Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1993-11-23
2000-07-04
McKelvey, Terry A.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 71, 435 75, 435 77, 435 78, 435 79, 435 792, G01N 33574, G01N 3353, G01N 33537, G01N 33543
Patent
active
060837098
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced by arabic numbers within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Cellular oncogenes are normal genes which have been conserved throughout evolution and are believed to have normal functional roles in the cell. In their non-activated (wild-type) state such cellular oncogenes are sometimes referred to as proto-oncogenes. Proto-oncogenes are not oncogenic or tumorigenic until they are activated in some way. A number of different genetic mechanisms may cause the somatic mutation of oncogenes that results in the activated oncogenes found in tumor cells. These include point mutations, translocations, gene rearrangement, and gene amplification, all of which may be induced by chemical or physical carcinogenic means or by the integration of a viral genome adjacent to the proto-oncogene sequences in the host DNA. Certain oncogenes, such as ras and wild type p53 oncogenes, when "activated" encode mutant proteins while others such as myc may express elevated levels of normal protein.
The wild type p53 oncogene encodes wild type p53 polypeptide which functions as a negative regulator of cell division. The wild type p53 polypeptide has been found intracellularly in normal cells and tissues at low levels. Mutant p53 polypeptides encoded by activated p53 oncogenes are present intracellularly at high concentrations in mammalian tumors and tumor cell lines.
The wild type p53 oncogene is conserved across a wide variety of species including man, mouse, rat and frog (1). cDNA sequence analysis has indicated that there are five blocks of very highly conserved sequences (2, 3). These conserved residues have been grouped in blocks beginning at amino acid 117 and ending at amino acid 286 (4). Point mutations, occurring principally in these five blocks of very highly conserved sequences and also in highly conserved regions of the wild type p53 oncogene lying outside of these blocks, produce an activated p53 oncogene (SEQ ID NO:2-SEQ ID NO:7). Changes in these conserved areas have a significant impact on the function of the mutant p53 polypeptide. Changes in these regions of the wild type p53 oncogene generate an activated p53 oncogene which encodes a protein having a conformational change identical to the vast majority of the mutant p53 polypeptides so expressed.
The product of the activated p53 oncogene, i.e. mutant p53 polypeptide, is present at high levels in a high percentage of virtually all classes of human tumors including tumors of the colon, lung, and breast (2). Biochemical analyses of mutant p53 polypeptides demonstrate that activating mutations affect the polypeptide's structure in similar ways. Mutant p53 polypeptides have a much longer half-life as compared to normal p53 polypeptide. In addition, mutant p53 polypeptides are able to complex with the heat-shock-protein-70 family of proteins but not to SV40 large T antigen (5-8). Finally, in histological or cell-based assays, mutant and wild-type p53 polypeptides have been distinguished on the basis of differential reactivity with monoclonal antibodies. Antibody secreted by clone PAb246 is reactive with wild-type p53 polypeptides but not with any mutant p53 polypeptide tested to date, while antibody secreted by clone PAb240 reacts with all mutant p53 polypeptides tested to date but not with a wild-type p53 polypeptide (5-21).
The human, wild-type p53 oncogene is found on chromosome 17p. Allelic loss in 17p occur at high frequency in human breast cancer (22), colon cancer (23), astrocytomas (24) and small cell lung carcinoma (25). The question of allele loss of the wild-type p53 oncogene was addressed by cytogenetic analysis of a number of colon cancer samples using specific DNA probes (23).
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Reynolds, Jr. Frederick H.
Sorvillo John M.
Stephenson John R.
Zeheb Ron
McKelvey Terry A.
OSI Pharmaceuticals, Inc.
White John P.
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