Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-21
2004-06-01
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S471000, C540S561000, C540S555000, C514S220000, C514S219000, C514S411000, C514S375000, C514S366000, C514S257000, C544S249000, C548S427000, C548S219000, C548S217000, C548S150000
Reexamination Certificate
active
06743785
ABSTRACT:
Cancer is a heterogeneous group of diseases presenting in various forms in various tissues but having in common the characteristic of uncontrolled cell proliferation. For some time, cancer has been recognized as a disease of uncontrolled cell proliferation. Thus, the rapidly proliferating cell has been the target of cancer chemotherapy. The goal is to find agents that are more effective against cancer cells than against normal cells. As the basic science of the cell progressed, it was shown that certain anticancer agents were more effective against malignant cells at certain stages of the cell cycle than against cells at other stages of the cell cycle.
Attempts were made to develop treatment regimens that took advantage of these observations (SHACKNEY, S. E. et al Cell Kinetics. IN: Bruce Chabner (ed.), Pharmacologic Principles of Cancer Treatment; W. B. Saunder Company: Philadelphia, pp. 45-76, (1982)). Cell replication is now recognized to be controlled by the transient, sequential, highly-regulated expression of a series of cyclins which associate with specific cyclin-dependent kinases (CDK's) (TAULES, M., et al, J. Biol. Chem. 273, 33279-33286 (1998; FISHER, R. P. Current Opinion in Genetics & Develop. 7, 32-38 (1997); ARELLANO, M. et al., Int. J. Biochem. Cell Biol. 29, 559-573 (1997); and RAVITZ, M. J., et al. Adv. Cancer Res. 1997, 165-207 (1997)). These are serine/threonine protein kinases, which activate various enzymes and thereby initiate a cascade of phosphorylations allowing the cell to progress to the next stage of replication (COLLINS, et al., Proc. Natl. Acad. Sci. USA 94, 2776-2778 (1997); JACKS, T. et al., Science 280, 1035-1036 (1998)).
It has been found that cancerous cells often have mutated or missing components in the chain of proteins and enzymes, which control cell division. For example, the Rb protein, often called pRb, is a substrate for the cyclin-CDK's and is frequently missing or mutated in human tumors (KONSTANTINIDIS, A. K. et al, J. Biol. Chem. 273, 26506-26515 (1998); HARRINGTON, E. A., et al., Proc. Natl. Acad. Sci. USA 95, 11945-11950 (1998); YAMAMOTO, et al., Oncol. Rep. 5, 447-451 (1997); BARTEK, J., et al., Exp. Cell Res. 237, 1-6 (1997); SELLERS, et al., J. Clin. Oncol. 15, 3301-3312 (1997); HERWIG, S. et al., Eur. J. Biochem. 246, 581-601 (1997)).
In addition to the kinases, which can help to move the cell from one phase of division to the next, there are CDK inhibitors (CKIs) that block the actions of specific cyclin-CDK complexes. The CKIs halt cell cycle progression and cause cells to enter the quiescent G
o
phase. The CKIs of the INK4 group, including p15, p16, p18, and p19, block the cyclin-CDK4 and cyclin-CDK6 complexes.
Calmodulin is essential for cyclin-dependent kinase 4 (CDK4) activity and nuclear accumulation of cyclin D1-CDK4 during the G
1
phase (TAULES, M., et al, J. Biol. Chem. 273, 33279-33286 (1998)). CDKs and cyclins are important in transition(s) (FISHER, R. P. Current Opinion in Genetics & Develop. 7, 32-38 (1997)). CDK/cyclin complexes are regulated during the cell cycle (ARELLANO, M. et al., Int. J. Biochem. Cell Biol. 29, 559-573 (1997)). Cyclin-dependent kinase during the G
1
phase, and the cell cycle generally are regulated by TGF-&bgr; (RAVITZ, M. J., et al. Adv. Cancer Res. 1997, 165-207 (1997)).
The most frequent alteration in human malignant disease thus far recognized is the overexpression, mutation, and/or disregulation of cyclin D (IMOTO, M., et al., Exp. Cell Res. 236, 173-180 (1997); JUAN, G., et al., Cell Prolif. 29, 259-266 (1996); GONG, J. et al., Cell Prolif. 28, 337-346 (1995) et al., 1995). The cyclin D1 gene, CCND1, is amplified in about 20% of breast cancers and the protein, cyclin D1, is overexpressed in about 50% of breast cancers (BARNES, D. M. et al., Breast Cancer Res. Treat. 52, 1-15 (1998); KAMALATI, T., et al., Clin. Exp. Metastasis 16, 415-426 (1998); STEEG, P. S. et al. Breast Cancer Res. Treat. 52, 17-28 (1998); LANDBERG, G. et al., APMIS 105, 575-589 (1997); ALLE, et al., Clin. Cancer Res. 4, 847-854 (1998)). Overexpression of cyclin D1 has been reported in proliferative breast disease and in ductal carcinoma in situ, indicating that this change is important at the earliest stages of breast oncogenesis (ALLE, et al., Clin. Cancer Res. 4, 847-854 (1998); STEEG, et al., Breast Cancer Res. Treat. 52, 17-28 (1998)).
One researcher (KAMALATI, T., et al., Clin. Exp. Metastasis 16, 415-426 (1998) et al. (1998)) treated normal human epithelial cells so that they overexpressed cyclin D1. These transfected cells had reduced growth factor dependency, a shortened cell cycle time, thus providing the cells with a growth advantage. In 123 colorectal carcinoma specimens, those staining strongly for cyclin D1 corresponded to patients with a 5-year survival rate of 53.3% while those that were negative or weakly staining had 5-year survival rates of 96.2 and 78.8% (MEEDA, K., et al., Oncology 55, 145-151 (1998); PALMQVIST, R., et al., Europ. J. Cancer 34, 1575-1581 (1998)).
Amplification of CCND1 was found in 25% of dysplastic head-and-neck lesions, and 22% of head-and-neck carcinomas. Overexpression of cyclin D1 was found in 53% of head-and-neck carcinomas. This indicates that in this disease, like breast cancer, alterations in cyclin D1 occur at the very earliest stages of tumorigenesis (KYOMOTO, R., et al., Int. J. Cancer (Pred. Oncol.) 74, 576-581 (1997); PIGNATARO, L., et al., J. Clin. Oncol. 16, 3069-3077 (1998) et al., 1998). In a study of 218 specimens of esophageal squamous cell carcinoma, patients with cyclin D1-positive tumors had significantly worse survival than patients with cyclin D1-negative tumors (SARBIA, M. et al., Int. J. Cancer (Pred. Oncol. 84, 86-91 (1999)).
In eight human esophageal carcinoma cell lines, 7 (87.5%) and 6 (75%) cell lines had homozygous deletions of the p16 and p15 genes (KITAHARA, K. et al., J. Exp. Therap. Oncol. 1, 7-12 (1996)). All of the p16-negative cell lines express high levels of cyclin D1 and CDK4.
The Rustgi laboratory (MUELLER, A, et al., Cancer Res. 57, 5542-5549 (1997); NAKAGAWA, H, et al., Oncogene 14, 1185-1190 (1997)) developed a transgenic mouse which the Epstein-Barr virus ED-L2 promoter was linked to human cyclin D1 cDNA. The transgene protein localizes to squamous epithelium in the tongue and esophagus, resulting in a dysplastic phenotype associated with increased cell proliferation and indicating that cyclin D1 overexpression may be a tumor-initiating event. In a series of 84 specimens of soft-tissue sarcomas, there was no amplification of the CCND1 gene but there was overexpression of cyclin D1 in 29% of cases. The overexpression of cyclin D1 was significantly associated with worse overall survival (KIM, S. H., et al., Clin. Cancer Res. 4, 2377-2382 (1998); YAO, J., et al., Clin. Cancer Res. 4, 1065-1070 (1998)).
Another researcher (MARCHETTI, A., et al., Int. J. Cancer 75, 187-192 (1998)) found that abnormalities of cyclin D1 and/or Rb at the gene and/or expression level were present in more than 90% of a series of non-small cell lung cancer specimens, indicating that cyclin D1 and/or Rb alterations represent an important step in lung tumorigenesis. In 49 out of 50 pancreatic carcinomas (98%), the Rb/p16 pathway was abrogated exclusively through inactivation of the p16 gene (SCHUTTE, M., et al., Cancer Res. 57, 3126-3130 (1997)).
Mantle cell lymphoma is defined as a subentity of malignant lymphomas characterized by the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1 and, in addition, about 50% of these tumors have deletion of the p16 gene (DREYLING, M. H., et al., Cancer Res. 57, 4608-4614 (1997); TANIGUCHI, T., et al., Jpn. J. Cancer Res. 89, 159-166 (1998)).
In a series of 17 hepatoblastomas, 76% showed overexpression of cyclin D1 and 88% showed overexpression of CDK4 (KIM, H., et al., Cancer Lett. 131, 177-183 (1998)). There was a correlation between high level cyclin D1 expression and tumor recurrence. Alterations in the cyclin D1/CDK4/pRb pathway have also been associated with a high p
Al-Awar Rima Salim
Hecker Kyle Andrew
Huang Jian-ping
Joseph Sajan
Ray James Edward
Eli Lilly and Company
Liu Hong
Raymond Richard L.
Tucker Tina M.
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