain rights in the invention.FIELD OF THE INVENTION [0003] The present invention is directed to fields of medicine, biochemistry, cell biology, and chemistry. More specifically, the present invention addresses a novel compound and derivatives thereof having growth inhibitory a...

AI Technical Summary

Benefits of technology

[0015] As delineated in Rashid et al. (2004), in specific embodiments APF is a cell-cycle modulator. That is, explanted cells from normal bladder biopsy specimens were exposed to APF, which increased significantly the proportion of tetraploid and hypertetraploid cells compared to controls. Thus, in a particular aspect of the invention, exposure of a cell to APF provides a block in cell cycling in the G2 and / or M phase cell cycle block and / or the production of polyploidy. As such, APF affects cell cycle distribution, which in particular embodiments contributes at least in part to the pathogenesis of bladder disorders such as interstitial cystitis, for example through disruption of normal urothelial proliferation and repair processes. In further embodiments, exposure of one or more cells to APF results in inhibition of proliferation of the one or more cells, which may comprise a cell cycle block at any point in the cell cycle, although in particular embodiments the block is primarily in G2 or M phase. In particular embodiments, removal of APF permits the cell cycle to resume.

[0020] In a specific embodiment of the present invention, the peptide component of APF is hydrophobic and may be substituted for a non-proteinaceous moiety that is also hydrophobic, such as a lipid. Thus, in particular aspects of the invention, the peptide / lipid moiety of APF facilitates association with a membrane, such as being inserted, linked, bound, intercalated, or otherwise associated thereto, or, alternatively, by binding to a membrane surface receptor, and the sugar moiety of native APF comprises a high level of the functional activity of the molecule.

[0036] The present invention is directed to methods of treating cancer comprising administering an effective amount of APF or derivatives thereof to a patient in need of such treatment. Any kind of cancer may be treated, such as bladder, lung, breast, prostate, brain, stomach, colon, spleen, liver, pancreatic, melanoma, head and neck, thyroid, and so forth. In specific embodiments, though, the invention is useful for treating bladder or prostate cancer, comprising co-administering an effective amount of APF or derivatives thereof to a patient in need of such treatment. In additional aspects of the invention, the APF improves, facilitates, or assists in overcoming resistance or improving sensitivity to a cancer therapy selected from the group of chemotherapy, radiotherapy, surgery gene therapy, and / or immunotherapy.

[0041] As is also well known in the art, the immunogenicity of a particular immunogen composition can be enhanced by the use of non-specific stimulators of the immune response, known as adjuvants. Suitable adjuvants include all acceptable immunostimulatory compounds, such as cytokines, chemokines, cofactors, or toxins, for example. Adjuvants that may be used include IL-1, IL-2, IL-4, IL-7, IL-12, γ-interferon, GMCSP, BCG, aluminum hydroxide, MDP compounds, such as thur-MDP and nor-MDP, CGP (MTP-PE), lipid A, and monophosphoryl lipid A (MPL). RIBI, which contains three components extracted from bacteria, MPL, trehalose dimycolate (TDM) and cell wall skeleton (CWS) in a 2% squalene / Tween 80 emulsion is also contemplated. MHC antigens may even be used. Exemplary, often preferred adjuvants include complete Freund's adjuvant (a non-specific stimulator of the immune response containing killed Mycobacterium tuberculosis), incomplete Freund's adjuvants and aluminum hydroxide adjuvant.

[0080] In another embodiment, there is a method of enhancing cancer treatment of an individual, comprising administering to the individual a therapeutically effective amount of an APF composition. Administration of the composition may enhance chemotherapy, radiotherapy, immunotherapy, gene therapy, or a combination thereof. The composition may be administered prior to the cancer treatment being enhanced, concomitant with the cancer treatment being enhanced, subsequent to the cancer treatment being enhanced, or a combination thereof.

Problems solved by technology

These findings suggest that interstitial cystitis may be caused by an inhibition of normal bladder epithelial cell proliferation, resulting in a loss of epithelial barrier integrity with subsequent exposure of sensory nerve cells in the bladder wall to urinary constituents.

APF is found in minute quantities in both patient urine specimens and explanted patient bladder cell supernatants, making conventional methods of structural analysis, such as NMR spectroscopy, unfeasible.

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