Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-08-20
2003-12-30
Ungar, Susan (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023100, C536S023500, C536S024300, C530S350000
Reexamination Certificate
active
06670119
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for detecting a cancer cell characterized by detecting an expression product of a gene capable of changing an expression level thereof owing to canceration. The present invention relates to a gene capable of changing an expression level thereof and a product of the gene owing to canceration.
2. Discussion of the Related Art
Cancers constitute the top of the causes for mortality in Japan since 1981, and a gastric cancer occurs especially at the highest frequency. Recently, there has been known that there is a multi-stage carcinogenic mechanism in the course from a normal cell to a cancer cell [Fearon, E. R. et al.,
Cell
, 61, 759-767 (1990); Sugimura, T.,
Science
, 258, 603-607 (1992)] for which the accumulation of the abnormality in a plurality of genes including DNA repair genes, tumor suppressor genes and oncogenes is essential. Generally, the instability of a gene and the inactivation of a tumor suppressor gene are involved in the development of a cancer, and the activation of an oncogene and/or the overexpression of a growth factor are involved in the advancement and malignancy of a cancer.
The instability of a gene includes the instability of gene associated with abnormality in a DNA mismatch repair system and the instability at a chromosomal level. An example of the former includes the difference in the chain length of a simple repeated sequence present in a genome between a cancer site and a non-cancer site in the same individual (microsatellite instability) [Thibodeau, S. N. et al.,
Science
, 260, 816-819 (1993)], and an example of the latter includes an interchromosomal translocation. The interchromosomal translocation may cause to express a protein which is not found in normal cells, or the interchromosomal translocation may affect an expression level of a protein, even if it is expressed in normal cells. In fact, in human chronic myelocytic leukemia, bcr gene is fused with c-abl gene by the interchromosomal translocation, and there has been confirmed an expression of a hybrid mRNA transcribed from bcr-abl fusion gene, which is absent in normal cells. Further, there has been confirmed that an introduction of bcr-abl fusion gene into an animal results in an onset of leukemia [Watson, J. D. et al.,
Molecular Biology of Recombinant DNAS
, 2nd Ed., Maruzen K. K., 309 (1992)].
The inactivation of a tumor suppressor gene includes, for example, an inactivation of p53 gene. The inactivation is considered to be caused by a deletion within the gene, or a point mutation occurring in a particular portion of an encoding region [Nigro, J. M. et al.,
Nature
, 342, 705-708 (1989); Malkin, D. et al.,
Science
, 250, 1233-1238 (1990)]. In addition, since the deletion and the point mutation of the p53 gene are observed in various cancers, and are as frequent as 60% or higher especially in cases of a gastric cancer at an early stage [Yokozaki, H. et al.,
Journal of Cancer Research and Clinical Oncology
, 119, 67-70 (1992)], the detection of these mutations is considered to be useful for detecting a cancer at an early stage.
On the other hand, p16/MTS1 gene has been known to be a gene which is inactivated owing to a homologous deletion, and high-frequency homologous deletions have been observed in cases of a glioma, a pancreatic cancer and a urinary bladder cancer [Cairns, P. et al.,
Nature Genetics
, 11, 210-212 (1995)]. p16 Protein regulates a cell cycle, and the abnormality in p16 expression has been suggested to be involved in the canceration of a cell [Okamoto, A. et al.,
Proceedings of the National Academy of Sciences of the United States of America
, 91, 11045-11049 (1994)].
As the causation for the activation of an oncogene, there can be included, for example, a viral insertion mutation in a proximity of an oncogene and an interchromosomal translocation. For example, a viral insertion mutation has been confirmed in lymphoma of a chicken which is caused by an avian leukosis virus (ALV). In this case, it has been found that DNA of an ALV is inserted in the proximity of a gene c-myc, and, by potent viral enhancer and promoter, a normal c-myc is overexpressed, and a new sequence which is different partially from the normal gene has been expressed. In addition, in a certain kind of human B cell tumor, there has been confirmed that c-myc, which is one of oncogenes, is located near a potent transcription signal of immunoglobulin by the interchromosomal translocation, whereby increasing its expression level of the mRNA. In this case, no difference has been found between a protein for c-myc in a cancer cell and a protein for c-myc expressed in a normal cell, and the canceration is considered to be caused by an increase in the expression level of the c-myc mRNA [Watson, J. D. et al.,
Molecular Biology of Recombinant DNAS
, 2nd Ed., Maruzen K. K., 305-308 (1992)].
An overexpression of a growth factor includes, for example, an overexpression of C-Met which encodes a hepatocyte growth factor receptor. There has been confirmed that the abnormality in expression of the C-Met is observed as an expression of mRNA having the length of 6.0 kb which is not found in a normal mucous membrane at an early stage of gastric cancer [Kuniyasu, H. et al.,
International Journal of Cancer
, 55, 72-75 (1993)], or is observed at a high frequency, and that a correlation between the gene amplification and the degree of the cancer malignancy is observed [Kuniyasu, H. et al.,
Biochemical and Biophysical Research Communications
, 189, 227-232 (1992)].
As examples of confirming the correlation between the gene abnormality and the degree of cancer malignancy, in addition to that of the c-Met mentioned above, there have been confirmed that an amplification and/or an overexpression of an oncogene C-erbB2 gene is found in mammary cancers, ovarian cancers, gastric cancers and uterine cancers [Wright, C. et al.,
Cancer Research
, 49, 2087-2090 (1989); Saffari, B. et al.,
Cancer Research
, 55, 5693-5698 (1995)]; and that an amplification and/or an overexpression of an oncogene K-sam gene is found in a poorly-differentiated adenocarcinoma which is one tissue type of gastric cancer [Tahara, E. et al.,
Gastric Cancer
, Tokyo, Springer-Verlag, Published in 1993, 209-217], respectively.
As described above, the information concerning the gene involved in the development and the advancement of a cancer as well as the abnormality of such genes has been increasing, and the genetic diagnosis of a biopsy material may serve for an early diagnosis and an assessment of the degree of malignancy of a cancer. However, since a carcinogenic mechanism comprises multiple steps and requires an accumulation of a plurality of mutations, a large part of the genes associated with the canceration have still yet been unknown, and further study is necessary. Recently, a gene therapy in which a normal p53 gene is introduced into a cancer cell whereby suppressing the proliferation of the cancer cell is now at a stage of a clinical trial. Therefore, the solution for a cancer-suppressing gene can shed light not only in the diagnosis but also in the gene therapy.
SUMMARY OF THE INVENTION
Accordingly, a first object of the present invention is to provide a method for detecting cancerated cell and a method for determining a degree of malignancy, on the basis of finding a gene usable as an index for carcinogenesis, particularly a gene capable of changing expression conditions thereof by canceration of a cell, and measuring an expression level of the gene in a resected specimen. A second object of the present invention is to provide a kit used for the above method for detecting a cancer cell and/or a method for determining a degree of malignancy of the cell. A third object of the present invention is to provide a method for controlling proliferation of a cancer cell by using a substance specifically binding to a gene capable of serving
Asada Kiyozo
Hino Fumitsugu
Kato Ikunoshin
Mukai Hiroyuki
Yoshikawa Yoshie
Birch & Stewart Kolasch & Birch, LLP
Davis Minh Tam
Takara Shuzo Co. Ltd.
Ungar Susan
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