Extensive documentation has validated the role of UV irradiation as a tumor initiator and promoter, inducing both squamous and basal cell carcinomas. Human epidermis is a tissue which undergoes active metabolism of arachidonic acid to prostaglandins which is regulated by the action of prostaglandin H synthase (also known as cyclooxygenase). One mechanism for the promotional activity of UV light may involve its ability to induce prostaglandin formation. Work in our laboratory has demonstrated that acute exposure of human keratinocytes to UVB irradiation results in increased production of prostaglandin E2 (PGE2). When cultured human keratinocytes were examined after irradiation with 30 mJ/cm2 UVB in vitro, Western blot analysis showed a 6-fold increase in COX-2 protein which was evident at 6 h and peaked 24 h after irradiation. Furthermore, when human subjects were irradiated on sun-protected skin with up to four times their minimal erythema dosage (MED) and biopsied 24 h later, upregulation of COX-2 protein expression was observed via immunofluorescence microscopy. RNAase protection assays supported this observation, showing induction of COX-2 message which peaked at approximately 12 h following irradiation in vitro. Furthermore, human squamous cell carcinoma biopsies exhibited strongly enhanced staining for COX-2 protein via immunohistochemistry and Western analysis when compared to normal non-sun-exposed control skin. Together, these data demonstrate acute upregulation of COX-2 via UVB irradiation and suggest the need for further studies of COX-2 expression as a potential pharmacological target mediating human skin tumor development.

Objectives. To determine the association between obesity and prostate cancer recurrence after primary treatment with radical prostatectomy. Methods. Data were abstracted from CaPSURE, a disease registry of 10,018 men with prostate cancer. We included 2131 men who had undergone radical prostatectomy between 1989 and 2003 and had body mass index (BMI) information available. Recurrence was defined as two consecutive prostate-specific antigen (PSA) levels of 0.2 ng/mL or greater or any second treatment. Patients were risk stratified using the PSA level, Gleason grade, and clinical T stage. Results. Patients were followed up for a median of 23 months. Of the 2131 patients, 251 (12%) developed recurrence at a median of 13 months (range 1 to 107); 183 (9%) of these men had PSA failure and 68 (3%) received a second treatment. After adjusting for risk group, ethnicity, age, and comorbidities, a significant association was found between an increasing BMI and disease recurrence (P ϭ 0.028). Very obese patients (BMI 35 kg/m 2 or more) were 1.69 times more likely to have recurrence relative to men of normal weight (BMI less than 25.0 kg/m 2 ; 95% confidence interval [CI] 1.01 to 2.84). An increasing PSA level (P Ͻ0.0001) and Gleason grade (P Ͻ0.0001) were also associated with recurrence. Ethnicity was not significantly associated with either BMI or PSA recurrence (P ϭ 0.685 and P ϭ 0.068, respectively). Conclusions. The results of our study have shown that obesity is an independent predictor of prostate cancer recurrence. Because of the increased comorbidities and greater rates of recurrence, obese individuals undergoing radical prostatectomy need vigilant follow-up care. UROLOGY 66: 1060-1065, 2005.

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Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a Mr 170,000 transmembrane calcium-dependent efflux pump that is inactivated in prostate cancer. We hypothesize that inactivation of the MDR1 gene through CpG methylation contributes to the pathogenesis and progression of prostate cancer. To test this hypothesis, CpG methylation status of the MDR1 promoter and its correlation with clinicopathological findings were evaluated in 177 prostate cancer samples and 69 benign prostate hypertrophy (BPH) samples. Cellular proliferation index and apoptotic index were determined by proliferating cell nuclear antigen (PCNA) and single-strand DNA immunostaining, respectively. After 5-aza-2-deoxycytidine treatment, increased expression of MDR1 mRNA transcript was found in prostate cancer cell lines (DU145, DuPro, and ND1). MDR1 methylation frequency was significantly higher in prostate cancer samples compared with BPH samples (54.8 versus 11.6%, respectively, P < 0.001). Logistic regression analysis revealed that PC patients are 11.5 times more likely to have MDR1 methylation than BPH patients (95% confidence interval 4.87-27.0) and that MDR1 methylation is independent of the age. Significant correlation of MDR1 methylation was observed with high pT category (P < 0.001), high Gleason sum (P ‫؍‬ 0.008), high preoperative prostate-specific antigen (P ‫؍‬ 0.01), and advancing pathological features. In addition, PCNA-labeling index were significantly higher in methylation-specific PCR (MSP)-positive than in MSP-negative prostate cancer samples (P ‫؍‬ 0.048). In contrast, no significant difference in apoptotic index was found between MSP-positive and -negative prostate cancer samples. These findings suggest that CpG hypermethylation of MDR1 promoter is a frequent event in prostate cancer and is related to disease progression via increased cell proliferation in prostate cancer cells.