Risk Of Urothelial Bladder Cancer Research Articles

Abdominal Adipose Tissue Distribution in Male Patients with Urothelial Bladder Cancer

Background: Adiposopathy is characterized by excessive accumulation of adipose tissue, mainly visceral, which may determine adipocyte and adipose tissue-related disorder. A connection between adipose tissue secreted factors and bladder cancer (BC) cell migration has been shown in vitro. These mediators may be related to the pathogenesis of BC. Objective: The aim of this study is to evaluate the relationship between visceral adipose tissue (VAT) and urothelial bladder cancer (UBC) in male patients. Methods: In this retrospective study two groups were included. Total adipose tissue (TAT) area, VAT area and subcutaneous adipose tissue (SAT) area were measured in both groups. VAT/SAT ratio was subsequently calculated. Results: No statistically significant differences between the two groups were found in the TAT area, VAT area, SAT area and VAT/SAT ratio. Conclusion: The results of the present study suggest that VAT is not likely to be a biomarker for UBC risk in male patients.

Polymorphisms of Antioxidant Enzymes SOD2 (rs4880) and GPX1 (rs1050450) Are Associated with Bladder Cancer Risk or Its Aggressiveness.

Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p ˂ 0.049) and pathohistological grade (p ˂ 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease.

Can We Predict a Higher Risk of Urothelial Bladder Cancer With a Simple Blood Test?

The COVID-19 pandemic highlighted the need to develop tools prioritizing high risk patients for urgent evaluation. Our objective was to determine whether Glasgow Prognostic Score (GPS), an inflammation-based score, can predict higher grade and stage urothelial bladder cancer in patients with gross hematuria who need urgent evaluation. We analyzed a database of 129 consecutive patients presenting with gross hematuria. GPS was calculated using pretreatment C-reactive protein (CRP) and albumin levels. Patients with bacteriuria or other known malignancies were excluded. The relationship between GPS and final diagnosis was analyzed with multivariate logistic regression. A total of 101 patients were included in the study and 24 patients were identified without any pathology and 77 with a bladder tumor. Pathology demonstrated 21 with muscle invasive, 18 with high grade non-muscle invasive, and 38 with low grade superficial bladder cancer. Twenty-six of 39 (67%) patients with high grade tumors had a GPS of 1 or 2 compared to only 8 out of 62 (13%) patients with either low grade or negative findings (p<0.0001). Ten of 21 (48%) patients with muscle invasive disease had a GPS of 2 compared to 1 out of 18 (6%) with high grade non muscle invasive tumors (p=0.04). On multivariate analysis, GPS was a strong independent predictor of high grade and stage bladder cancer. GPS may serve as a highly accessible predictor of high grade, high stage, and large urothelial bladder tumors at the time of initial evaluation and can help identify patients who need urgent evaluation.

Interaction Effects of Plasma Vitamins A, E, D, B9, and B12 and Tobacco Exposure in Urothelial Bladder Cancer: A Multifactor Dimensionality Reduction Analysis

The study aimed to examine circulating vitamins A, E, D, and B12 and folate in patients with urothelial bladder cancer (UBC) and detect potential interaction effects of these micronutrients on UBC risk. A case–control study was conducted on 262 UBC patients and 254 matched controls. Vitamins A and E were assessed by ultra performance liquid chromatography, and vitamins D and B12 and folate were assessed by immunological methods. Binary logistic regression models were used to test associations of plasma vitamins tertiles with UBC risk. A multifactor dimensionality reduction method (MDR) was applied to assess interactive effects of the vitamins and tobacco on UBC risk. Higher levels in vitamins A, E, and D were associated with lower occurrence of UBC. No significant association was observed in plasma folate or vitamin B12 with UBC. There were redundancy interactions of plasma vitamin D with tobacco and with plasma vitamin A on UBC risk. Even though the study could not ascertain causality, the findings suggest that vitamins A, E, and D might be protective against UBC. Vitamins A and D interact antagonistically with each other’s and with tobacco to modulate UBC risk. These interactions should be taken in consideration for the prevention of UBC.

Are genetic polymorphisms of glutathione S-Transferase P1 gene associated with urothelial carcinoma of the urinary bladder?

Background: Polymorphisms in genes encoding glutathione S-transferase (GST) may affect susceptibility to develop urothelial carcinomas (UCs). One of the extensively studied genes in this group is GST P1 (GSTP1), but studies of the relationship of polymorphisms of GSTP1 and UC of the bladder have been equivocal. Hence, we assessed the association between genetic polymorphism of GSTP1 gene and the development of UC of the urinary bladder. Materials and Methods: This prospective, case–control study was conducted in the departments of urology and clinical genetics at a tertiary care teaching hospital in South India, which included 52 patients with histopathologically confirmed UC bladder and matched with 46 controls from August 2012 to July 2013. The study participants provided a single venous blood sample for extraction of genomic DNA. Laboratory personnel was blinded to sample groups. The primary outcome of the study was to detect association of genetic polymorphism of GSTP1 gene with UC of the bladder. The secondary outcome was to assess if the risk of urothelial bladder cancer is increased in smokers with polymorphism of GSTP1 gene. Statistical Analysis Used: We used the Chi-square or Fisher's (F) exact test to compare discrete variables. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Results: Although the heterozygous polymorphic genotype ile/val (AG) was seen more frequently in cancer group (34.6% vs. 23.9%), the difference was not statistically significant (P = 0.202). None of the smokers had homozygous polymorphic valine allele and GSTP1 did not add to the susceptibility of UC bladder even among smokers. Conclusions: A lack of association between GSTP1 313 G/G polymorphism and urothelial cancer of bladder was observed.

Haplotype-based association of Vascular Endothelial Growth Factor gene polymorphisms with urothelial bladder cancer risk in Tunisian population.

Accumulated data suggested that Vascular Endothelial Growth Factor is a major mediator in vasculogenesis, angiogenesis and recently in tumorigenesis. Therefore, we aimed to investigate for the first time the association between VEGF gene variants (-2549I/D (rs35569394), -2578C/A (rs699947), and +936C/T (rs3025039)) with urothelial bladder cancer (UBC) in Tunisian population. A total of 218 UBC patients and 204 controls were recruited and genotyped by Polymerase Chain Reaction technique. Odds ratios (OR) and 95% confidence intervals (CIs) were used to access the association between the VEGFA gene polymorphisms and UBC. We found a significant decreased risk association of -2578 C/A polymorphism with UBC (OR (95% CI), 0.62 (0.41-0.94), P=.026) for CA genotype and (OR (95% CI), 0.40 (0.21-0.76), P=.005) for double homozygous mutant genotype. No associations were found in case of both polymorphic sites of VEGF, vis. -2549I/D and +936C/T, respectively. Haplotype analysis revealed a strong linkage disequilibrium between -2578C/A and -2549I/D and CIC combination is the significant haplotype associated with increased risk of UBC (OR (95% CI), 3.63 (1.47-8.97), P=.005). Regarding tumor grade/stage and family history of cancer, no associations were found for -2578C/A polymorphism. CIC haplotype of VEGF gene may be important risk factor for UBC development in Tunisia.

A Stratified Meta-Analysis of the Association between Exposure to Environmental Tobacco Smoke during Childhood and Adulthood and Urothelial Bladder Cancer Risk.

Background: Active smoking is a major risk factor for urothelial bladder cancer (UBC). However, the evidence that exposure to environmental tobacco smoke (ETS) either in childhood or adult life is also associated with UBC risk is ambiguous. With this meta-analysis, we aim to summarise how exposure to ETS is associated with UBC risk. Methods: In total, 11 studies (3 cohort studies, 8 case-control studies) were included in this meta-analysis and summary odds ratios (SORs) for UBC risk were calculated for never smokers who were exposed to ETS during childhood at home, during adulthood at home, or during adulthood in a work environment compared to never smokers who were never exposed to ETS. Sensitivity analyses were conducted to test the robustness of findings. Results: Never smokers exposed to ETS during childhood (SOR = 1.04, 95% confidence interval (CI) = 0.82–1.26), during adulthood at work (SOR = 0.98, 95% CI = 0.78–1.18) or at home (SOR = 0.99, 95% CI = 0.83–1.15) were at a similar risk of UBC compared to never smokers who were never exposed to ETS. Results for males and females were similar. Also, when pooling all estimates during both childhood and adulthood, no effect was observed (SOR = 1.00, 95% CI = 0.89–1.10). Conclusions: Although measurement of exposure to ETS was imprecise, there does not seem to be an association between UBC risk and exposure to ETS during childhood or adulthood. However, the current body of evidence mostly overlooks the duration and intensity of exposure to ETS.

The Genomic Alterations of 5α-Reductases and Their Inhibitor Finasteride's Effect in Bladder Cancer.

Since androgens affect urothelial bladder cancer (UBC), we examined whether 5α-reductases (5-AR) have genomic alterations in UBC and whether 5α-reductase inhibitors (5-ARI) affect UBC. The cBioPortal was used to analyze genomic alternations of 5-ARs in UBC cancer genomic datasets. Next, we used the Taiwan National Health Insurance Research database to conduct a population-based case-control study to investigate the effect of a 5-ARI, finasteride on UBC incidence. We also performed an XTT assay to examine the direct effect of finasteride on UBC cells. We found that 5-AR genomic alternations were observed in 29% of UBC patients and patients with alternations had shorter disease-free survival. Also, the use of finasteride with >180 cDDDs reduced the risk of UBC. Finasteride could directly inhibit UBC cell growth. Based on our findings, we concluded that 5-AR could be explored as a therapeutic target for UBC with 5-ARIs.

Asthma status is associated with decreased risk of aggressive urothelial bladder cancer.

Previous studies suggested an association between atopic conditions and specific cancers. The results on the association with urothelial bladder cancer (UBC) are scarce and inconsistent. To evaluate the association between asthma and risk of UBC, we considered 936 cases and 1,022 controls from the Spanish Bladder Cancer/EPICURO Study (86% males, mean age 65.4 years), a multicenter and hospital-based case-control study conducted during 1998-2001. Participants were asked whether they had asthma and detailed information about occupational exposures, smoking habits, dietary factors, medical conditions and history of medication was collected through face-to-face questionnaires performed by trained interviewers. Since asthma and UBC might share risk factors, association between patients' characteristics and asthma was studied in UBC controls. Association between UBC and asthma was assessed using logistic regression unadjusted and adjusted for potential confounders. The complex interrelationships, direct and mediating effect of asthma on UBC, were appraised using counterfactual mediation models. Asthma was associated with a reduced risk of UBC (odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.37, 0.79) after adjusting for a wide range of confounders. No mediating effect was identified. The reduced risk associated with asthma was restricted to patients with high-risk non-muscle invasive (OR = 0.25, 95%CI 0.10, 0.62) and muscle invasive UBC (OR = 0.32, 95%CI 0.15, 0.69). Our results support that asthma is associated with a decreased risk of UBC, especially among aggressive tumors. Further work on the relationship between asthma and other atopic conditions and cancer risk should shed light on the relationship between immune response mechanisms and bladder carcinogenesis.

Association of FokI polymorphism of vitamin D receptor with urothelial bladder cancer in Tunisians: role of tobacco smoking and plasma vitamin D concentration.

The aim of the study was to test whether the VDR FokI polymorphism is associated with the risk of urothelial bladder cancer (UBC) in Tunisians. The study included 200 unrelated patients with UBC and 200 healthy controls. Genotyping of the VDR FokI polymorphism was determined by PCR-RFLP method. Plasma 25-hydroxyvitamin D concentrations were measured by immunoassay. Binary logistic regression model was applied to test how the association of VDR FokI polymorphism is independent of potential confounding factors. Genotype distribution (FF, 45 vs. 55%; Ff, 52.1 vs. 47.9%, and ff, 12 vs. 5.5%, respectively) and allele frequencies (F, 66.5 vs. 74.8% and f, 33.5 vs. 25.2%, respectively) were significantly different between UBC patients and controls. The "ff" genotype [OR (95% CI), 2.66 (1.24-5.73); p = 0.012] and "f" allele [1.49 (1.09-2.02); p = 0.010] were associated with increased risk of UBC. The association remained significant in multivariate analysis. Stratified analyses showed that VDR FokI polymorphism is only associated with UBC risk in ever-smokers, subjects exposed to chemical carcinogens and those with plasma 25-hydroxyvitamin D over 12μg/L. The "f" allele of VDR FokI polymorphism is associated with a higher risk of UBC in Tunisians, especially in smokers as well as subjects with occupational exposition and subjects without vitamin D deficiency. These results should be replicated in other ethnic groups and the influence of other genetic factors and environments on this association should be investigated.

LINE-1 methylation in granulocyte DNA and trihalomethane exposure is associated with bladder cancer risk

DNA methylation changes contribute to bladder carcinogenesis. Trihalomethanes (THM), a class of disinfection by-products, are associated with increased urothelial bladder cancer (UBC) risk. THM exposure in animal models produces DNA hypomethylation. We evaluated the relationship of LINE-1 5-methylcytosine levels (LINE-1%5mC) as outcome of long-term THM exposure among controls and as an effect modifier in the association between THM exposure and UBC risk. We used a case-control study of UBC conducted in Spain. We obtained personal lifetime residential THM levels and measured LINE-1%5mC by pyrosequencing in granulocyte DNA from blood samples in 548 incident cases and 559 hospital controls. Two LINE-1%5mC clusters (above and below 64%) were identified through unsupervised hierarchical cluster analysis. The association between THM levels and LINE-1%5mC was evaluated with β regression analyses and logistic regression was used to estimate odds ratios (OR) adjusting for covariables. LINE-1%5mC change between percentiles 75th and 25th of THM levels was 1.8% (95% confidence interval (CI): 0.1, 3.4%) among controls. THM levels above vs. below the median (26 μg/L) were associated with increased UBC risk, OR = 1.86 (95% CI: 1.25, 2.75), overall and among subjects with low levels of LINE-1%5mC (n = 975), OR = 2.14 (95% CI: 1.39, 3.30), but not associated with UBC risk among subjects’ high levels of LINE-1%5mC (n = 162), interaction P = 0.03. Results suggest a positive association between LINE-1%5mC and THM levels among controls, and LINE-1%5mC status may modify the association between UBC risk and THM exposure. Because reverse causation and chance cannot be ruled out, confirmation studies are warranted.

Low RKIP expression associates with poor prognosis in bladder cancer patients

Urothelial bladder cancer (UBC) is a heterogeneous type of disease. It is urgent to screen biomarkers of tumour aggressiveness in order to clarify the clinical behaviour and to personalize therapy in UBC patients. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor, and its downregulation is associated with metastatic events in an increasing number of solid tumours. We evaluated the clinical and prognostic significance of RKIP expression in patients with high risk of progression UBC. Using immunohistochemistry, we determined RKIP expression levels in a series of 81 patients with high-grade pT1/pTis or muscle-invasive UBC. Staining of CD31 and D2-40 was used to assess blood and lymphatic vessels, in order to distinguish between blood and lymphatic vessel invasion (LVI). We found that 90 % of pT1/pTis tumours, 94 % of non-muscle invasive papillary tumours and 76 % of the cases without LVI occurrence expressed RKIP in >10 % of cells. In this group, we observed a subgroup of tumours (42 %) in which the tumour centre was significantly more intensely stained than the invasion front. This heterogeneous pattern was observed in 63 % of the cases with LVI. Low RKIP expression was associated with poorer 5-year disease-free and overall survival rates, and remained as an independent prognostic factor for disease-free survival. Loss of RKIP expression may be an important prognostic factor for patients with high risk of progression bladder cancer.

Plasma 25-Hydroxyvitamin D3 and Bladder Cancer Risk According to Tumor Stage and FGFR3 Status: A Mechanism-Based Epidemiological Study

Previous evidence suggests that 25-hydroxyvitamin D(3) [25(OH)D(3)] protects against several cancers. However, little is known regarding urothelial bladder cancer (UBC). We analyzed the association between plasma 25(OH)D(3) and overall risk of UBC, as well as according to stage and FGFR3 molecular subphenotypes. Plasma concentrations of 25(OH)D(3) in 1125 cases with UBC and 1028 control subjects were determined by a chemiluminescence immunoassay. FGFR3 mutational status and expression in tumor tissue were assessed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression adjusting for potential confounders. Analyses were further stratified by tumor invasiveness and grade, FGFR3 expression, and smoking status. Cell proliferation was measured in human UBC cell lines cultured with 1α,25-dihydroxyvitamin D(3). A statistically significantly increased risk of UBC was observed among subjects presenting the lowest concentrations of 25(OH)D(3) (OR(adj) = 1.83; 95% CI = 1.19 to 2.82; P = .006), showing a dose-response effect (P (trend) = .004). The association was stronger for patients with muscle-invasive tumors, especially among low-FGFR3 expressers (OR(adj) = 5.94; 95% CI = 1.72 to 20.45; P = .005). The biological plausibility of these associations is supported by the fact that, in vitro, 1α,25-dihydroxyvitamin D(3) upregulates FGFR3 expression in UBC cell lines with low levels of wild-type FGFR3. These findings support a role of vitamin D in the pathogenesis of UBC and show that 25(OH)D(3) levels are associated with FGFR3 expression in the tumor. Because FGFR3 mutation and overexpression are markers of better outcome, our findings suggest that individuals with low levels of plasma 25(OH)D(3) may be at high risk of more aggressive forms of UBC.

Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

BackgroundColorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether carriers of mutations...

Do DNA repair genes OGG1, XRCC3 and XRCC7 have an impact on susceptibility to bladder cancer in the North Indian population?

Objective Polymorphisms in DNA repair genes may be associated with altered DNA repair capacity, thereby influencing an individual's susceptibility to smoking-related cancers such as bladder cancer. Therefore, we sought to examine the correlation between single nucleotide polymorphisms in DNA repair genes and bladder cancer. Methodology We undertook a case-control study of 212 urothelial bladder cancer (UBC) cases and 250 controls to investigate the association between OGG1 (C1245G rs1052133), XRCC3 (C18067T, rs861539) and XRCC7 (G6721T, rs7003908) polymorphisms and bladder cancer susceptibility by PCR–RFLP and the ARMS method. We also investigated gene-environment interactions. Results The OGG1 GG genotype was associated with an elevated risk of urothelial bladder cancer (UBC) (OR, 2.10; p, 0.028). XRCC7 + 6721 GG was also associated with increased susceptibility to UBC (OR, 4.45; p, 0.001). In a recessive model, the OGG1 GG genotype showed an increased risk of TaG 2,3 + T1G 1–3 tumors. Additionally, the OGG1 GG genotype in non-smokers represented a 2.46-fold greater risk (OR, 2.46; p, 0.035) in bladder cancer patients. Subsequent analysis demonstrated more pronounced association of XRCC7 with smokers (OR, 4.39; p, 0.001). XRCC7 also showed increased association with TaG 2,3 + T1G 1–3 tumors and muscle invasive tumors (OR, 3.16; p, 0.001 and OR, 4.24; p, 0.001, respectively). Multiple Cox regression analysis in non-muscle invasive bladder tumor (NMIBT) patients demonstrated an association of the OGG1 GG polymorphism with a high risk of recurrence in patients on cystoscopic surveillance (HR, 4.04; p, 0.013). Subsequently, shorter recurrence-free survival (log rank p, 0.024; CC/GG, 42/24) was observed. Conclusion Our data suggest association of a variant (GG) genotype of OGG1 with increased UBC susceptibility and a high risk of tumor recurrence in NMIBT patients on cystoscopic surveillance. XRCC7 G allele carriers (TG + GG) are also at an elevated risk for susceptibility to UBC as evidenced by a high odds ratio throughout the analysis.

Interleukin-10 G-1082A and C-819T Polymorphisms as Possible Molecular Markers of Urothelial Bladder Cancer

Interleukin-10 (IL-10) is an immunosuppressive cytokine that may promote tumor growth and metastasis in later stages of cancer development. DNA sequence variations in IL-10 gene may lead to altered production and/or activity, and this can modulate an individual's susceptibility to urothelial bladder cancer (UBC). To test this hypothesis, we investigated the association of rs 1800896 and rs 3021097 polymorphisms in IL-10 gene and their haplotypes with the risk of UBC in a Northern Indian population. We analyzed two single nucleotide polymorphisms of IL-10 gene at G-1082A (rs 1800896) and C-819T (rs 3021097) in 214 histologically confirmed UBC patients and 385 matched controls by allele-specific polymerase chain reaction (AS-PCR). IL-10 C-819T CT, TT genotypes and T carriers (CT + TT) had significant association with UBC susceptibility (OR 1.75, 95% CI 1.09-2.80; OR 1.81, 95% CI 1.09-3.01 and OR 1.77, 95% CI 1.14-2.75, respectively). Similarly, GA, AA genotypes and A carriers (G-1082A) demonstrated increased risk for UBC (OR 1.91, 95% CI 1.04-3.50; OR 2.01, 95% CI 1.08-3.74 and OR 1.95, 95% CI 1.09-3.50, respectively). TT (C-819T) and T carriers showed protective association with high-risk tumors; (OR 0.34, 95% CI 0.13-0.88 and OR 0.41, 95% CI 0.17-0.97, respectively). We did not observe any association of IL-10 polymorphisms with smoking habits and UBC risk. The study suggested that the low-producing genotypes of IL-10 (C-819T and G-1082A) polymorphisms are associated with increased UBC risk. Individuals with (C-819T) TT genotype and T carriers, however, showed a protective association with high-risk tumors. Our data suggest that IL-10 G-1082A and C-819T polymorphisms may be used as a molecular marker of urothelial bladder cancer.

Induction of GST and NQO1 in Cultured Bladder Cells and in the Urinary Bladders of Rats by an Extract of Broccoli (Brassica oleraceaitalica) Sprouts

Deficiency of glutathione S-transferase (GST) or NAD(P)H:quinone oxidoreductase 1 (NQO1) in humans is associated with increased risk of urothelial bladder cancer. Broccoli sprouts are a rich source of several isothiocyanates (ITCs), particularly sulforaphane (SF) which has shown promising chemopreventive activities. We report herein that a broccoli sprout ITC extract significantly induced both GST and NQO1 in cultured bladder cells in vitro and in rat bladder tissues in vivo. The inducer activity of the extract was comparable to that of pure SF on the basis of total ITC concentrations. The bladder was one of the most responsive organs to induction of the enzymes by the extract. Induction of the enzymes by the extract was largely mediated by Nrf2, a transcriptional factor that plays a critical role in the induction of many detoxification enzymes. Moreover, induction of GST and NQO1 in the rat bladder in vivo by the extract was associated with high levels of urinary ITC metabolites, but no toxic effects on the bladder mucosa were detected. In conclusion, broccoli sprout ITC extract is a potent inducer of GST and NQO1 in the bladder and is a promising agent for prevention of bladder cancer.