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Effects of 2-Phenethyl Isothiocyanate on Metabolism of 1,3-Butadiene in Smokers.
Boldry, EJ, Yuan, JM, Carmella, SG, Wang, R, Tessier, K, Hatsukami, DK, Hecht, SS, Tretyakova, NY
Cancer prevention research (Philadelphia, Pa.). 2020;(1):91-100
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Abstract
2-Phenethyl isothiocyanate (PEITC) is a natural product found as a conjugate in cruciferous vegetables. It has been reported to have preventative properties against lung cancer and to inhibit metabolic activation of tobacco carcinogens. In this study, we evaluated the ability of PEITC to influence the metabolism of the human carcinogen 1,3-butadiene in current smokers in a phase II clinical trial with a crossover design. Urinary mercapturic acids of 1,3-butadiene were quantified at baseline and during PEITC treatment. Seventy-nine smokers were randomly assigned to one of two arms: PEITC followed by placebo or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. Oral ingestion of PEITC increased urinary levels of BD-mercapturic acids (MHBMA and DHBMA) by 11.1% and 3.7%, respectively, but these increases were not statistically significant (P = 0.17 and 0.64, respectively). A much stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals, PEITC increased urinary levels of MHBMA by 58.7% (P = 0.004) and 90.0% (P = 0.001), respectively, but did not have a significant effect on urinary DHBMA. These results reveal a potentially protective effect of PEITC treatment with respect to the detoxification of 1,3-butadiene in cigarette smokers, specifically in those null for GSTT1, and provide further evidence in support of stronger chemopreventive effects from consumption of dietary isothiocyanates in these individuals.
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Effects of genistein supplementation on genome‑wide DNA methylation and gene expression in patients with localized prostate cancer.
Bilir, B, Sharma, NV, Lee, J, Hammarstrom, B, Svindland, A, Kucuk, O, Moreno, CS
International journal of oncology. 2017;(1):223-234
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Abstract
Epidemiological studies have shown that dietary compounds have significant effects on prostate carcinogenesis. Among dietary agents, genistein, the major isoflavone in soybean, is of particular interest because high consumption of soy products has been associated with a low incidence of prostate cancer, suggesting a preventive role of genistein in prostate cancer. In spite of numerous studies to understand the effects of genistein on prostate cancer, the mechanisms of action have not been fully elucidated. We investigated the differences in methylation and gene expression levels of prostate specimens from a clinical trial of genistein supplementation prior to prostatectomy using Illumina HumanMethylation450 and Illumina HumanHT-12 v4 Expression BeadChip Microarrays. The present study was a randomized, placebo-controlled, double-blind clinical trial on Norwegian patients who received 30 mg genistein or placebo capsules daily for 3-6 weeks before prostatectomy. Gene expression changes were validated by quantitative PCR (qPCR). Whole genome methylation and expression profiling identified differentially methylated sites and expressed genes between placebo and genistein groups. Differentially regulated genes were involved in developmental processes, stem cell markers, proliferation and transcriptional regulation. Enrichment analysis suggested overall reduction in MYC activity and increased PTEN activity in genistein-treated patients. These findings highlight the effects of genistein on global changes in gene expression in prostate cancer and its effects on molecular pathways involved in prostate tumorigenesis.
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Difference in Association of Obesity With Prostate Cancer Risk Between US African American and Non-Hispanic White Men in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
Barrington, WE, Schenk, JM, Etzioni, R, Arnold, KB, Neuhouser, ML, Thompson, IM, Lucia, MS, Kristal, AR
JAMA oncology. 2015;(3):342-9
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Abstract
IMPORTANCE African American men have the highest rates of prostate cancer incidence and mortality in the United States. Understanding underlying reasons for this disparity could identify preventive interventions important to African American men. OBJECTIVE To determine whether the association of obesity with prostate cancer risk differs between African American and non-Hispanic white men and whether obesity modifies the excess risk associated with African American race. DESIGN, SETTING, AND PARTICIPANTS Prospective study of 3398 African American and 22,673 non-Hispanic white men who participated in the Selenium and Vitamin E Cancer Prevention Trial (2001-2011) with present analyses completed in 2014. MAIN OUTCOMES AND MEASURES Total, low-grade (Gleason score <7), and high-grade (Gleason score ≥7) prostate cancer incidence. RESULTS With a median (interquartile range) follow-up of 5.6 (1.8) years, there were 270, 148, and 88 cases of total, low-, and high-grade prostate cancers among African American men and a corresponding 1453, 898, and 441 cases in non-Hispanic white men, respectively. Although not associated with risk among non-Hispanic white men, BMI was positively associated with an increase in risk among African American men (BMI, <25 vs ≥35: hazard ratio [HR], 1.49 [95% CI, 0.95, 2.34]; P for trend = .03). Consequently, the risk associated with African American race increased from 28% (HR, 1.28 [95% CI, 0.91-1.80]) among men with BMI less than 25 to 103% (HR, 2.03 [95% CI, 1.38-2.98]) among African American men with BMI at least 35 (P for trend = .03). Body mass index was inversely associated with low-grade prostate cancer risk within non-Hispanic white men (BMI, <25 vs ≥35: HR, 0.80 [95% CI, 0.58-1.09]; P for trend = .02) but positively associated with risk within African American men (BMI, <25 vs ≥35: HR, 2.22 [95% CI, 1.17-4.21]; P for trend = .05). Body mass index was positively associated with risk of high-grade prostate cancer in both non-Hispanic white men (BMI, <25 vs ≥35: HR, 1.33 [95% CI, 0.90-1.97]; P for trend = .01) and African American men, although the increase may be larger within African American men, albeit the racial interaction was not statistically significant (BMI, <25 vs ≥35: HR, 1.81 [95% CI, 0.79-4.11]; P for trend = .02). CONCLUSIONS AND RELEVANCE Obesity is more strongly associated with increased prostate cancer risk among African American than non-Hispanic white men and reducing obesity among African American men could reduce the racial disparity in cancer incidence. Additional research is needed to elucidate the mechanisms underlying the differential effects of obesity in African American and non-Hispanic white men.
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A phase 2 cancer chemoprevention biomarker trial of isoflavone G-2535 (genistein) in presurgical bladder cancer patients.
Messing, E, Gee, JR, Saltzstein, DR, Kim, K, diSant'Agnese, A, Kolesar, J, Harris, L, Faerber, A, Havighurst, T, Young, JM, et al
Cancer prevention research (Philadelphia, Pa.). 2012;(4):621-30
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Abstract
The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being the inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/d as the purified soy extract G-2535) for 14 to 21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age, 71 years). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects' but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (P = 0.07). This difference was most prominent when comparing the 300-mg group with placebo (P = 0.015), but there was no significant reduction in p-EGFR staining between the 600-mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups were observed for COX-2, Ki-67, activated caspase-3, Akt, p-Akt, mitogen-activated protein kinase (MAPK), or p-MAPK. No significant differences in urinary survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents.
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Prognostic effect of circulating adiponectin in a randomized 2 x 2 trial of low-dose tamoxifen and fenretinide in premenopausal women at risk for breast cancer.
Macis, D, Gandini, S, Guerrieri-Gonzaga, A, Johansson, H, Magni, P, Ruscica, M, Lazzeroni, M, Serrano, D, Cazzaniga, M, Mora, S, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;(2):151-7
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PURPOSE Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer. PATIENTS AND METHODS We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period. RESULTS At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels. CONCLUSION Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.
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Topical treatment of actinic keratoses with potassium dobesilate 5% cream. a preliminary open-label study.
Cuevas Sánchez, P, Espinoza, W, Pérez, C, Angulo, J, Giménez-Gallego, G
European journal of medical research. 2011;(2):67-70
Abstract
BACKGROUND Fibroblast growth factor (FGF) is involved in skin tumorigenesis: it promotes cell viability, induces angiogenesis and stimulates invasiveness. Dobesilate is a drug that blocks the activity of FGF. The primary objective was to evaluate the efficacy and tolerability of potassium dobesilate 5% cream in the treatment of actinic keratoses. METHODS Potassium dobesilate 5% cream was applied twice daily for 16 weeks to actinic keratosis lesions in 30 patients. The lesions were evaluated clinically at an initial baseline visit, at intermediate visits, and at 16 weeks of treatment. - RESULTS The use of potassium dobesilate 5% cream for 16 weeks induced complete regression in 70% of evaluated actinic keratoses, corresponding to grade I, II and III clinical variants, and a partial response (at least 75% reduction of lesions) in 20% of the cases. CONCLUSION Our preliminary trial shows that potassium dobesilate exerts anti-tumorigenic effects and may play a useful role in the chemoprevention of skin cancers.
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Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer.
Veronesi, U, Mariani, L, Decensi, A, Formelli, F, Camerini, T, Miceli, R, Di Mauro, MG, Costa, A, Marubini, E, Sporn, MB, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2006;(7):1065-71
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PURPOSE The synthetic retinoid fenretinide administered for 5 years for prevention of second breast cancer showed no difference after a median of 8 years, but a possible reduction in premenopausal women. We conducted a long-term analysis in a subgroup of women who were regularly followed up in a single center. PATIENTS AND METHODS We analyzed data after a median follow-up of 14.6 years (IQ range, 12.3-16.3 years) from 1739 women aged 30-70 (872 in the fenretinide arm and 867 in the observation arm), representing 60% of the initial cohort of 2867 women. The main efficacy endpoint was second primary breast cancer (contralateral or ipsilateral). RESULTS The number of second breast cancers was 168 in the fenretinide arm and 190 in the control arm (hazard ratio = 0.83, 95% CI, 0.67-1.03). There were 83 events in the fenretinide arm and 126 in the observation arm in premenopausal women (HR = 0.62, 95% CI, 0.46-0.83), and 85 and 64 events in postmenopausal women (HR = 1.23, 95% CI, 0.63-2.40). The younger were the women, the greater was the risk reduction associated with fenretinide, which attained 50% in women aged 40 years or younger and disappeared after age 55 (P-age*treatment interaction = 0.023). There was no difference in cancers in other organs, distant metastases or survival. CONCLUSIONS Fenretinide induces a significant risk reduction of second breast cancer in premenopausal women, which is remarkable at younger ages, and persists several years after treatment cessation. Since adverse events are limited, a trial in young women at high-risk is warranted.
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How do intermediate endpoint markers respond to lycopene in men with prostate cancer or benign prostate hyperplasia?
van Breemen, RB
The Journal of nutrition. 2005;(8):2062S-4S
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Study on chemoprevention of hepatocellular carcinoma by ginseng: an introduction to the protocol.
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Journal of Korean medical science. 2001;(Suppl):S70-4
Abstract
In patients with chronic hepatitis C virus disease, there is a high incidence of development of hepatocellular carcinoma (HCC) in the process of transition from chronic hepatitis to hepatic cirrhosis. Although ginseng traditionally has been used mainly as a nutritional supplement in Asian countries, a case-control study found that it may inhibit the development of HCC. We therefore planned a clinical study of HCC prevention by medicinal ginseng. The subjects are patients with chronic C virus disease (chronic hepatitis and hepatic cirrhosis), who are high risk group for HCC. This intervention study is a multi-center, double-blind, randomized controlled trial. The participants will be randomly divided into two groups. The test sample (1 g of red ginseng powder per day) will be administered for 5 yr, and ginseng intake will be prohibited during the administration period. The primary endpoint of this study is the development of HCC. Target number of recruiting subjects are 300. The participants should be registered from February 2001 to January 2003.
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The treatment of cutaneous T-cell lymphoma with a novel retinoid.
Heald, P
Clinical lymphoma. 2000;:S45-9
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The clinical experience with bexarotene for cutaneous T-cell lymphoma (CTCL) at our center is reviewed here. Disease activity assessment was monitored every 4 weeks in all patients. Five target lesions were monitored, an area score was performed, and a CTCL-specific health assessment questionnaire was administered. Four patients with refractory plaque CTCL were treated with bexarotene gel. All target lesions disappeared after 8 weeks of therapy, with recurrences observed in untreated areas. In the follow-up period, no recurrences of the original target lesions were observed. One patient withdrew from the study. Patients with refractory patch/plaque disease were randomized to a high-dose (300 mg/m(2)) or low-dose (6.5 mg/m(2)) daily oral regimen of bexarotene. After showing disease progression, the two patients on the low-dose arm were entered into the high-dose arm after 8 weeks. Marked clinical responses were seen in all patients treated. The target lesions showed either complete disappearance or a reduction in lesion size, duration, and scale. No new lesions were noted in patients on high-dose bexarotene. Self-assessments also confirmed the palliative properties of the observed responses. All patients had hypertriglyceridemia despite the concomitant administration of atorvastatin at 60 mg/day. Dose reductions were required to maintain safe lipid levels. Four patients with erythrodermic CTCL were treated with high-dose oral therapy, and all patients showed rapid (within 2 weeks) improvement of erythroderma and symptoms.