Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2002-09-30
2004-12-28
Chen, Shin-Lin (Department: 1632)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S134100, C424S139100, C424S155100
Reexamination Certificate
active
06835380
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout the application various publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in the application in order to more fully describe the state of the art to which this invention pertains.
1. Field of the Invention
The present invention relates to a method of inhibiting neoplastic cellular proliferation and/or transformation of mammalian cells, in vitro and in vivo.
2. Related Art
Neoplasms, including cancers and other tumors, are the second most prevalent cause of death in the United States, causing 450,000 deaths per year. One in three Americans will develop cancer, and one in five will die of cancer (Scientific American Medicine, part 12, I, 1, section dated 1987). While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, the statistics for the cancer death rate indicates a need for substantial improvement in the therapy for cancer and related diseases and disorders.
A number of cancer genes, i.e., genes that have been implicated in the etiology of cancer, have been identified in connection with hereditary forms of cancer and in a large number of well-studied tumor cells. Studies of cancer genes have helped provide some understanding of the process of tumorigenesis. While a great deal more remains to be learned about cancer genes, the presently known cancer genes serve as useful models for understanding tumorigenesis.
Cancer genes are broadly classified into “oncogenes” which, when activated, promote tumorigenesis, and “tumor suppressor genes” which, when damaged, fail to suppress tumorigenesis. While these classifications provide a useful method for conceptualizing tumorigenesis, it is also possible that a particular gene may play differing roles depending upon the particular allelic form of that gene, its regulatory elements, the genetic background and the tissue environment in which it is operating.
More than 100 oncogenes have been discovered, but only a small percentage appear mutated in tumors. (Bishop, J M.,
Molecular themes in oncogenesis
, Cell 64:235-248 [1991]; Sager, R.,
Expression genetics in cancer: shifting the focus from DNA to XNA
, Proc. Natl. Acad Sci. 94:952-955 [1997]). Most cancer-related genes exhibit altered expression patterns (increasing or decreasing), causing phenotypic changes involving signal transduction, cell proliferation, DNA repair, angiogenesis, and apoptosis. (Pawson, T., and Hunter, T.,
Signal transduction and growth control in normal and cancer cells
, Curr. Opin Gene Dev.4:1-4 [1994]; Bartek, J., et al.,
Defects in cell cycle control and cancer
, J Pathol, 187:95-99 [1999]; Sancer, A.,
Mechanisms of DNA excision repair
, Science 266:1954-1956 [1994]; Hanahan, D., and Folkman, J.,
Pattern and emerging mechanisms of the angiogenic switch during tumorigenesis
, Cell 86:353-346 [1996]; Wyllie, A. H.,
The genetic regulation of apoptosis
, Curr, Opin. Gene Dev. 5:97-104 [1995]). Identifying specific regulators modulating oncogene expression is important to provide the basis for development of potential subcellular therapeutic strategies. (Gibbs, J. B., and Oliff A.,
Pharmaceutical research in molecular oncology
, Cell 79:193-198 [1994]; Levitzki A.,
Signal
-
transduction therapy: a novel approach to disease management
, Eur. J. Biochem. 226:1-13 [1994]).
Tumor suppressor genes play a role in regulating oncogenesis. Tumor suppressor genes are genes that in their wild-type alleles, express proteins that suppress abnormal cellular proliferation. When the gene coding for a tumor suppressor protein is mutated or deleted, the resulting mutant protein or the complete lack of tumor suppressor protein expression may fail to correctly regulate cellular proliferation, and abnormal cellular proliferation may take place, particularly if there is already existing damage to the cellular regulatory mechanism. A number of well-studied human tumors and tumor cell lines have been shown to have missing or nonfunctional tumor suppressor genes. Examples of tumor suppressor genes include, but are not limited to the retinoblastoma susceptibility gene or RB gene, the p53 gene, the deleted in colon carcinoma (DDC) gene and the neurofibromatosis type 1 (NF-1) tumor suppressor gene (Weinberg, R. A.,Science,254:1138-46 [1991]). Loss of function or inactivation of tumor suppressor genes may play a central role in the initiation and/or progression of a significant number of human cancers.
Anterior pituitary tumors are mostly benign hormone-secreting or non-functioning adenomas arising from a monoclonal expansion of a genetically mutated pituitary epithelial cell. Pathogenesis of tumor formation in the anterior pituitary has been intensively studied. Mechanisms for pituitary tumorigenesis involve a multi-step cascade of recently characterized molecular events. The most well characterized oncogene in pituitary tumors is gsp; a constitutively activated G(s)&agr; protein results from certain point mutations in gsp. (E.g., Fragoso, M. C., et al.,
Activating mutation of the stimulatory G protein [gsp] as a putative cause of ovarian and testicular human stromal Leydig cell tumors
, J. Clin. Endocrinol. 83(6):2074-78 [1999]; Barlier, A. et al.,
Impact of gsp oncogene on the expression of genes coding for Gsalpha, Pit
-1
, Gi
2
alpha, and somatostatin receptor
2
in human somatotroph adenomas: involvement of octreotide sensitivity
, J. Clin. Endocrinol. Metab. 84(8):2759-65 [1999]; Ballare, E., et al.,
Activating mutations of the Gs alpha gene are associated with low levels of Gs alpha protein in growth hormone
-
secreting tumors
, J. Clin. Endocrinol. Metab. 83(12):4386-90 [1999]).
G(s)&agr; mutations occur in about 40% of growth hormone (GH)-secreting tumors, and constitutively activated CREB transcription factor is also found in a subset of these tumors. Although the importance of GS&agr; mutant proteins in the development of growth-hormone secreting pituitary tumors is well established, only about one third of these tumors contains these mutations, indicating the presence of additional transforming events in pituitary tumorigenesis. Although point mutations of Ras oncogene, loss of heterozygosity (LOH) near the Rb locus on chromosome 13, and LOH on chromosome 11 have been implicated in some pituitary tumors, the mechanism that causes pituitary cell transformation remains largely unknown.
Recently, a novel pituitary tumor transforming gene, PTTG (previously known as pituitary-tumor-specific-gene [PTSG]), was isolated. PTTG encodes a securin protein the expression of which causes cell transformation, induces the production of basic fibroblast growth factor (bFGF), is regulated in vitro and in vivo by estrogen, and inhibits chromatid separation. (Pei, L., and Melmed S.,
Isolation and characterization of a pituitary tumor transforming gene
, Mol. Endocrinol. 11:433-441 [1997]; Zhang, X., et al.,
Structure, expression, and function of human pituitary tumor-transforming gene
(PTTG), Mol. Endocrinol. 13:156-166 [1999a]; Heaney, A. P., et al.,
Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis
, Nature Med. 5:1317-1321 [1999]; Zou, H., et al.,
Identification of a vertebrate sister
-
chromatid separation inhibitor involved in transformation and tumorigenesis
, Science 285:418-422 [1999]).
By dysregulating chromatid separation, PTTG overexpression may also lead to aneuploidy, i. e., cells having one or a few chromosomes above or below the normal chromosome number (Zou et al. [1999]). Like most cancer-related genes, the expression of PTTG is restricted in normal tissues, but PTTG expression is dramatically increased in malignant human cell lines, pituitary tumors, colon carcinomas and colorectal tumors.
Horwitz Gregory A.
Melmed Shlomo
Zhang Xun
Cedars-Sinai Medical Center
Chen Shin-Lin
Pillsbury & Winthrop LLP
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