P202 is a tumor suppressor

Details P202 is a tumor suppressor P202 is a tumor suppressor

2000-06-08

2001-12-18

Guzo, David (Department: 1636)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

C424S093100, C424S093200, C424S093600, C435S320100, C435S455000, C435S456000, C435S458000, C514S002600, C514S04400A, C530S350000, C536S023100, C536S023500, C536S024100

Reexamination Certificate

active

06331284

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of cancer therapy and gene therapy. More particularly, it concerns the use of p202 to prevent and treat cell transformation.
2. Description of Related Art
Oncogenesis was described by Foulds (1958) as a multistep biological process, which is presently known to occur by the accumulation of genetic damage. On a molecular level, the multistep process of tumorigenesis involves the disruption of both positive and negative regulatory effectors (Weinberg, 1989). The molecular basis for human colon carcinomas has been postulated, by Vogelstein and coworkers (1990), to involve a number of oncogenes, tumor suppressor genes and repair genes. Similarly, defects leading to the development of retinoblastoma have been linked to another tumor suppressor gene (Lee et al., 1987). Still other oncogenes and tumor suppressors have been identified in a variety of other malignancies. Unfortunately, there remains an inadequate number of treatable cancers, and the effects of cancer are catastrophic—over half a million deaths per year in the United States alone.
Cancer is fundamentally a genetic disease in which damage to cellular DNA leads to disruption of the normal mechanisms that control cellular proliferation. Two of the mechanisms of action by which tumor suppressors maintain genomic integrity is by cell arrest, thereby allowing for repair of damaged DNA, or removal of the damaged DNA by apoptosis (Ellisen and Haber, 1998; Evan and Littlewood, 1998). Apoptosis, otherwise called “programmed cell death,” is a carefully regulated network of biochemical events which act as a cellular suicide program aimed at removing irreversibly damaged cells. Apoptosis can be triggered in a number of ways including binding of tumor necrosis factor, DNA damage, withdrawal of growth factors, and antibody cross-linking of Fas receptors (Cohen, 1993; Lowe et al., 1993; Sentman et al., 1991; Smith et al., 1994; Suda et al., 1993; Williams and Smith, 1993). Although several genes have been identified that play a role in the apoptotic process, the pathways leading to apoptosis have not been fully elucidated.
Interferons (IFNs), a family of cytokines, consists of three major glycoproteins, INF-&agr;, INF-&bgr;, and INF-&ggr;. IFNs possess a wide variety of biological properties such as anti-virus, anti-proliferation, immunoregulation, anti-angiogenesis, and anti-neoplasia (Gutterman, 1994). The anti-neoplastic activity of IFNs can be attributed, in part, to their anti-proliferation function and the activation of host defense systems on tumor cells. In addition, the demonstration of anti-angiogenic activity of IFNs has led to clinical trials using IFN treatment for vascular tumors, that include Kaposi sarcoma (Oettgen et al., 1986), pulmonary hemangiomatosis (Grzegorzewski et al., 1989) and hemangioma (Ezekowitz et al., 1992), resulting in tumor regression in these patients. Apart from the therapeutic effects of IFNs in certain clinical settings, there were also undesirable side effects (e.g., fever, chills, anorexia, and anemia) associated with the high dose IFN treatment often required to obtain a significant response (Ahre et al., 1998; Kirkwood et al., 1985).
p202 is a 52 kDa nuclear IFN-inducible phosphoprotein. This protein may inhibit the transcription of certain genes by interacting with various transcription modulators (Choubey et al., 1996; Choubey et al., 1997; Choubey and Lengyel, 1995; Datta et al., Datta et al., 1998; 1996; Min et al., 1996). p202 expression has been associated with an increase in both p21 and Rb and a decrease in Cdk2 protein kinase activity (Gutterman and Coubey, 1999) and constitutive expression of p202 may be associated with cell cycle arrest in mammalian cells (Lembo et al., 1995; Yan et al., 1999).
SUMMARY OF THE INVENTION
The present invention generally relates to methods for repressing or preventing transformation in a cell, the method comprising contacting the cell with a p202 polypeptide in an amount effective to inhibit a transformed phenotype. Inhibition of transformation may be indicated by a reduction in a transforming, tumorigenic, or metastatic potential of a cell. Such cells may be in cell culture. More preferably, the cell in which transformation is to be repressed are cells in a living organism, for example a human. The inhibition of such transformation has great utility in the prevention and treatment of such transformation-driven events as cancer, tumorigenesis, and metastasis.
A p202 polypeptide may be contacted with or introduced to a cell through any of a variety of manners known to those of skill. The p202 polypeptide may be introduced through direct introduction of a p202 polypeptide to a cell. In this case, the p202 polypeptide may be obtained through any method known in the art, although it is expected that in vitro expression of the p202 polypeptide in a cell culture system may be a preferred manner of obtaining p202.
p202 may also be introduced to a cell via the introduction of a polynucleotide that encodes the p202 polypeptide to the cell. For example, RNA or DNA encoding p202 may be introduced to the cell by any manner known in the art. In certain preferred embodiments, the p202 is introduced into the cell through the introduction of a DNA segment which encodes p202. In some such embodiments, it is envisioned that the DNA segment further comprises the p202 gene operatively linked to its associated control sequences. For example, the p202 gene may be operatively linked to a suitable promoter and a suitable terminator sequence. The construction of such gene/control sequence DNA constructs is well-known within the art. In particular embodiments the promoter is selected from the group comprising of CMV IE, SV40 IE, RSV LTR, or &bgr;-actin. In certain embodiments for introduction, the DNA segment may be located on a vector, for example, a plasmid vector or a viral vector. The virus vector may be, for example, selected from the group comprising retrovirus, adenovirus, herpesvirus, vaccina virus, and adeno-associated virus. Such a DNA segment may be used in a variety of methods related to the invention. The vector may be used to deliver a p202 gene to a cell in one of the gene-therapy embodiments of the invention. Also, such vectors can be used to transform cultured cells, and such cultured cells could be used, inter alia, for the expression of p202 in vitro.
In particular embodiments the p202 is introduced into a cell that is a human cell. In many embodiments the cell is a tumor cell. In some presently preferred embodiments the tumor cell is a breast tumor cell, a prostrate tumor cell, or an ovarian tumor cell. However, p202 may be introduced into other tumor cells including, but not limited to, a bladder tumor cell, a testicular tumor cell, a colon tumor cell, a skin tumor cell, a lung tumor cell, a pancreatic tumor cell, a stomach tumor cell, an esophageal tumor cell, a brain tumor cell, a leukemia tumor cell, a liver tumor cell, an endometrial tumor cell, or a head and neck tumor cell. In some embodiments, the p202 is introduced by injection.
In some embodiments of the present invention, the inventor's discovery that p202 is able to inhibit transformation will be used in combination with other anti-transformation/anti-cancer therapies. These other therapies may be known at the time of this application, or may become apparent after the date of this application. p202 may be used in combination with other therapeutic polypeptides, polynucleotides encoding other therapeutic polypeptides, or chemotherapeutic agents. For example, p202 may be used in conjunction with other known polypeptides, such as TNF&agr; or P53. p202 may be used in conjunction with any suitable chemotherapeutic agent. In one representative embodiment, the chemotherapeutic agent is taxol. p202 also may be used in conjunction with radiotherapy. The type of ionizing radiation constituting the radiotherapy may be selected from the group comprising x-rays, &ggr;-rays, and microwaves. In certai

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