Limited options for the treatment of cancer of the prostate gland (CaP) and its increasing incidence have spurred the search on novel treatment and preventive approaches for this disease. One preventive approach is chemoprevention, a means of cancer control by which the occurrence of the disease can be entirely prevented, slowed or reversed by the administration of one or more naturally occurring and/or synthetic compounds. Indeed, CaP is an excellent candidate disease for chemoprevention because it is typically diagnosed in elderly men and therefore even a modest delay in the neoplastic development achieved through pharmacological or nutritional intervention could result in a substantial reduction in the incidence of this clinically detectable disease. For this reason, concerted efforts are required to develop i) markers for detection and monitoring the efficacy of the disease, and ii) novel chemopreventive strategies against CaP. In recent years there has been intense activity in defining the role of cyclooxygenase-2 (COX)-2, the rate-limiting enzyme involved in the conversion of arachidonic acid to prostaglandins in many cancer types. Aberrant or increased expression of COX-2 has been implicated in the pathogenesis of many cancer types. The most important implication of these findings for carcinogenesis emerged from the recent concept that the US Food and Drug Administration (US FDA) has approved a new class of selective COX-2 inhibitor, celecoxib in the treatment/prevention of colon cancer. Since COX-2 is found to be upregulated in many epithelial cancers including breast, skin, colon and esophageal cancers, we considered that increased COX-2 and prostaglandin levels may also play a role in CaP. Our recent findings are noteworthy where using pair-matched samples of benign and CaP tissue from same individuals we showed overexpression of COX-2 in human prostate adenocarcinoma (The Prostate 43: 7378, 2000). An important implication of this finding could be that COX-2 inhibitors may have preventive effects against the development of human CaP. To our knowledge no prior study has assessed the effect of selective COX-2 inhibitor(s) on prostate carcinogenesis. In this proposal, we will test this hypothesis in a recently developed transgenic animal model TRAMP (transgenic adenocarcinoma mouse prostate), that mimics progressive forms of human prostatic disease. This is important because this animal model emulate human disease where disease progression occurs without the need of administration of unrealistic large doses of chemical carcinogen or hormones. Importantly, in preliminary studies we found that these animals exhibit significantly high basal levels (>3 fold) of COX-2 protein expression in the dorso-lateral prostate compared to their non-transgenic littermates. In the present proposal we will employ TRAMP mouse, which are excellent model to investigate the cancer chemopreventive effects of celecoxib, a specific COX-2 inhibitor, against the development of CaP. The hypothesis to be tested in this proposal is that celecoxib, a specific COX-2 inhibitor will afford protection against the development of CaP via inhibition of COX-2 in the prostate. We believe that the outcome of this proposal will set a platform to define the use of selective COX-2 inhibitors against prevention of CaP in humans.
| Gupta, Sanjay; Adhami, Vaqar M; Subbarayan, Murugesan et al. (2004) Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 64:3334-43 |
| Hussain, Tajamul; Gupta, Sanjay; Mukhtar, Hasan (2003) Cyclooxygenase-2 and prostate carcinogenesis. Cancer Lett 191:125-35 |
