Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1995-04-28
2001-03-20
Eyler, Yvonne (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S006120, C436S064000
Reexamination Certificate
active
06204000
ABSTRACT:
FIELD OF INVENTION
This invention is in the field of cancer diagnostics and therapeutics. In particular, this invention relates to detection of alterations of wild-type KAI1 gene sequence, KAI1 mRNA and KAI1 protein useful in determining the presence of malignant cancer in a subject or a genetic predisposition to malignancy in a subject. The invention further relates to the use of gene therapy to restore the wild-type KAI1 gene product.
BACKGROUND OF INVENTION
It has been widely accepted that carcinogenesis is a multistep process involving genetic and epigenetic changes that dysregulate molecular control of cell proliferation and differentiation. The genetic changes can include activation of proto-oncogenes and/or the inactivation of tumor suppressor genes that can initiate tumorigenesis as well as lead to the progression of tumors. For example, the tumor suppressor gene p53 may be involved in late stages of colorectal carcinomas (Baker, S. J. et al., (1989)
Science,
244: 217-221) and a putative metastasis suppressor gene, nm23, was found down-regulated in metastatic tumors versus nonmetastatic tumors (Steeg, P. S. et al., (1988)
J. Natl. Canc. Inst.,
80:200-204). In addition, the activation of ras oncogene and the amplification of N-myc have been associated with progression of human tumors such as breast carcinomas (Liu, E. et al., (1988)
Oncogene
3:323-327); and neuroblastomas (Brodeur, G. M. et al., (1984)
Science,
224:1121-1124; Schwab, M. et al., (1984)
Proc. Natl. Acad. Sci. U.S.A.,
81:4940-4944) but they are unlikely to be universal determinants of tumor progression (Nicolson, G. L.
Bio Essays,
13:337-342 (1991).
However despite these advances in understanding the genetic changes underlying carcinogenesis, metastasis, which is the main cause of death for most cancer patients (Rosenberg, S. A., Surgical Treatment of Metastasis Cancer (Lippincott, Philadelphia Pa. 1987)), remains one of the most important but least understood aspects of cancer (Liotta, L. A. et al. (1991)
Cell,
64:327-336; Nicolson, G. L. (1991)
BioEssays,
13:337-342 and Steeg, P. S. (1992)
Curr. Opin. Oncol.,
4:134-141). Accordingly, the isolation of metastasis tumor suppressor genes is of great importance for the diagnosis and therapy of cancers.
Cell fusion studies by Ramshaw et al. ((1983)
Int. J. Cancer,
32:471-478) in which hybridization of non-metastatic and metastatic tumor cells produced cell hybrids which are tumorigenic but no longer metastatic demonstrated the existence of metastasis suppressor genes. More recently, Ichikawa et al. (1991)
Cancer Res.,
51:3788-3792) demonstrated that the metastatic ability of rat prostatic cancer cells was suppressed when fused to non-metastatic cancer cells and that the reexpression of metastasis was associated with the consistent loss of a normal rat chromosome. A subsequent study using micro-cell-mediated chromosome transfer further mapped a putative human metastasis suppressor gene to the 11p11.2-13 region of human chromosome 11. (Ichikawa et al. (1992)
Cancer Res.,
52:3486-3490) In this study, these researchers demonstrated that a hybrid retaining human chromosome 11cent-p13 showed a suppression of metastasis while hybrids retaining 11cent-p11.2 did not.
In sum, the data presented in the Ichikawa et al. papers suggested that a putative suppressor gene in the p11.2-13 region of human chromosome 11 may play a role in metastasis. However to date, no gene has been identified in this region which is a candidate metastasis suppressor gene. Thus, there is a need in the art to identify such gene(s) in this chromosome region and to determine if any such gene(s) is associated with metastasis.
SUMMARY OF INVENTION
The present invention relates to methods for detecting alterations of the wild-type KAI1 gene where detection of such alterations is useful in determining the presence of a malignant cancer in a subject or a genetic predisposition to malignancy in a subject. A first method for detecting alterations of the wild-type KAI1 gene comprises analyzing the DNA of a subject for mutations of the KAI1 gene. A second method for detecting alterations of the KAI1 gene comprises analyzing the RNA of a subject for mutations and altered expression of the mRNA product of the KAI1 gene.
The present invention therefore provides nucleic acid probes for detection of alterations of the wild-type KAI1 gene.
The present invention further provides a diagnostic kit containing purified and isolated nucleic acid sequences useful as PCR primers in analyzing RNA or DNA of a subject for alterations of the wild-type KAI1 gene. These PCR primers can also be used to determine the nucleotide sequence of KAI1 alleles.
A third method for detecting alterations of the wild-type KAI1 gene comprises analyzing protein of a subject for alterations in the expression of KAI1 protein.
The invention therefore relates to antibodies to the KAI1 protein and to a diagnostic kit containing antibodies to KAI1 protein useful for detecting alterations in KAI1 protein expression in a subject.
The present invention further provides a method for supplying the wild-type KAI1 gene to a cell having altered expression of the KAI1 protein, the method comprising: introducing a wild-type KAI1 gene into a cell having altered expression of KAI1 protein such that the wild-type gene is expressed in the cell.
REFERENCES:
Dong et al. “Down-Regulation of the KAI1 metastasis suppressor gene during the progression of thuman prostatic cancer infrequently involves gene mutations or allelic loss” Cancer Research. vol. 56, pp. 4387-4390, Oct. 1, 1996.*
A.A. Dong, et al., “KAI1, a Metastasis Suppressor Gene for Prostate Cancer on Human Chromosome 11p11.2” Science 268(5112): 884-86 (May 12, 1995).
BB. Adachi, et al., “Correlation of Kai1/CD82 Gene Expression with Good Prognosis in Patients with Non-Small Cell Lung Cancer” Cancer Research 56(8): 1751-55 (Apr. 15, 1996).
CC. Rinker-Schaeffer, et al., “Differential Suppression of Mammary and Prostate Cancer Metastasis by Human Chromosomes 17 and 11” Cancer Research 54(23): 6249-56 (Dec. 1, 1994).
Ichikawa et al., (1991)Cancer Res., 51:3788-3792, Genetic Factors and Suppression of Metastatic Ability of Prostatic Cancer.
Ichikawa et al., (1992)Cancer Res., 52:3486-3490, Localization of Metastasis Suppressor Gene(s) for Prostatic Cancer to the Short Arm of Human Chromosome 11.
Imai et al., (1992)J. Immunol., 149:2879-2886, C33 Antigen Recognized by Monoclonal Antibodies Inhibitory to Human T Cell Leukemia Virus Type 1-Induced Syncytium Formation is a Member of a New Family of Transmembrane Proteins Including CD9, CD37, CD53, and CD63.
Fukudome et al. (1992)J. Virol., 66:1394-1401, Identification of Membrane Antigen C33 Leukemia Virus Type 1 (HTLV-1) -Induced Syncytium Formation: Altered Glycosylation of C33 Antigen in HTLF-1-Positive T Cells.
Gaugitsch et al., (1991)Eur. J. Immunol., 21:377-383, A New Superfamily of Lymphoid and Melanoma Cell Proteins with Extensive homology to Schistosoma Mansoni antigen SM23.
Gil et al., (1992)J. Immunol., 148:2826-2833, A Member of the Tetra Spans Transmembrane Protein Superfamily is Recognized by a Monoclonal Antibody Raised Against an HLA Class I-Deficient, Lymphokine-Activated Killer-Susceptible, B Lymphocyte Line.
Dong et al., (Mar. 1994) Proc. of the Amer. Assoc. for Cancer Res.; vol. 35, p. 186, Abstract No. 1111, Cloning and Characterization of a Putative Metastasis Suppressor Gene on Human Chromosome 11 p11.2-13 for Prostate Cancer.
Dong et al., (Mar. 1995) Proc. of the Amer. Assoc. for Cancer Res., vol. 36, p. 105, Abstract 630, A Metastasis Suppressor Gene KAI1 for Prostate Cancer from the p11.2 Region of Human Chromosome 11.
Dong et al., (Mar. 1995) Proc. of the Amer. Assoc. for Cancer Res., vol. 36, p. 692, Chromosomal Locations of Metastasis Suppressor Genes for Prostatic Cancer.
Barrett J. Carl
Dong Jin-Tang
Isaacs John T.
Lamb Patricia W.
Eyler Yvonne
Klarquist Sparkman Campbell Leigh & Whinston
The United States of America as represented by the Department of
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