Chronic use of NSAIDs and/or statins does not affect PSA or PSA velocity in men at high risk for prostate cancer.

BACKGROUND: PSA and PSA velocity (PSAV, rate of PSA change over time) are biomarkers for diagnosis and prognosis of prostate cancer. Men who are at high risk for prostate cancer also have associated comorbidities for which they are taking NSAIDs and statins for long periods; therefore, it is important to understand the effect of these medications on markers used to assess prostate cancer risk. METHODS: Using a population of 699 men, multiple linear regressions were used to investigate the associations between PSA and concomitant medications, and mixed-effects models were used to investigate these associations with PSAV. RESULTS: After adjusting for selenium use, age, race, body mass index, and pack-years of smoking, aspirin, other NSAIDs, or statins did not demonstrate statistically significant associations with PSA (P = 0.79, 0.68, and 0.79, respectively) or PSAV (P = 0.23, 0.43, and 0.84, respectively). Results were not altered upon stratifying the sample between men who developed prostate cancer during the course of the study and those who did not. CONCLUSIONS: Results from this study indicate that chronic use of aspirin, other NSAIDs, or statins did not affect PSA levels or PSAV in men at high risk for prostate cancer. Larger prospective studies designed to investigate these relationships are needed to confirm this result. IMPACT: Long-term use of NSAIDs or statins in men at high risk for prostate cancer may not interfere with the diagnosis or prognosis of this disease, and supports appropriate use of these medications with regard to prostate cancer risk.

Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer.

PURPOSE: This study was conducted to investigate the effect of Se supplementation on prostate cancer incidence in men at high risk for prostate cancer. METHODS: A Phase 3 randomized, double-blind, placebo-controlled clinical trial was conducted in 699 men at high risk for prostate cancer (prostate specific antigen (PSA) >4 ng/ml and/or suspicious digital rectal examination and/or PSA velocity >0.75 ng/ml/year), but with a negative prostate biopsy. Participants were randomized to receive daily oral placebo (N = 232), 200 µg selenium (N = 234), or 400 µg selenium (N = 233) as selenized yeast. They were followed every 6 months for up to 5 years. The time to diagnosis of prostate cancer was compared between treatment groups using the Cox proportional hazards model. RESULT: Compared to placebo, the hazard ratios [95% confidence intervals] for risk of developing prostate cancer in the selenium 200 µg/day or the selenium 400 µg/day group were 0.94 [0.52, 1.7] and 0.90 [0.48, 1.7], respectively. PSA velocity in the selenium arms was not significantly different from that observed in the placebo group (P = 0.18 and P = 0.17, respectively). CONCLUSION: Selenium supplementation appeared to have no effect on the incidence of prostate cancer in men at high risk. In conjunction with results of other studies, these data indicate that selenium supplementation may not have a role in prostate cancer chemoprevention.

Association of obesity and smoking with PSA and PSA velocity in men with prostate cancer.

Significant number of prostate tumors are slow growing and could probably be left untreated. However, many are aggressive and can spread rapidly causing patient suffering and/or death. Current technology does not allow physicians to differentiate between slow growing and aggressive tumors at diagnosis. Hence, many patients are exposed to invasive treatment and its associated morbidities such as incontinence and impotence. Markers that enable differentiation between slow and fast progressing cancer will allow physicians to prevent unnecessary treatments on men who may not need them, and focus on the men with aggressive disease. A longitudinal study was conducted (N = 140) using mixed effects regression models to determine the association of obesity and smoking toward prostate cancer progression. These models account for correlation because of repeated measures over time, thus, using maximum amount of information provided by the subject. Estimates thus obtained are more robust and reliable than those obtained using data from a single time point. Rate of change of prostate-specific antigen (PSA) over time (PSA velocity) was used as a measure of prostate cancer progression. Results indicate that PSA velocity of overweight and obese subjects (0.59 and 1.05 ng/mL/year) was not significantly different as compared with normal weight subjects (p values .91 and .31, respectively). For men in the highest tertile of pack-years of smoking, PSA velocity was significantly higher as compared with never smokers 1.57 ng/mL/year (p = .04). Further studies with larger sample sizes and study designs specific to above exposures are needed before recommendations can be made to reduce weight or reduce/quit smoking.

Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer.

The Nutritional Prevention of Cancer trial showed a 52% lower incidence of prostate cancer in men supplemented with selenium. As a result, our study was designed to assess whether selenium supplementation attenuates the progression of prostate cancer. A phase 2 randomized, double-blind, placebo-controlled clinical trial was conducted in men with localized nonmetastatic prostate cancer who had elected to forgo active treatment and be followed by active surveillance. A total of 140 men were randomized to placebo (n = 46), 200 microg/d (n = 47), or 800 microg/d (n = 47) selenium p.o. (as selenized yeast) and followed every 3 months for up to 5 years. Prostate-specific antigen (PSA) velocity was used as a marker of prostate cancer progression and was estimated using mixed-effects regression. Adjusting for age, body mass index, baseline selenium, smoking, baseline PSA, race, PSA method, and Gleason score, PSA velocities for the 200 microg/d and 800 microg/d treatment groups were not statistically significantly different from placebo (P = 0.32 and P = 0.61, respectively). In the highest quartile of baseline selenium, men supplemented with 800 microg selenium showed statistically significantly higher PSA velocity as compared with placebo (P = 0.018). Selenium supplementation did not show a protective effect on PSA velocity in subjects with localized prostate cancer. On the contrary, supplementation with high-dose selenium was observed to be a risk factor for increased PSA velocity in men with high baseline plasma selenium concentrations.

Effect of aspirin, other NSAIDs, and statins on PSA and PSA velocity.

BACKGROUND: Aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs), and statins have been associated with lower risk of prostate cancer and its progression, though results have been inconsistent. METHODS: Data from 140 men with prostate cancer enrolled in a Phase 2 clinical trial of selenium to prevent prostate cancer progression were analyzed to determine association between aspirin, other NSAIDs, or statin use with baseline serum prostate-specific antigen (PSA) levels and PSA velocity (rate of PSA change over time) using repeated measures over an average follow-up time of 3.2 years. Multiple linear regression and mixed effects models were used to model the association of medication use with PSA at baseline and with PSA velocity, respectively. RESULTS: Baseline PSA levels were significantly lower in aspirin users compared to non-users (5.17 ng/ml vs. 7.58 ng/ml, P = 0.001). This association was statistically significant in never smokers (aspirin users vs. non-users: 4.19 ng/ml vs. 8.24 ng/ml, P = 0.004) but not in ever smokers (aspirin users vs. non-users: 5.52 ng/ml vs. 7.3 ng/ml, P = 0.101). Statin and other NSAID use was not associated with baseline PSA. Aspirin, statin, or other NSAID use at baseline demonstrated a non-significant negative association with PSA velocity. CONCLUSION: These findings support an effect of aspirin use on PSA, particularly among never smokers. However, they do not suggest a protective effect on the disease and support previous findings that aspirin use may mask accurate measurement of PSA warranting consideration of washout procedures prior to testing.

A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function in photodamaged skin.

The effects of myristyl nicotinate (MN), a nicotinic acid derivative designed to deliver nicotinic acid to skin without vasodilatation, on subjects with photodamaged skin have been studied. MN increased skin cell nicotinamide adenine dinucleotide (NAD) by 25% (P = 0.001) demonstrating effective delivery of nicotinic acid to skin. Relative to placebo, MN treatment of photodamaged facial skin increased stratum corneum thickness by approximately 70% (P = 0.0001) and increased epidermal thickness by approximately 20% (P = 0.001). In two separate studies, MN treatment increased rates of epidermal renewal by 6% (P = 0.003) to 11% (P = 0.001) and increased the minimal erythemal dose by 8.9 (P = 0.07) and 10% (P = 0.05) relative to placebo. MN treatment resulted in reductions in the rates of transepidermal water loss (TEWL) of approximately 20% relative to placebo on cheeks (P = 0.012) and arms (P = 0.017) of study subjects. Results of a tape stripping challenge before and after MN treatment demonstrated a significant correlation (P = 0.03) between increased skin NAD content and resistance to changes in TEWL for MN treated but not placebo subjects. Rates of TEWL changed more rapidly and to a greater extent in atopic subjects compared with normal subjects. The results indicate that MN enhances epidermal differentiation and barrier function in skin, suggesting that this method of nicotinic acid delivery may prove useful in limiting progression of actinic skin damage and possibly in treating other conditions involving skin barrier impairment.

A report of high-dose selenium supplementation: response and toxicities.

Concerns about the toxicity of selenium has limited the doses used in chemoprevention. Based on previous studies, intakes of 400 microg/day and plasma selenium of 1000 ng/ml (Dietary Reference Intakes, Academy Press, New York, 2000, p. 384) were established as the no observed adverse effect level (NOAEL). This investigation summarizes the plasma response and toxicity reports from 24 men with biopsy-proven prostate cancer who were randomized to either 1600 or 3200 microg/day of selenized yeast as part of a controlled clinical trial testing selenium as a chemopreventive agent for prostate cancer progression. Subjects were on these doses for averages of almost 12 months. Plasma selenium levels were monitored throughout the course of follow-up. Symptoms of selenium toxicity were assessed by patient interview with specific questions regarding breath, hair and nail changes. Several liver and kidney function tests and hematology were measured at 6-month intervals. 8 subjects were randomized to the 1600 microg/day and 16 to the 3200 microg/day group. The mean plasma selenium levels achieved with supplementation were 492.2 ng/ml (SD = 188.3) and 639.7 ng/ml (SD = 490.7) for the 1600 and 3200 microg/ day doses, respectively. The 3200 microg/day group reported more selenium-related side effects. Blood chemistry and hematology results were all within normal limits for both treatment groups. More subjects on 3200 microg/day reported symptoms of selenium toxicity; however, these reports did not correspond to peaks in plasma selenium levels. We observed no obvious selenium-related serious toxicities. As selenium is used in more chemoprevention and therapeutic settings, additional information on selenium species, sequestration of selenium in specific organs, excretion, and toxicities is needed.

Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial.

The Nutritional Prevention of Cancer Trial was a double-blind, randomized, placebo-controlled clinical trial designed to test whether selenium as selenized yeast (200 microg daily) could prevent nonmelanoma skin cancer among 1312 patients from the Eastern United States who had previously had this disease. Results from September 15, 1983, through December 31, 1993, showed no association between treatment and the incidence of basal and squamous cell carcinomas of the skin. This report summarizes the entire blinded treatment period, which ended on January 31, 1996. The association between treatment and time to first nonmelanoma skin cancer diagnosis and between treatment and time to multiple skin tumors overall and within subgroups, defined by baseline characteristics, was evaluated. Although results through the entire blinded period continued to show that selenium supplementation was not statistically significantly associated with the risk of basal cell carcinoma (hazard ratio [HR] = 1.09, 95% confidence interval [CI] = 0.94 to 1.26), selenium supplementation was associated with statistically significantly elevated risk of squamous cell carcinoma (HR = 1.25, 95% CI = 1.03 to 1.51) and of total nonmelanoma skin cancer (HR = 1.17, 95% CI = 1.02 to 1.34). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer continue to demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer.

Karyometry of nuclei from actinic keratosis and squamous cell cancer of the skin.

OBJECTIVE: To use karyometric analysis methods to compare actinic keratoses (AKs) to squamous cell carcinomas (SCCs) to determine if SCCs showed a logical progression beyond that seen in AKs and to explore variability within and between lesion types to better understand distinctions between the 2. STUDY DESIGN: Biopsies from 31 subjects with AKs were obtained from upper inner arm skin, forearm skin and AK lesions. Biopsies from 23 different subjects in a related subproject provided SCC biopsies for comparison. RESULTS: Karyometric measures of nuclear abnormality and sun damage were derived. Mean actinic damage levels progressed logically from inner arm to sun-exposed skin, to AK, to SCC. Considerable heterogeneity existed at the case level. Unsupervised learning methods revealed 2 distinct clusters of progressed lesions with different nuclear signatures, reflecting differing levels of actinic damage. Number of AKs and SCCs and invasiveness and differentiation of SCCs were distributed across both clusters in roughly equivalent proportions. CONCLUSION: Karyometric methods, shown previously to be capable of sensitively detecting subtle nuclear changes, revealed the possibility of 2 progression pathways, each containing AKs and SCCs. This finding may have prognostic implications.

Mechanism of action of a dominant negative c-jun mutant in inhibiting activator protein-1 activation.

The dominant negative c-jun TAM-67 has been shown to inhibit tumor promotion induced by 12-O-tetradecanoylphorbol-13-acetate and okadaic acid (OA). To better understand this phenomenon, we investigated the mechanism of action of TAM-67 in response to OA. To identify the mechanism of action, we used a 6xHis-tagged TAM-67 as well as chimeric constructs of TAM-67 that either cannot bind DNA or cannot heterodimerize with wild-type transcription factors. The results of these studies indicated that TAM-67 acts by blocking or squelching. The results of elecrophoretic mobility-shift assays showed that TAM-67 must act by squelching in response to OA, as TAM-67 cannot be found in DNA-binding complexes. We then identified some of the proteins with which TAM-67 interacts. They include all members of the jun and fos families as well as the cAMP response element binding protein, activating transcription factor-1, activating transcription factor-2, and RelA (p65). Thus, we have shown that TAM-67 squelches the induction of activating transcription factor-1 transactivation in response to OA and that TAM-67 is capable of interacting with proteins that control transactivation by binding to the 12-O-tetradecanoylphorbol-13-acetate response element, cAMP response element and nuclear factor-kappaB sites.

Androgens block interleukin-1 beta-induced promatrilysin expression in prostate carcinoma cells.

BACKGROUND: We have shown previously that interleukin (IL) -1 beta- and IL-6-induced promatrilysin expression is mediated by an indirect pathway that requires NF kappa B-dependent synthesis of IL-6 and STAT3 signaling. We now demonstrate that IL-1 beta-induced but not IL-6-induced promatrilysin expression can be blocked by androgens in the prostate carcinoma cell line LNCaP (lymph node-derived carcinoma cells of the prostate). METHODS: By using enzyme-linked immunosorbent assay analyses, promatrilysin was measured in LNCaP cells stimulated with IL-1 beta or IL-6 LNCaP-treated cells pretreated with testosterone. In addition, promatrilysin message was measured by using Northern analyses after IL-6-treated cells pretreated with testosterone. RESULTS: In LNCaP treated with testosterone before IL-1 beta stimulation induced promatrilysin expression was completely abrogated. Furthermore, testosterone completely abrogated NF kappa B transactivation activity and induction of IL-6 protein expression and mRNA. Testosterone and 5 alpha-dihydrotestosterone did not have an inhibitory effect on IL-6-induced promatrilysin expression. Testosterone also had no effect on basal promatrilysin expression or basal NF kappa B transactivation activity. CONCLUSION: From these data, we conclude that testosterone blocks IL-1 beta-induced promatrilysin expression by inhibition of NF kappa B transactivation activity, which in turn, blocks IL-6 expression. These data suggest a mechanism in vivo by which invasive and metastatic prostatic carcinoma cell clones refractory to hormone ablation therapy may develop after chemical or surgical castration. Furthermore, these data suggest that, perhaps, upstream targets such as the cytokines IL-1 beta and IL-6 may provide alternative drug targets for inhibiting prostate cancer progression.

Statistical analysis of chemopreventive efficacy of vitamin A in sun-exposed, normal skin.

OBJECTIVE: To develop numeric, statistically secured measures of chemopreventive efficacy and to derive procedures with high sensitivity of detection. STUDY DESIGN: Karyometric features were computed for nuclei from the basal cell layer of biopsies taken from sun-exposed but histologically "normal" skin. Biopsies were collected from placebo-treated subjects and subjects treated for one year with daily, oral doses of 25,000, 50,000 and 75,000 IU of vitamin A. A total of 22,600 nuclei were recorded from 113 cases, at baseline and after one year. RESULTS: Two numeric measures of chemopreventive efficacy were applied: a measure of nuclear abnormality and a measure based on discriminant function scores. Both showed statistically significant chemopreventive effects of vitamin A. Dose-response curves were derived. A novel procedure, second order discriminant analysis, resulted in very high sensitivity for the detection of change in nuclear chromatin patterns. CONCLUSION: Karyometric analysis has increased in sensitivity such that changes on the order of 10%, found in only a low percentage of nuclei in a biopsy specimen, can be reliably documented. The methodology lends itself to cost-efficient screening of compounds for chemopreventive efficacy.

Current application of selective COX-2 inhibitors in cancer prevention and treatment.

The multistep process of carcinogenesis, which can take many years, provides many opportunities for intervention to inhibit disease progression. Effective chemoprevention agents may reduce the risk of cancer by inhibiting the initiation stage of carcinoma through induction of apoptosis or DNA repair in cells harboring mutations, or they may act to prevent promotion of tumor growth. Similarly, chemoprevention may entail blocking cancer progression to an invasive phenotype. Over the past decade, in vitro, preclinical, and clinical data have supported the hypothesis that cyclooxygenase (COX)-2 plays a central role in oncogenesis and that treatment with COX-2 inhibitors offers an effective chemoprevention strategy, as exemplified by the activity of celecoxib (Celebrex) in familial adenomatous polyposis. These COX-2 data have contributed to initiation of clinical trials testing COX-2 inhibitors for the chemoprevention of a wide variety of cancers that overexpress COX-2.