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Fhit proteins and nucleic acids and methods based thereonRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Immunoglobulin, Antiserum, Antibody, Or Antibody Fragment, Except Conjugate Or Complex Of The Same With Nonimmunoglobulin Material, Monoclonal Antibody Or Fragment Thereof (i.e., Produced By Any Cloning Technology), Binds Eukaryotic Cell Or Component Thereof Or Substance Produced By Said Eukaryotic Cell, Cancer CellFhit proteins and nucleic acids and methods based thereon description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070178105, Fhit proteins and nucleic acids and methods based thereon. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This is a continuation of U.S. patent application Ser. No. 09/717,054, filed Nov. 21, 2000, which is a continuation of U.S. patent application Ser. No. 08/605,430, filed Feb. 22, 1996, which issued as U.S. Pat. No. 6,242,212 on Jun. 5, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 08/598,873, filed Feb. 9, 1996, which issued as U.S. Pat. No. 5,928,884 on Jul. 27, 1999, the entire disclosure of which is incorporated herein by reference. 1. INTRODUCTION [0003] The present invention relates to nucleotide sequences of the tumor suppressor FHIT genes and amino acid sequences of their encoded proteins, as well as derivatives and analogs thereof and antibodies thereto. The present invention relates to the use of nucleotide sequences of FHIT genes and amino acid sequences of their encoded proteins, as well as derivatives and analogs thereof and antibodies thereto, as diagnostic and therapeutic reagents for the detection and treatment of cancer. The present invention also relates to therapeutic compositions comprising Fhit proteins, derivatives or analogs thereof, antibodies thereto, nucleic acids encoding the Fhit proteins, derivatives or analogs, and FHIT antisense nucleic acids. 2. BACKGROUND OF THE INVENTION [0004] Cancer remains one of the most severe health problems in America, accounting for substantial fatality and health costs in society. Tumorigenesis in humans is a complex process involving activation of oncogenes and inactivation of tumor suppressor genes (Bishop, 1991, Cell 64:235-248). Tumor suppressor genes in humans have been identified through studies of genetic changes occurring in cancer cells (Ponder, 1990, Trends Genet. 6:213-218; Weinberg, 1991, Science 254:1138-1146). [0005] There is a close association between particular chromosomal abnormalities, e.g., chromosomal translocations, inversions, and deletions, and certain types of malignancy, indicating that such abnormalities may have a causative role in the cancer process. Chromosomal abnormalities may lead to gene fusion resulting in chimeric oncoproteins, such as is observed in the majority of the tumors involving the myeloid lineage. Alternatively, chromosomal abnormalities may lead to deregulation of protooncogenes by their juxtaposition to a regulatory element active in the hematopoietic cells, such as is observed in the translocation occurring in the lymphocytic lineage (Virgilio et al., 1993, Proc. Natl. Acad. Sci. USA 90:9275-9279). Deletions may cause loss of tumor suppressor genes, leading to malignancy. [0006] Nonrandom chromosomal translocations are characteristic of most human hematopoietic malignancies (Haluska et al., 1987, Ann. Rev. Genet. 21:321-345) and may be involved in some solid tumors (Croce, 1987, Cell 49:155-156). In B and T cells, chromosomal translocations and inversions often occur as a consequence of mistakes during the normal process of recombination of the genes for immunoglobulins (Ig) or T-cell receptors (TCR). These rearrangements juxtapose enhancer elements of the Ig or TCR genes to oncogenes whose expression is then deregulated (Croce, 1987, Cell 49:155-156). In the majority of the cases, the rearrangements observed in lymphoid malignancies occur between two different chromosomes. [0007] The TCL-1 locus on chromosome 14 band q32.1 is frequently involved in the chromosomal translocations and inversions with the T-cell receptor genes observed in several post-thymic types of T-cell leukemias and lymphomas, including T-prolymphocytic leukemias (T-PLL) (Brito-Babapulle and Catovsky, 1991, Cancer Genet. Cytogenet. 55:1-9), acute and chronic leukemias associated with the immunodeficiency syndrome ataxia-telangiectasia (AT) (Russo et al., 1988, Cell 53:137-144; Russo et al., 1989, Proc. Natl. Acad. Sci. USA 86:602-606), and adult T-cell leukemia (Virgilio et al., 1993, Proc. Natl. Acad. Sci. USA 90:9275-9279). [0008] In 1979, a large Italian-American family in Boston was observed to be transmitting a constitutional reciprocal t(3;8)(p14.2;q24) chromosome translocation (Cohen et al., 1979, N. Engl. J. Med. 301:592-595; Wang and Perkins, 1984, Cancer Genet. Cytogenet. 11:479-481) which segregated in the family with early onset, bilateral and multifocal clear cell renal carcinoma (RCC). Follow-up cytogenetic studies in several familial tumors demonstrated that the tumors had lost the derivative 8 chromosome carrying the translocated 3p14-pter region; consequently, the tumors were homozygous for all loci telomeric to the 3p14.2 break (Li et al., 1993, Annals of Internal Medicine 118:106-111). It was suggested that the translocation affects expression of a tumor suppressor gene (Cohen et al., 1979, N. Engl. J. Med. 301:592-595) and several investigators have sought candidate suppressor genes. We had suggested the protein tyrosine phosphatase gamma gene (PTPRG) as a candidate tumor suppressor gene (LaForgia et al., 1991, Proc. Natl. Acad. Sci. USA 88:5036-5040), and that the majority of clear cell RCCs exhibit loss of heterozygosity of a 0.5 Mb region flanking the translocation (Lubinski et al., 1994, Cancer Res. 54:3710-3713; Druck et al., 1995, Cancer Res. 55:5348-5355), although we did not observe aberrations in the remaining PTPRG gene. The 3p14.2 region is also included in deletions in numerous other tumor types, including nasopharyngeal carcinomas (Lo et al., 1994, Int. J. Oncol. 4:1359-1364). [0009] The t(3;8) translocation breakpoint was cloned and a 3 kb transcript of a candidate tumor suppressor gene was detected using a probe from near the breakpoint (Boldog et al., 1993, Proc. Natl. Acad. Sci. USA 90:8509-8513); further details concerning this transcript have not been reported in spite of a later publication from this group relating to this subject, and reporting a YAC contig of approximately 6 Mb DNA spanning the 3p14.2 3;8 translocation breakpoint (Boldog et al., 1994, Genes, Chromosomes & Cancer 11:216-221). It has also been suggested that there may not be a suppressor gene at 3p14.2, that in fact the t(3;8) translocation was a mechanism for losing the von Hippel-Lindau gene, a tumor suppressor gene at 3p25 (Gnarra et al., 1994, Nature Genet. 7:85-90). [0010] Another cytogenetic landmark in chromosome region 3p14.2 is the most common of the constitutive aphidicolin inducible fragile sites, FRA3B, which is cytogenetically indistinguishable from the t(3;8) translocation (Glover et al., 1988, Cancer Genet. Cytogenet. 31:69-73). Fragile sites, of which over 100 have been described in human (for review, see Sutherland, 1991, Genet. Anal. Tech. Appl. 8:1616-166), are regions of the human genome which reveal cytogenetically detectable gaps when exposed to specific reagents or culture conditions; several folate sensitive, heritable, X-linked and autosomal fragile sites have been localized to unstable CCG or CGG repeats (Yu et al., 1991, Science 252:1179-1181; Kremer et al., 1991, Science 252, 1711-1714; Verkerk et al., 1991, Cell 65:905-914; Fu et al., 1991, Cell 67:1047-1058), and for one of these, the FRA11B at 11q23.3, the CCG repeat is within the 5' untranslated region of the CBL2 gene, a known protooncogene (Jones et al., 1995, Nature 376:145-149). Also this fragile site, FRA11B, is associated with Jacobsen (11q-) syndrome, showing a direct link between a fragile site and in vivo chromosome breakage (Jones et al., 1994, Hum. Mol. Genet. 3:2123-2130). Because the induced fragile sites resemble gaps or breaks in chromosomes, it has frequently been speculated that fragile sites could be sites of chromosomal rearrangement in cancer (Yunis and Soreng, 1984, Science 226:1199-1204). Previously identified fragile sites have also been shown to be hypermethylated (Knight et al., 1993, Cell 74:127-134); thus methylation of a fragile site in a tumor suppressor gene regulatory region might cause loss of transcription of the suppressor gene, serving as one "hit" in the tumorigenic process, as pointed out previously (Jones et al., 1995, Nature 376:145-149). These authors also suggested that an important contribution of fragile site expression in tumorigenesis might be to increase the incidence of chromosome deletion during tumorigenesis. [0011] The FRA3B region has been delineated by studies of several groups using rodent-human hybrids; hybrid cells retaining human chromosome 3 or 3 and X, on a hamster background, were treated with aphidicolin or 6-thioguanine (to select hybrids which had lost the X chromosome) and subclones selected. Subclones retaining portions of chromosome 3 with apparent breaks in region 3p14-p21 were characterized for loss or retention of specific 3p markers to determine the position of 3p14-21 breaks (LaForgia et al., 1991, Proc. Natl. Acad. Sci. USA 88:5036-5040, LaForgia et al., 1993, Cancer Res. 53:3118-3124; Paradee et al., 1995, Genomics 27:358-361). [0012] Alterations in oncogenes and tumor suppressor genes in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) have been described, the most frequent target being alterations of p53 (Takahashi et al., 1989, Science 246:491-494; Chiba et al., 1990, Oncogene 5:1603-1610; Mitsudomi et al., 1992, Oncogene 7:171-180) and retinoblastoma (Harbour et al., 1988, Science 241:353-357; Xu et al., 1994, J. Natl. Cancer Inst. 86:695-699) genes and allelic deletions of the short arm of chromosome 3 (3p) (Kok et al., 1987, Nature 330:578-581; Naylor et al., 1987, Nature 329:451-454; Rabbitts et al., 1989, Genes Chrom. Cancer 1:95-105). In addition to cytogenetically visible deletions (Whang-Peng et al., 1982, Science 215:181-182; Testa et al., 1994, Genes Chrom. Cancer 11:178-194), loss of heterozygosity (LOH) at loci on 3p has been reported in nearly 100% of SCLC (Kok et al., 1987, Nature 330:578-581; Naylor et al., 1987, Nature 329:451-454; Brauch et al., 1987, N. Engl. J. Med. 317:1109-1113; Yokota et al., 1987, Proc. Natl. Acad. Sci. USA. 84:9252-9256) and in 50% or more of NSCLC (Brauch et al., 1987, N. Engl. J. Med. 317:1109-1113; Yokota et al., 1987, Proc. Natl. Acad. Sci. USA. 84:9252-9256; Rabbitts et al., 1990, Genes Chrom. Cancer 2:231-238; Hibi et al., 1992, Oncogene 7:445-449; Yokoyama et al., 1992, Cancer Res. 52:873-877; Horio et al., 1993, Cancer Res. 53:1-4), strongly suggesting the presence of at least one tumor suppressor gene in this chromosomal region. [0013] However, the observation that allelic losses often involve most of the 3p has hampered the isolation of the involved gene(s). Candidate loci have been identified such as the von-Hippel Lindau gene, located at 3p25, which was subsequently found to be rarely mutated in lung cancer cell lines (Sekido et al., 1994, Oncogene 9:1599-1604). Other loci located in a region within 3p21 were reported to be sites of recurrent homozygous deletions in SCLC (Daly et al., 1993, Oncogene 8:1721-1729; Kok et al., 1993, Proc. Natl. Acad. Sci. USA 90:6071-6075; Kok et al., 1994, Cancer Res. 54:4183-4187). In addition, transfer of subchromosomal fragments of the region 3p21.3-p21.2 to tumor cell lines has suggested tumor suppressor activity (Killary et al., 1992, Proc. Natl. Acad. Sci. USA 89:10877-10881; Daly et al., 1993, Oncogene 8:1721-1729). More proximal deletions in the 3p12-14 region have also been reported (Rabbitts et al., 1989, Genes Chrom. Cancer 1:95-105; Rabbitts et al., 1990, Genes Chrom. Cancer 2:231-238; Daly et al., 1991, Genomics 9:113-119). [0014] Lung cancer is a major cause of mortality worldwide and the overall survival rate has not improved significantly in the last 20 years. Despite the success achieved by primary prevention, lung cancer is still an overwhelming medical and social problem. Even in the cohort of ex-smokers lung cancer incidence remains high for several years, as a consequence of the accumulated damage, and there is an objective need for strategies aimed at reducing cancer mortality in individuals who have stopped smoking. [0015] There remains an unfulfilled need to isolate and characterize the genes associated with digestive tract and other cancers for use as a diagnostic and therapeutic/prophylactic reagent in the detection, treatment, and prevention of such cancers. [0016] Citation of a reference hereinabove shall not be construed as an admission that such reference is prior art to the present invention. 3. SUMMARY OF THE INVENTION [0017] The present invention relates to nucleotide sequences of PHIT genes, and amino acid sequences of their encoded FHIT proteins, as well as derivatives (e.g., fragments) and analogs thereof, and antibodies thereto. The present invention further relates to nucleic acids hybridizable to or complementary to the foregoing nucleotide sequences as well as equivalent nucleic acid sequences encoding a FHIT protein. In a specific embodiment, the FHIT genes and proteins are human genes and proteins. [0018] Mutations (in particular, deletions) of FHIT gene sequences are associated with esophageal, gastric, colon, kidney, and other cancers. [0019] The present invention also relates to expression vectors encoding a FHIT protein, derivative or analog thereof, as well as host cells containing the expression vectors encoding the FHIT protein, derivative or analog thereof. As used herein, "FHIT" shall be used with reference to the FHIT gene, whereas "Fhit" shall be used with reference to the protein product of the FHIT gene. [0020] The present invention further relates to the use of nucleotide sequences of FHIT genes and amino acid sequences of their encoded Fhit proteins as diagnostic reagents or in the preparation of diagnostic agents useful in the detection of cancer or precancerous conditions or hyperproliferative disorders, in particular those associated with chromosomal or molecular abnormalities, in particular at 3p14.2, and/or decreased levels of expression, or expression of dysfunctional forms, of the Fhit protein. The invention further relates to the use of nucleotide sequences of FHIT genes and amino acid sequences of their encoded Fhit proteins as therapeutic/prophylactic agents in the treatment/prevention of cancer, in particular, associated with chromosomal or molecular abnormalities at 3p14.2, and/or decreased levels of expression, or expression of dysfunctional forms, of the Fhit protein. [0021] The invention also relates to Fhit derivatives and analogs of the invention which are functionally active, i.e., they are capable of displaying one or more known functional activities associated with a full-length (wild-type) Fhit protein. Such functional activities include but are not limited to antigenicity [ability to bind (or compete with Fhit for binding) to an anti-Fhit antibody], immunogenicity (ability to generate antibody which binds to Fhit), and ability to bind (or compete with Fhit for binding) to a receptor/ligand or substrate for Fhit, and ability to multmerize with Fhit. [0022] The invention further relates to fragments (and derivatives and analogs thereof) of Fhit which comprise one or more domains of a Fhit protein, e.g., the histadine triad, and/or retain the antigenicity of a Fhit protein (i.e., are able to be bound by an anti-Fhit antibody). Continue reading about Fhit proteins and nucleic acids and methods based thereon... 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