Uses of phospholipase C inhibitors

Details Uses of phospholipase C inhibitors Uses of phospholipase C inhibitors

1997-03-25

2001-05-22

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S477000

Reexamination Certificate

active

06235729

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of tumor and cell biology, pharmacology and protein chemistry. More specifically, the present invention relates to a novel uses of phospholipase C inhibitors.
2. Description of the Related Art
Prostate tumor invasion and metastatic spread present major obstacles to successful cancer control. The critical step in tumor progression is the ability to transmigrate an extracellular matrix and reach the general circulation or invade adjacent tissues. Transmigration of an extracellular matrix (ECM) is a complex process which requires active interactions between the invading cell and the extracellular matrix and other stromal elements [1, 2]. At least three processes are necessary for cell invasiveness: tumor cell recognition of and adhesion to the extracellular matrix, proteolytic remodeling or destruction of the extracellular matrix, and cell migration through the resultant defect. The relative contributions of these processes to cell invasiveness may vary under different circumstances.
The receptor for the epidermal growth factor (EGF) is the peptide growth factor receptor most often found upregulated in human carcinomas [13]. Epidermal growth factor receptor (EGFR) gene amplification or elevated levels of epidermal growth factor binding sites correlate with tumor progression to invasiveness and metastasis. Gene amplification is noted in the majority of glioblastomas but is not seen in encapsulated gliomas [14, 15]. Increased levels of epidermal growth factor receptor are detected in invasive bladder carcinoma [16, 17] and advanced gastric carcinoma [18]; and elevated levels of epidermal growth factor receptor correlate with metastasis and decreased survival in breast cancer patients [19, 20]. In an experimental model system, metastatic potential of human colon carcinoma cells correlated with epidermal growth factor receptor level and functioning [21]. This finding is similar to metastasis of a non-small cell lung carcinoma line being dependent on the level of the epidermal growth factor receptor-related c-erbB-2
eu [22]. In vitro exogenous epidermal growth factor has been shown to promote thyroid tumor cell invasiveness through matrigel [23].
Prostate carcinoma is the most widespread malignancy encountered in the human male population. The frequency and mortality rate of prostate cancer has increased over the past 40 years and is expected to rise steadily in the impending years (1). Androgen dependency of prostate carcinoma usually accompanies initial neoplastic growth, during which tumors respond favorably to hormonal therapy. However, androgen-independent tumors often emerge (2). Deaths related to prostate cancer are invariably due to tumor invasion and metastasis to the lungs, skeleton, and lymph nodes (1, 3). Once the tumor escapes it natural surroundings to invade and metastasize, none of the available treatments yield positive affects on patient survival (3-6). Consequently, efforts to improve the understanding of the basic biology of this disease and particularly the progression to the invasive and metastatic stages should enhance the chances for developing therapeutic approaches.
Polypeptide hormones or growth factors play important roles in the normal and pathologic development of the prostate. Various growth factors promote cell proliferation, motility, and invasiveness of epithelial cells in vitro, all properties required for tumor invasiveness and metastasis. Growth of explanted cells is stimulated by nonsteroidal growth factors, such as epidermal growth factor, (7) and not by steroids such as DHT (8, 9). Prostatic fluid has the highest concentration of epidermal growth factor in the human body (10). Numerous epidermal growth factor-like factors are expressed by normal and neoplastic prostatic cells (9, 11-14). Recent evidence suggests androgens stimulate prostate proliferation in the androgen-dependent cell line, ALVA-31, by upregulating an autocrine stimulatory growth loop involving the epidermal growth factor receptor and one of its ligands, transforming growth factor-&agr; (TGF-&agr;) (14). However, the roles of epidermal growth factor receptor and its ligands in tumor progression have not been defined.
Epidermal growth factor receptor, a transmembrane protein which possesses intrinsic tyrosine kinases activity, is the growth factor receptor found most often upregulated in human carcinomas (15). In an animal model, a direct correlation was seen in the metastatic potential of human colon carcinoma cells and epidermal growth factor receptor level and function (23). Examination of normal prostate epithelial, benign prostatic hyperplasia (BPH) and carcinoma cells demonstrate increased levels of epidermal growth factor receptor expression as one progresses through the different hyperproliferative states (9, 24), the highest levels of epidermal growth factor receptor expression correlating with the loss of androgen-dependency by prostate carcinoma cells (25). In prostate cancer, one detects either an increase in the level of epidermal growth factor receptor (25, 26) or in the production of its activating ligands, epidermal growth factor and transforming growth factor-&agr; (9, 27), or both (28, 29). In many cancers, the synchronous overexpression of epidermal growth factor/transforming growth factor-&agr; and epidermal growth factor receptor has been associated with more invasive phenotypes (30-33). This autocrine stimulatory loop is often present in prostate carcinoma, e.g., in the DU-145 human prostate carcinoma cell line (34), which produces transforming growth factor-&agr; and expresses epidermal growth factor receptor (28, 29, 35, 36).
Previously, DU-145 cells were genetically-engineered to overexpress a full length, wild-type epidermal growth factor receptor in order to delineate the role epidermal growth factor receptor signaling plays in cell proliferation and invasion (36). In vitro transmigration of a human extracellular matrix was increased for the cells overexpressing wild type epidermal growth factor receptor. Disruption of the transforming growth factor-&agr;-epidermal growth factor receptor autocrine stimulatory loop by an epidermal growth factor receptor antibody diminished DU-145 parental and wild type epidermal growth factor receptor-expressing cell invasion through the extracellular matrix in vitro; thus emphasizing the importance of epidermal growth factor receptor signaling in cell migration and invasion. Epidermal growth factor receptor-dependent migration and invasion observed in DU-145 sublines expressing wild type epidermal growth factor receptor was not linked to increased proteolytic activity (36), but did correlate with signals which lead to increased cell motility (37, 38).
The prior art is deficient in the lack of effective means of inhibiting tumor cell motility which is critical for tumor invasion and metastasis. The present invention fulfills this longstanding need and desire in the art.
SUMMARY OF THE INVENTION
Prostate carcinomas often present an autocrine stimulatory loop in which the transformed cells both express the epidermal growth factor receptor and produce activating ligands (transforming growth factor-&agr; and epidermal growth factor forms). Upregulated epidermal growth factor receptor signaling has been correlated with tumor progression in other human neoplasias; however, the cell behavior which is promoted remains undefined. To determine whether an epidermal growth factor receptor-induced response contributes to cell invasiveness, DU-145 human prostate carcinoma cells were transduced with either a full-length (wild type) or a mitogenic-active but motility-deficient, truncated (c'973) epidermal growth factor receptor. The DU-145 parental and two transgene sublines all produced epidermal growth factor receptor and transforming growth factor-&agr;, but the transduced wild type and c'973 epidermal growth factor receptor un

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