Soy food frequency questionnaire does not correlate with baseline isoflavone levels in patients with bladder cancer.

BACKGROUND: The isoflavone genistein, a natural soy product with receptor tyrosine kinase-inhibiting activity, as well as phytoestrogenic and other potential anticarcinogenic effects, is being studied as an anticancer agent. Since isoflavones are commonly consumed in food products containing soy proteins, a method to control for baseline isoflavone consumption is needed. METHODS: HPLC was used to evaluate baseline plasma and urine concentrations of isoflavone in fifty-four participants with bladder cancer enrolled on a phase II chemoprevention study of G-2535. The soy food frequency questionnaire was used to assess participant's baseline soy intake. The association between baseline isoflavone concentrations and intakes for genistein and daidzein was assessed by the Spearman's rank correlation coefficient. RESULTS: The majority of participants had no detectable genistein or daidzein in plasma at baseline. The median and range of values were 0 (0-1480) nmol/L for genistein, and 0 (0-1260) nmol/L for daidzein. In urine, the median and range of values were 91.0 (0-9030) nmol/L for genistein and 623 (0-100,000) nmol/L for daidzein. The median and range of weekly estimated genistein intake was 0 (0-236) mg/wk; the median and range of weekly estimated daidzein intake was 0 (0-114) mg/wk. There was no relationship to soy intake as measured by the food frequency questionnaire and baseline isoflavone levels in plasma or urine and the Spearman's rank correlation coefficients were not significant. CONCLUSION: The soy food frequency questionnaire did not correlate with plasma or urine concentrations of either isoflavone. IMPACT: Alternative methods for controlling for soy consumption, including measuring plasma and urine concentrations, in isoflavone chemoprevention trials should be considered.

Prostate cancer prevention: agent development strategies.

Despite advances in surgery, radiation, and medical therapy over the past decade and the widespread adoption of PSA screening, prostate cancer continues to be the second leading cause of cancer death in men in the United States. Invasive cancer is the end result of carcinogenesis, a chronic process occurring over many years driven by genetic and epigenetic alterations. The protracted nature of this transformation to the malignant phenotype provides an opportunity to intervene pharmacologically to prevent, reverse, or delay carcinogenesis, i.e. chemoprevention. Herein, we describe the unique features of cancer prevention, as opposed to cancer treatment, agent development clinical trials, and provide a summary of the ongoing research in this field being supported by the National Cancer Institute.

Prostate cancer prevention: strategies for agent development.

PURPOSE OF REVIEW: This article provides an update of clinical research supported by the National Cancer Institute's Phase I/II prostate cancer chemoprevention agent development program. RECENT FINDINGS: Numerous clinical trials of pharmacologic interventions to delay, prevent or reverse carcinogenesis ('chemoprevention') with the ultimate goal of reducing cancer incidence have been conducted over the past decade. These trials range from relatively small, short-duration studies with biomarker endpoints to very large, long-term, general population trials with definitive cancer endpoints. Two large, population-based, Phase III prostate cancer prevention trials have shown a significant benefit for 5-α-reductase inhibitors. However, this class of agents was also associated with increased detection of high-grade prostate cancer. Another large, Phase III prostate cancer prevention trial showed no benefit for either selenium or vitamin E, given individually or in combination; in fact, a significant increase in prostate cancer was observed among men randomized to the vitamin E alone arm. SUMMARY: A number of early phase trials and three definitive Phase III trials have been conducted in the field of prostate cancer prevention over the past decade. Although a great deal has been learned from these studies, significant work remains to be done to fully realize the potential of chemoprevention in this disease.

Lack of association of the N-acetyltransferase NAT1*10 allele with prostate cancer incidence, grade, or stage among smokers in Finland.

Genetic variations in xenobiotic metabolizing genes can influence susceptibility to many environmentally induced cancers. Inheritance of the N-acetyltransferase 1 allele (NAT1*10), linked with increased metabolic activation of pro-carcinogens, is associated with an increased susceptibility to many cancers in which cigarette- or meat-derived carcinogens have been implicated in their etiology. The role of NAT1*10 in prostate cancer is under studied. Although cigarette smoking is not considered a risk factor for prostate cancer, a recent review suggests it may play a role in disease progression. Consequently, we examined the association of NAT1*10 with prostate cancer risk, grade, and stage among 400 Finnish male smokers using a case-control study design. Following genotyping of 206 patients and 196 healthy controls, our results do not support the role of NAT1*10 in relation to prostate cancer risk (OR = 1.28; 95% CI, 0.66-2.47), aggressive disease (OR = 0.58; 95% CI, 0.13-2.67), or advanced disease (OR = 1.19; 95% CI, 0.49-2.91).

The usefulness of the detection of GSTP1 methylation in urine as a biomarker in the diagnosis of prostate cancer.

PURPOSE: Prostate cancer has a unique set of problems associated with its early detection and diagnosis that might be aided by the addition of molecular markers, such as DNA hypermethylation. DNA methylation is an important epigenetic mechanism of gene regulation that has a critical role in normal developmental processes. Aberrant DNA methylation is a hallmark of carcinogenesis and GSTP1 hypermethylation is the most common molecular alteration in human prostate cancer. To our knowledge the clinical usefulness of the detection of gene methylation is yet to be established. MATERIALS AND METHODS: We evaluated GSTP1 hypermethylation in urine collected after prostatic massage and in core needle biopsies from 100 men referred for diagnostic biopsy. RESULTS: Methylation of GSTP1 in urine specimens had 75% sensitivity and 98% specificity for prostate cancer. GSTP1 methylation in the biopsy had 88% specificity and 91% sensitivity. Interestingly we observed a higher frequency of GSTP1 methylation in the urine of men with stage III vs II disease (100% vs 20%, p = 0.05). CONCLUSIONS: This study suggests that the detection of GSTP1 methylation in prediagnostic urine may improve the specificity of PSA and help distinguish men with prostate cancer from those with benign prostatic hyperplasia. This finding should be further explored in a larger, prospective screening trial.

Genetic variation in interleukin 8 and its receptor genes and its influence on the risk and prognosis of prostate cancer among Finnish men in a large cancer prevention trial.

The cytokine interleukin 8 (IL-8) may play a role in the pathogenesis of prostate cancer through the modulation of tumour immune response or enhanced angiogenesis. A common polymorphism of the IL-8 (-251) gene, which may affect the production level of the cytokine, has been inversely associated with a number of diseases, including prostate cancer. We examined the most representative single nucleotide polymorphisms (SNPs) for the IL-8 and its receptors (CXCR1 and CXCR2) genes, and conducted a case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine if these SNPs are associated with susceptibility to and prognosis of prostate cancer. Using incidence density sampling, 584 cases of primary prostate cancer and 584 matched controls were selected. In this population, we observed no strong association between the SNPs for IL-8 -251 (A-->T), CXCR1 +860 (C-->G) and CXCR2 -1010 (A-->G) and either the subsequent risk of prostate cancer or individual prognostic factors among cases. Although none of the SNPs studied are likely to have major effects on prostate cancer susceptibility, a role for other polymorphisms associated within these genes cannot be excluded.

Serum insulin-like growth factor I: tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish men.

Recent epidemiological studies suggest an association between higher blood levels of insulin-like growth factor I (IGF-I) and increased risk of prostate cancer. We evaluated the association between prediagnostic levels of IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) and prostate cancer risk in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Within the same cohort (using different cases and controls who had sequential serum samples available) we also examined changes in serum IGF-I and IGFBP-3 levels over time by case status. The risk association study included incident prostate cancer cases (n = 100) diagnosed at least 5 years after baseline blood draw (range, 5-12 years; median 9 years) and frequency-matched (4:1) controls. The sequential serum study included all of the prostate cancer cases (n = 21) with prediagnostic (2-3 years before diagnosis) and diagnostic serum available, and pair-matched controls (1:1). An ELISA was used to quantitate serum levels of IGF-I and IGFBP-3 for both studies. The association between IGF-I or IGFBP-3 and prostate cancer risk was assessed using conditional logistic regression, and paired t tests were used to evaluate case-control differences in change in serum analytes over time. We found no significant association between either IGF-I or IGFBP-3 and prostate cancer risk. In a multivariate analysis, we observed an odds ratio of 0.52 (95% confidence interval, 0.23-1.16) for the fourth versus the first quartile of serum IGF-I. Serum IGF-I, but not IGFBP-3, increased significantly over time in cases (18% increase) but not controls (4% decrease; P = 0.02). In contrast to previous reports, we found no evidence to support a causal association between serum IGF-I or IGFBP-3 and the risk of prostate cancer. It is possible that serum IGF-I may be serving as a tumor marker rather than an etiologic factor in prostate cancer.

Characteristics of a human prostate stromal cell line related to its use in a stromal-epithelial coculture model for the study of cancer chemoprevention.

An immortalized human prostate stromal cell line (PS30) was previously established using recombinant retrovirus encoding human papillomavirus 16 gene products. In this study, we further characterize this stromal cell line for its potential use in a stromal-epithelial coculture model for prostate cancer prevention. Using reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunocytochemistry, we examined expression of androgen receptor (AR), vitamin D receptor (VDR), prostate-specific antigen (PSA), transforming growth factor-beta (TGF-beta), and insulin-like growth factors (IGF) families and their receptors, metalloproteinases (MMP) MMP-2 and MMP-9, as well as the cells' ability to respond to the synthetic androgen R1881. The PS30 stromal cells do not express PSA, confirming their stromal origin. They are positive for both AR messenger ribonucleic acid (mRNA) and protein; however, they do not respond to growth stimulation by the synthetic androgen R1881. The PS30 cells express mRNA for VDR, TGF-betas, IGFs and their receptors, as well as the MMPs. Moreover, they produce significant amounts of TGF-beta1, TGF-beta2, IGFBP-3, and MMP-2 proteins. Our observations confirm the use of PS30 for the study of stromal-epithelial interactions in the modulation of prostate carcinogenesis.

Serum carotenoids and alpha-tocopherol and risk of nonmelanoma skin cancer.

BACKGROUND: Carotenoids and tocopherols have been hypothesized to protect against cancer. METHODS: We prospectively evaluated associations of several carotenoids and alpha-tocopherol with risk of nonmelanoma skin cancer using serum collected at baseline from 302 subjects in the Isotretinoin-Basal Cell Carcinoma Prevention Trial. All subjects had at least two BCCs in the 5 years prior to randomization. During 5 years of follow-up, 70 subjects did not develop a nonmelanoma skin cancer, 221 developed a BCC, and 85 developed a squamous cell carcinoma (SCC). Cox proportional hazards models were used to estimate risk ratios. Models were stratified by clinical center and gender and adjusted for age, solar damage, skin type, number of prior BCCs and/or SCCs, treatment group, body mass index, and serum low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol. RESULTS: Risk of developing a subsequent BCC was not related to serum levels of any of the carotenoids measured or to alpha-tocopherol. Serum levels of alpha-carotene, beta-carotene, lycopene, and alpha-tocopherol also were not independently related to risk of a subsequent SCC. However, serum lutein, zeaxanthin, and beta-cryptoxanthin were positively related to SCC risk; risk ratios for subjects in the highest versus lowest tertiles of these micronutrients were 1.63 [95% confidence interval (95% CI) 0.88-3.01; P for trend = 0.01], 2.40 (95% CI 1.30-4.42; P for trend = 0.01), and 2.15 (95% CI 1.21-3.83; P for trend = 0.09), respectively. CONCLUSION: Additional research is needed on the relationship of carotenoids to SCC risk in the general population and in subsets of the population who are at increased risk.

Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland.

Associations between lung cancer risk and common polymorphisms in the DNA repair genes xeroderma pigmentosum complementation group D (XPD), X-ray repair cross-complementing group 1 (XRCC1), XRCC3 and apurinic/apyrimidinic endonuclease/redox factor 1 were examined within a randomized clinical trial designed to determine whether alpha-tocopherol, beta-carotene, or both would reduce cancer incidence among male smokers in Finland. We found no direct association between lung cancer risk and any of the DNA repair genotypes studied, however, the association between XPD codon 751 genotype and lung cancer was modified by alpha-tocopherol supplementation, and the association between XRCC1 codon 399 genotype and lung cancer was modified by the amount of smoking. Our results suggest that common alterations in single DNA repair genes are not major determinants of lung cancer susceptibility among smokers.

Aspirin use and mortality from cancer in a prospective cohort study.

UNLABELLED: There is evidence that use of aspirin offers several potential health benefits including cancer prevention and cardiovascular disease prevention. The purpose of this study was to assess the association between aspirin use and death from cancer and cardiovascular diseases with a special emphasis on cancer mortality. MATERIALS AND METHODS: The baseline data for this prospective cohort study were collected in 1971--1975 for the first National Health and Nutrition Examination Study (NHANES I) and 1976--1980 as part of the second NHANES (NHANES II) with mortality follow-up using the National Death Index (NDI) through December 31, 1992. The main analyses were the relative risks of total mortality and cause-specific mortality for persons who used aspirin compared to persons who did not use aspirin adjusted for confounding using Cox proportional hazards. RESULTS: The proportion of aspirin users was lower among cancer cases than non-cases (58% versus 66%) and use of aspirin decreased with age. Consequently, age was a negative confounder attenuating the protective association between aspirin use and cancer and cardiovascular mortality. After adjusting for age, BMI, sex, race, poverty index, education and smoking, we observed a significant association of reduced all cause mortality among all aspirin users (relative risk [RR] = 0.88; 95% confidence interval [CI] 0.85 - 0.99) and lung cancer mortality among male aspirin users (RR = 0.69; CI 0.49-0.96). However, for women we observed adverse associations between aspirin use and bladder (RR=12.31; CI 2.98-50.80) and brain cancer mortality (RR=3.13; CI 1.09-9.00), although case numbers were small. CONCLUSION: Aspirin use appears to offer protection from all causes of mortality and lung cancer among men. In women aspirin use is associated with increased risk of bladder and brain cancer. Because of the small number of female bladder (n=15) and brain (n=20) cancer cases in this cohort the findings require confirmation.

A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology.

On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed.

Randomized, double-blind, placebo-controlled trial of polyphenon E in prostate cancer patients before prostatectomy: evaluation of potential chemopreventive activities.

Compelling preclinical and pilot clinical data support the role of green tea polyphenols in prostate cancer prevention. We conducted a randomized, double-blind, placebo-controlled trial of polyphenon E (enriched green tea polyphenol extract) in men with prostate cancer scheduled to undergo radical prostatectomy. The study aimed to determine the bioavailability of green tea polyphenols in prostate tissue and to measure its effects on systemic and tissue biomarkers of prostate cancer carcinogenesis. Participants received either polyphenon E (containing 800 mg epigallocatechin gallate) or placebo daily for 3 to 6 weeks before surgery. Following the intervention, green tea polyphenol levels in the prostatectomy tissue were low to undetectable. Polyphenon E intervention resulted in favorable but not statistically significant changes in serum prostate-specific antigen, serum insulin-like growth factor axis, and oxidative DNA damage in blood leukocytes. Tissue biomarkers of cell proliferation, apoptosis, and angiogenesis in the prostatectomy tissue did not differ between the treatment arms. The proportion of subjects who had a decrease in Gleason score between biopsy and surgical specimens was greater in those on polyphenon E but was not statistically significant. The study's findings of low bioavailability and/or bioaccumulation of green tea polyphenols in prostate tissue and statistically insignificant changes in systemic and tissue biomarkers from 3 to 6 weeks of administration suggests that prostate cancer preventive activity of green tea polyphenols, if occurring, may be through indirect means and/or that the activity may need to be evaluated with longer intervention durations, repeated dosing, or in patients at earlier stages of the disease.

Epidemiological and clinical studies of nutrition.

In this review, we briefly summarize some of the key developments in nutritional epidemiology and cancer over the past two decades with a focus on the strengths and limitations of study designs and dietary assessment methods. We present the evidence on dietary fat, meat, fiber, antioxidant nutrients, and calcium in relation to carcinogenesis from large cohort studies and randomized clinical trials (RCTs) and refer to the conclusions of the 2007 World Cancer Research Fund/American Institute for Cancer Research summary report. One prominent theme that emerged is the lack of concordance of results from RCTs and observational studies. There are multiple potential reasons for these discrepancies, including differences in study population, dose and timing of the exposure, adherence to an intervention, length of follow-up, and the primary endpoint. Therefore, null findings of RCTs do not necessarily indicate a lack of effect for the tested dietary factors on cancer risk, as some of these nutrients may have chemopreventive effects if given at the right time and in the right dose. It is likely that potential benefits from diet are due to a combination of food constituents rather than single components acting in isolation. Future efforts need to recognize the integrative nature of dietary exposures and attempt to study nutrients in the larger context of the foods and diets in which they are consumed.

Association of IL-10 polymorphisms with prostate cancer risk and grade of disease.

Animal and in vitro models of prostate cancer demonstrate high IL-10 levels result in smaller tumors, fewer metastases, and reduced angiogenesis compared to controls. We sought to examine the hypothesis that genotypes correlated with low IL-10 production may be associated with increased prostate cancer risk among Finnish male participants from the Alpha-tocopherol Beta-carotene Cancer Prevention Study. DNA from 584 prostate cancer cases and 584 controls was genotyped for four IL-10 alleles, -1082, -819, -592, and 210. DNA from more of the controls than cases failed to amplify, resulting in 509 cases and 382 controls with genotype data for -1082; 507 and 384 for -819; 511 and 386 for -592; and 491 and 362 for 210. Odds ratios for the association between the IL-10 genotypes and risk of prostate cancer or, among cases only, high-grade disease were calculated using logistic regression. In this population, the -819 TT and -592 AA low expression genotypes were highly correlated. These two genotypes also were associated with increased prostate cancer susceptibility (OR = 1.92, 95% CI 1.07-3.43 for -819) and, among cases, with high-grade tumors (OR = 2.56, 95% CI 1.26-5.20 for -819). These data demonstrate genotypes correlated with low IL-10 production are associated with increased risk of prostate cancer and with high-grade disease in this population.

CD44 and PTGS2 methylation are independent prognostic markers for biochemical recurrence among prostate cancer patients with clinically localized disease.

Up to 30% of men with clinically localized disease who receive radical prostatectomy develop a biochemical recurrence. Gene methylation in tumor tissue may distinguish men with aggressive cancer. This study evaluated methylation of GSTP1, RARb2, CD44 and PTGS2 with biochemical recurrence among 60 patients who underwent radical prostatectomy using logistic regression and Kaplan Meier time to event analysis. Methylation of GSTP1 and RARbeta2 was not associated with recurrence, however, CD44 and PTGS2 methylation were significant predictors. In multivariate models adjusting for Gleason grade, the methylation profile of CD44 and PTGS2 combined was an independent predictor of biochemical recurrence (associated with 9-fold increased risk). In addition, Kaplan Meier analysis showed CD44 and PTGS2 methylation was associated with shorter time to recurrence. CD44 and PTGS2 methylation may predict biochemical recurrence in prostate cancer patients undergoing radical prostatectomy and if validated in larger studies, may identify patients with aggressive cancer.

Gene promoter methylation in prostate tumor-associated stromal cells.

BACKGROUND: Gene expression can be silenced through the methylation of specific sites in the promoter region. This mechanism of gene silencing has an important role in the carcinogenesis of prostate and other cancers. Although tumor-associated stromal cells also exhibit changes in gene expression, promoter methylation has not been described in these cells. METHODS: Tumor epithelia, tumor-associated stroma and normal epithelia, and stroma adjacent to tumor tissues were isolated from whole-mount prostatectomy specimens (two per patient) of patients (n = 5) with localized prostate cancer and from normal epithelia and stroma from benign prostate hyperplasia specimens (two per patient) from men (n = 5) without prostate cancer by using laser capture microdissection or expression microdissection. The methylation status of three genes important in prostate carcinogenesis, GSTP1, RARbeta2, and CD44, were evaluated using quantitative methylation-sensitive polymerase chain reaction. RESULTS: GSTP1 and RARbeta2 were methylated in the tumor epithelium of all five prostate cancer patients and in the tumor-associated stroma in four of the five patients. CD44 was methylated in the tumor epithelium from four of the five patients but not in the tumor stroma. GSTP1 and RARbeta2 were methylated in normal epithelium of two and four patients, respectively, and in normal stroma of one and two patients, respectively, that were isolated from regions adjacent to the tumors and may have resulted from a tumor-field effect; CD44 methylation was not observed in normal epithelium or stroma. In contrast, normal epithelia and stroma from benign prostate hyperplasia specimens showed no promoter methylation in GSTP1, RARbeta2, or CD44. CONCLUSIONS: The observation of promoter methylation in the non-neoplastic cells of the prostate tumor microenvironment may advance our understanding of prostate cancer development and progression and lead to new diagnostic and prognostic markers and therapeutic targets.

Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women.

Loss of imprinting (LOI) of insulin-like growth factor-II (IGF-II) may be an inherited epigenetic trait that is polymorphic in the population, and its presence may predispose an individual to the development of colorectal cancer. We evaluated the association between LOI of IGF-II in normal colonic mucosal samples and adenomas in women participating in a colonoscopy screening study. Among 40 participants, 11 (27.5%) had LOI of IGF-II in their normal colonic mucosal tissue. After adjusting for body mass index and family history of colorectal cancer, LOI status was associated with a fivefold increased risk of adenoma formation (odds ratio = 5.2, 95% confidence interval = 1.0 to 26.7). On average, IGF-II expression was more than threefold higher among women with LOI of IGF-II than among women with normal imprinting status. Our findings support the hypothesis that LOI of IGF-II is an epigenetic trait polymorphic in the population and suggest that LOI of IGF-II may play a role in colorectal cancer. These findings are intriguing and need to be confirmed in larger studies.