Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-11-17
2001-01-09
Schwartzman, Robert A. (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S325000, C435S366000, C536S023100, C536S024300, C536S024310
Reexamination Certificate
active
06171798
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to the area of gene regulation, in particular the area of regulation of genes involved in tumorigenesis.
BACKGROUND OF THE INVENTION
P53 is the name of a human tumor suppressor gene and its protein product. About 55 percent of all human cancers from many cell or tissue types suffer mutations in both alleles of the p53 gene. People who have inherited such mutations, will develop cancer over their lifetimes.
The p53 protein is a transcription factor, which regulates the expression of a large number of genes. High levels of an active wild type p53 protein in a cell cause these genes to be transcribed at a high rate. Elucidation of the functions of some of these “p53-regulated or -inducible genes” informs the art of how the p53 protein protects humans from cancers.
There is a need in the art to discover p53-inducible genes and their functions, so that we may have a chance to circumvent the effects of p53 mutations in cancer, by activating the p53-inducible genes and repressing the p53-repressible genes, so as to arrest the cancer's growth. Thus, the elucidation of such p53-regulated genes provides useful and valuable information.
SUMMARY OF THE INVENTION
In one embodiment, a method is provided for diagnosing cancer or for determining p53 status in a sample suspected of being neoplastic. The level of expression of an RNA transcript or its translation product in a first sample of a first tissue is compared to the level of expression of the transcript or translation product in a second sample of a second tissue. The first tissue is suspected of being neoplastic and the second tissue is a normal human tissue. The first and second tissue are of the same tissue type. The transcript is a transcript of a gene selected from the group consisting of gene numbers
1
-
8
,
10
,
12
,
14
-
58
,
60
-
68
, and
70
-
100
, as shown in FIG.
1
. The first sample is categorized as neoplastic or as having a mutant p53 when expression is found to be the same or lower in the first sample than in the second sample.
According to another embodiment a method is provided for diagnosing cancer or for determining p53 status in a sample suspected of being neoplastic. The level of expression of an RNA transcript or its translation product in a first sample of a first tissue is compared to the level of expression of the transcript or translation product in a second sample of a second tissue. The first tissue is suspected of being neoplastic and the second tissue is a normal human tissue. The first and second tissue are of the same tissue type. The transcript is a transcript of a gene selected from the group consisting of gene numbers
7
-
24
, and
26
-
100
as shown in FIG.
2
. The first sample is categorized as neoplastic or as having a mutant p53 when expression is found to be the same or higher in the first sample than in the second sample.
Another aspect of the invention is a method of diagnosing cancer or determining p53 status in a sample suspected of being neoplastic. The level of expression of at least one RNA transcript or its translation product in a first sample of a first tissue is compared to the level of expression of the transcripts or translation products in a second sample of a second tissue. The first tissue is suspected of being neoplastic and the second tissue is a normal human tissue. The first and second tissue are of the same tissue type. The first group of RNA transcripts consists of transcripts of genes selected from the group of genes numbered
1
-
8
,
10
,
12
,
14
-
58
,
60
-
68
, and
70
-
100
as shown in FIG.
1
. The second group of RNA transcripts consists of transcripts of genes selected from the group consisting of genes numbered
7
-
24
, and
25
-
100
as shown in FIG.
2
. The first sample is categorized as neoplastic or as having a mutant p53 when expression of at least one of the first group of RNA transcripts or translation products is found to be the same or lower in the first sample than in the second sample, and expression of at least one of the second group of transcripts or translation products is found to be the same or higher in the first sample than in the second sample.
According to another aspect of the invention a method is provided for evaluating carcinogenicity of an agent. A test agent is contacted with a human cell. The level of expression of at least one transcript or its translation product is determined in the human cell after contacting with the agent. The transcript is of a gene selected from the group consisting of genes numbered
1
-
8
,
10
,
12
,
14
-
58
,
60
-
68
, and
70
-
100
in FIG.
1
and genes numbered
7
-
24
, and
26
-
100
in FIG.
2
. An agent which decreases the level of expression of a gene identified in
FIG. 1
, or an agent which increases the level of expression of a gene identified in
FIG. 2
is identified as a potential carcinogen.
Another aspect of the invention is directed to a method of treating cancer in a patient. A polynucleotide is administered to cancer cells of a patient. The polynucleotide comprises a coding sequence of a gene selected from the group consisting of genes numbered
1
-
8
,
10
,
12
,
14
-
58
,
60
-
68
, and
70
-
100
in FIG.
1
. The cancer cells of the patient harbor a mutant p53 gene. As a result of the administration, the gene is expressed in cells of the cancer.
Yet another aspect of the invention is directed to a method of treating cancer in a patient. An antisense construct comprising at least 12 nucleotides of a coding sequence of a gene selected from the group consisting of genes numbered
7
-
24
, and
26
-
100
in
FIG. 2
is administered to cancer cells of a patient. The coding sequence is in 3′ to 5′ orientation with respect to a promoter which controls its expression. The cancer cells harbor a mutant p53 gene. As a result of the administration, an antisense RNA is expressed in cells of the cancer.
According to still another aspect of the invention a method is provided of screening for drugs useful in the treatment of cancer. A cell which harbors a p53 mutation is contacted with a test substance. Expression of a transcript or its translation product is monitored. The transcript is of a gene selected from the group consisting of genes numbered
1
-
8
,
10
,
12
,
14
-
58
,
60
-
68
, and
70
-
100
in FIG.
1
and genes numbered
7
-
24
, and
26
-
100
in
FIG. 2. A
test substance is identified as a potential drug for treating cancer if it increases expression of a gene as shown in
FIG. 1
or decreases expression of a gene as shown in FIG.
2
.
Another aspect of the invention is a method of screening for drugs useful in the treatment of cancer. A tumor cell which overexpresses MDM2 is contacted with a test substance. Expression of a transcript or its translation product is monitored. The transcript is of a gene selected from the group consisting of genes numbered
1
-
8
,
10
,
12
,
14
-
58
,
60
-
68
, and
70
-
100
in FIG.
1
and genes numbered
7
-
24
, and
26
-
100
in
FIG. 2. A
test substance is identified as a potential drug for treating cancer if it increases expression of a gene as shown in
FIG. 1
or decreases expression of a gene as shown in FIG.
2
.
Yet another aspect of the invention provides a set of at least two nucleotide probes which hybridize to a set of p53-regulated genes. The genes are selected from the group consisting of genes numbered
1
-
8
,
10
,
12
,
14
-
58
,
60
-
68
, and
70
-
100
in FIG.
1
and genes numbered
7
-
24
, and
26
-
100
in FIG.
2
.
These and other embodiments of the invention provide the art with methods for diagnosis, treatment and drug discovery for cancers. In addition, it provides a convenient and rapid carcinogenicity test.
REFERENCES:
patent: 0 390 323 (1990-10-01), None
patent: 89/10977 (1989-11-01), None
patent: 94/18992 (1994-09-01), None
patent: 95/19369 (1995-07-01), None
patent: 99/01581 (1999-01-01), None
Schena et al. “Parallel Human Genome Analysis: Microarray-Based Expression Monitoring of 1000 Genes” Proceedings of the Nat
Gish Kurt Carlyle
Levine Arnold L.
Mack David H.
Murphy Maureen Elizabeth
Tom Edward Yat Wah
Affymetrix Inc.
Banner & Witcoff , Ltd.
Lishibuya Mark
Schwartzman Robert A.
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