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Research On The Role And The Clinical Significance Of Cyclooxygenase In Prostate Cancer

Posted on:2005-06-03Degree:DoctorType:Dissertation
Country:ChinaCandidate:K YangFull Text:PDF
GTID:1104360125967510Subject:Surgery
Abstract/Summary:PDF Full Text Request
BACKGROUNDProstate cancer is a leading cause of death in much of the developed world. In 1998 alone, it was estimated that about 185,000 new cases (30% of all new cancers in men) were diagnosed and >39,000 patients died from prostate cancer in the USA. In the UK, 12,000 new cases of prostate cancer are diagnosed each year and the incidence has increase by 66% in the past 15 years. In China, though the incidence is less than that in Western countries, more and more new cases of prostate cancer have been diagnosed in recent years. Thus over the past few decades extensive research was directed towards understanding the mechanism(s) of prostate cancer development and providing practical measures for cure, prevention and early detection. This effort enabled researchers to identify several candidate molecules, genes and proteins that are linked to prostate cancer. Prostate cancer patients, although initially responsive to hormone- ablation therapy, often relapse with androgen-independent disease that is resistant to further therapeutic interventions. Prostate cancer mortality results from metastasis to the bone and lymph nodes and progression from androgen-dependent to androgen independent prostate growth.Cyclooxygenase (COX), also called prostaglandin H2 synthase or PGHS, is the rate-limiting enzyme for converting arachidonic acid to various proinflammatory prostaglandins. Two COX enzymes with similar catalytic features but different expression patterns have been cloned. COX-1 is expressed constitutively in a variety of tissues; in contrast, COX-2 is typically undetectable in most tissues but can be induced rapidly by proinflammatory signals, bacterial endotoxin, and some growth factors. COX-2, but not COX-1, has been shown to be up-regulated in transformed cells and malignant tissues, particularly in the large intestine. Recent studies on the effect of COX-2 in tumorigenesis have gone beyond colorectal cancer. Accumulating evidence suggests that up-regulation of COX-2 is associated with carcinogenesis in multiple organ systems including the small cell lung cancer, breast cancer, skin cancer and bladder cancer. The proposed underlying mechanisms by which COX-2 up-regulation promotes carcinogenesis include promoting angiogenesis, enhancing cellular motility, increasing resistance to apoptosis, etc. Research focusing on the tumor-promoting effects of COX-2 was stimulated by epidemiological studies, which have suggested that regular use of aspirin or other NSAIDs could significantly decrease the risk of developing colorectal cancer. The best-studied pharmacological targets for NSAIDs are the COX enzymes. These findings have led to the approval by the U.S. Food and Drug Administration of celecoxib (Celebrex?) for the adjuvant treatment of familial adenomatous polyposis. In addition, celecoxib has been tested in numerous advanced clinical trials against a variety of epithelial malignancies including colon, oesophagus, skin and bladder cancers. Elucidating the relationship between COX-2 expression and prostate cancer development is critical to understanding the molecular basis of the disease, and may suggest new views on the scheduling of chemotherapy. Comprehending the extent to which COX- 2 is involved in prostate cancer development may shed some light on the possibility of including NSAIDs, that specially inhibit COX-2, as an integral part of a reliable and effective strategy for cancer prevention and treatment. PART I Expression of Cyclooxygenase in Human ProstateOBJECTIVETo determine the expression of the two major isoforms of cyclooxygenase (COX-1 and COX-2) in human prostatic tissuesTo study the practice of cyclooxygenase in the diagnosis of prostate carcinomaMATERIALS AND METHODSTwenty-eight specimens of prostate carcinoma (PC) and thirty-one specimens of benign prostatic hyperplasia (BPH), one prostatic intraepithelial neoplasia (PIN) patient, and eight specimens of normal prostate tissue (NP) were stained with mouse antihuman COX-1 and COX-2 polyclonal antibodies. The stai...
Keywords/Search Tags:Prostate, Cyclooxygenase, Prostate carcinoma, Immunohistochemistry
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