8-hydroxy-2--deoxyguanosine and Prostatic-Neoplasms

Prostate cancer is one of the most common cancer types in men. In addition, it is the second leading cause of cancer death in the USA and Canada. Prostate cancer diagnosis is not a precise science yet. Discovery of potential biomarkers for early prostate cancer diagnosis and monitoring is crucially important. LC-MS and CE-MS have been widely used analytical techniques in the biomarker discovery. This review will describe the applications of LC-MS with different ionization techniques, such as ESI, atmospheric-pressure photoionization and atmospheric-pressure chemical ionization, and CE-MS techniques used in prostate cancer biomarker analysis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Chromatography, High Pressure Liquid; Creatinine; Deoxyadenosines; Deoxyguanosine; Electrophoresis, Capillary; Humans; Male; Prostaglandins; Prostatic Neoplasms; Spectrometry, Mass, Electrospray Ionization

Adducts arise from the chemical modification of bases in DNA or amino acids in proteins by toxic chemicals. Many chemicals known to be carcinogenic in humans have been shown to form adducts or to cause oxidative damage to genomic DNA in model systems. Biomarkers of carcinogenesis reflect biological events that take place between exposure to external or endogenous carcinogens and the subsequent development of cancer. Therapeutic intervention for the purpose of cancer chemoprevention may modify these biomarkers. In this article, the potential efficacy of DNA adducts as biomarkers of carcinogenesis and chemoprevention is discussed using criteria defined for phases of biomarker development. The sensitivity of adduct detection in histologically normal tissue offers opportunities for the early detection of carcinogenesis. Extensive evidence for aflatoxin B(1) adducts as biomarkers of risk and progression of hepatic carcinogenesis and for oxidative DNA adducts as biomarkers of the development of prostate carcinogenesis is reviewed together with the clinical trials measuring these adducts as biomarkers of the efficacy of chemoprevention. Favorable modification of oxidative DNA adducts by dietary intervention and chemoprevention has been demonstrated in preclinical and clinical studies. Protein adducts and DNA adducts in blood constituents or urine may act as useful surrogates for the target organ. Additional information regarding reliability, reproducibility, specificity, and confounding variables are required at the clinical level to validate adducts as suitable biomarkers of chemoprevention. "We do not administer antihypertensive drugs to patients in clinical trials without checking their blood pressure, so why should we give antioxidants without checking that they have decreased oxidant status.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aflatoxin B1; Anticarcinogenic Agents; Antioxidants; Biomarkers, Tumor; Carcinogens; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Clinical Trials as Topic; Deoxyguanosine; Diet; DNA; DNA Adducts; DNA Damage; DNA Repair; Humans; Immunochemistry; Male; Mass Spectrometry; Models, Chemical; Neoplasms; Oxidative Stress; Oxygen; Prostatic Neoplasms; Proteins; Risk; Sensitivity and Specificity

As part of a randomized placebo-controlled study to evaluate the effect of lycopene supplementation on DNA damage in men with prostate cancer, a nonrandomized 5th arm using tomato sauce was included and reported here. Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for 3 weeks (30 mg of lycopene/day) before their scheduled radical prostatectomy. Prostate tissue was obtained as biopsies at baseline and as resected tissue at the time of the prostatectomy. Serum and prostate lycopene, serum prostate specific antigen (PSA) concentrations, and leukocyte DNA 8-OH-deoxyguanosine/deoxyguanosine (8OHdG) were measured at baseline and at the end of the intervention. Cancer cells in paraffin sections of prostate biopsies and postintervention resected tissue were compared for 8OHdG staining and for apoptosis. Adherence to the daily consumption of tomato-based entrees was 81.6% of the intended dose, and serum and prostate lycopene concentrations increased 1.97- and 2.92-fold (P < 0.001), respectively. Mean serum PSA concentrations decreased by 17.5% (P < 0.002) and leukocyte 8OHdG decreased by 21.3% (P < 0.005) after tomato sauce consumption. Resected tissues from tomato sauce-supplemented patients had 28.3% lower prostate 8OHdG compared with the nonstudy control group (P < 0.03). Cancer cell 8OHdG staining of Gleason Score-matched resected prostate sections was reduced by 40.5% in mean nuclear density (P < 0.005) and by 36.4% in mean area (P < 0.018) compared with the presupplementation biopsy. Apoptotic index was higher in hyperplastic and neoplastic cells in the resected tissue after supplementation. These data taken as a whole indicate significant uptake of lycopene into prostate tissue and a reduction in DNA damage in both leukocyte and prostate tissue. Whether reduction in DNA damage to prostate cancer cells is beneficial awaits further research, although reduction in serum PSA concentrations is promising.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Anticarcinogenic Agents; Antioxidants; Apoptosis; Carotenoids; Deoxyguanosine; Humans; Lycopene; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Solanum lycopersicum

Preclinical and epidemiologic studies suggest chemopreventive effects of green tea (GT) and black tea (BT) in prostate cancer. In the current study we determined the effect of GT and BT consumption on biomarkers related to prostate cancer development and progression.. In this exploratory, open label, phase II trial 113 men diagnosed with prostate cancer were randomized to consume six cups daily of brewed GT, BT or water (control) prior to radical prostatectomy (RP). The primary endpoint was prostate tumor markers of cancer development and progression determined by tissue immunostaining of proliferation (Ki67), apoptosis (Bcl-2, Bax, Tunel), inflammation (nuclear and cytoplasmic nuclear factor kappa B [NFκB]) and oxidation (8-hydroxydeoxy-guanosine [8OHdG]). Secondary endpoints of urinary oxidation, tea polyphenol uptake in prostate tissue, and serum prostate specific antigen (PSA) were evaluated by high performance liquid chromatography and ELISA analysis.. Ninety three patients completed the intervention. There was no significant difference in markers of proliferation, apoptosis and oxidation in RP tissue comparing GT and BT to water control. Nuclear staining of NFκB was significantly decreased in RP tissue of men consuming GT (P = 0.013) but not BT (P = 0.931) compared to water control. Tea polyphenols were detected in prostate tissue from 32 of 34 men consuming GT but not in the other groups. Evidence of a systemic antioxidant effect was observed (reduced urinary 8OHdG) only with GT consumption (P = 0.03). GT, but not BT or water, also led to a small but statistically significant decrease in serum prostate-specific antigen (PSA) levels (P = 0.04).. Given the GT-induced changes in NFκB and systemic oxidation, and uptake of GT polyphenols in prostate tissue, future longer-term studies are warranted to further examine the role of GT for prostate cancer prevention and treatment, and possibly for other prostate conditions such as prostatitis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Apoptosis; Biomarkers, Tumor; Deoxyguanosine; Disease Progression; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; NF-kappa B; Phytotherapy; Plant Extracts; Polyphenols; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Tea; Treatment Outcome

Pomegranates slow prostate cancer xenograft growth and prolong prostate-specific antigen (PSA) doubling times in single-arm human studies. Pomegranates' effects on human prostate tissue are understudied. We hypothesized that orally administered pomegranate extract (POMx; Pom Wonderful) would lower tissue 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress biomarker. Seventy men were randomized to two tablets, POMx or placebo, daily up to four weeks before radical prostatectomy. Tissue was analyzed for intraprostatic urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NF-κB, and Ki67. Primary endpoint was differences in 8-OHdG, and the study was powered to detect 35% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (P = 0.095), which was not statistically significant. POMx was well tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21 of the 33 patients in the POMx group versus 12 of the 35 in the placebo group (P = 0.031). Cancer pS6 kinase, NF-κB, Ki67, and serum PSA changes were similar between arms. POMx before surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary endpoint in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitively test whether POMx reduces prostate oxidative stress, as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Chromatography, Liquid; Combined Modality Therapy; Coumarins; Deoxyguanosine; Double-Blind Method; Humans; Ki-67 Antigen; Lythraceae; Male; Mass Spectrometry; Middle Aged; Neoadjuvant Therapy; NF-kappa B; Oxidative Stress; Plant Extracts; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Ribosomal Protein S6 Kinases

The recent decade has witnessed the increasing potential of various flavonoids such as quercetin and thymoquinone in inhibiting cancer cells proliferation and growth and their therapeutic effects in various cancers. Therefore, in the current study, we aim to evaluate the expression levels of key factors of DNA damage response in human breast, lung and prostate cancer cell lines in response to treatment with quercetin and thymoquinone.. MTT assay was applied to assess the effects of quercetin and thymoquinone on the viability of MCF-7, A549, and PC3 cancer cells. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of p53, RAD51, Ku70, XRCC1, and H2AX in treated cells. In addition, the expression rate of 8-hydroxy-deoxyguanosine (8-OH-dG) was assessed by ELISA kit.. The quercetin and thymoquinone induce cytotoxicity in breast, lung, and prostate cancer cells effectively; MCF-7 cells were the most sensitive cells to quercetin with an IC50 value of 50 μM and PC3 cells were more sensitive to thymoquinone with an IC50 value of 20 μM. The expression levels of DNA damage markers, H2AX, and 8-OH-dG were significantly increased in all cancer cells treated with quercetin and thymoquinone (p < 0.05). Moreover, both flavonoids significantly decreased the expression levels of DNA repair mediators, RAD51, Ku70, XRCC1, in cell lines. P53 was also increased in MCF-7 and A549 cells.. We concluded that quercetin and thymoquinone may exert their effects through modulation of DNA damage response, increasing DNA damage, and suppressing DNA repair genes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Apoptosis; Cell Line, Tumor; DNA Damage; Flavonoids; Humans; Lung; Male; MCF-7 Cells; Prostatic Neoplasms; Quercetin; Tumor Suppressor Protein p53; X-ray Repair Cross Complementing Protein 1

Oxidative stress has been linked to cancer development in previous studies. However, the association between pre-diagnostic oxidatively generated DNA/RNA damage levels and incident cancer has rarely been investigated. Urinary oxidized guanine/guanosine (OxGua) concentrations, including 8-hydroxy-2'-deoxyguanosine, were assessed in 8,793 older adults in a population-based German cohort. 1,540 incident cancer cases, including 207 lung, 196 colorectal, 218 breast and 245 prostate cancer cases were diagnosed during over 14 years of follow-up. Associations of OxGua levels with cancer outcomes were not observed in the total population in multi-variable adjusted Cox regression models. However, in subgroup analyses, colorectal cancer incidence increased by 8%, 9% and 8% with one standard deviation increase in OxGua levels among current non-smokers, female and non-obese participants, respectively. Additionally, among non-smokers, overall and prostate cancer incidences statistically significantly increased by 5% and 13% per 1 standard deviation increase in OxGua levels, respectively. In contrast, OxGua levels were inversely associated with the risk of prostate cancer among current smokers. However, none of the subgroup analyses had p-values below a threshold for statistical significance after correction for multiple testing. Thus, results need to be validated in further studies. There might be a pattern that oxidatively generated DNA/RNA damage is a weak cancer risk factor in the absence of other strong risk factors, such as smoking, obesity and male sex.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Breast Neoplasms; Colorectal Neoplasms; DNA Damage; Female; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Obesity; Oxidative Stress; Prostatic Neoplasms; Risk Factors; Sex Factors; Smoking

Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anticarcinogenic Agents; Cyclooxygenase 2; Cytochrome P-450 CYP1A2; Deoxyguanosine; Diet; Disease Models, Animal; Humans; Imidazoles; Ki-67 Antigen; Male; Mice, Transgenic; NF-E2-Related Factor 2; Phosphorylation; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Tocopherols; Tyrosine

In this article we present ultra-sensitive, silicon nanowire (SiNW)-based biosensor devices for the detection of disease biomarkers. An electrochemically induced functionalisation method has been employed to graft antibodies targeted against the prostate cancer risk biomarker 8-hydroxydeoxyguanosine (8-OHdG) to SiNW surfaces. The antibody-functionalised SiNW sensor has been used to detect binding of the 8-OHdG biomarker to the SiNW surface within seconds of exposure. Detection of 8-OHdG concentrations as low as 1 ng/ml (3.5 nM) has been demonstrated. The active device has been bonded to a disposable printed circuit which can be inserted into an electronic readout system as part of an integrated Point of Care (POC) diagnostic. The speed, sensitivity and ease of detection of biomarkers using SiNW sensors render them ideal for eventual POC diagnostics.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antibodies; Biomarkers, Tumor; Biosensing Techniques; Deoxyguanosine; Humans; Male; Nanowires; Prostatic Neoplasms; Silicon

Oxidative stress has been linked to prostate carcinogenesis as human prostate tissue is vulnerable to oxidative DNA damage. Apigenin, a dietary plant flavone, possesses anti-proliferative and anticancer effects; however, its antioxidant properties have not been fully elucidated. We investigated sub-cellular distribution of apigenin, it's binding to DNA and protective effects against H2O2-induced DNA damage using transformed human prostate epithelial RWPE-1 cells and prostate cancer LNCaP, PC-3 and DU145 cells. Exposure of cells to apigenin exhibited higher accumulation in RWPE-1 and LNCaP cells, compared to PC-3 and DU145 cells. The kinetics of apigenin uptake in LNCaP cells was estimated with a Km value of 5 µmole/L and Vmax of 190 pmoles/million cells/h. Sub-cellular fractionation demonstrated that nuclear matrix retains the highest concentration of apigenin (45.3%), followed by cytosol (23.9%), nuclear membranes (17.9%) and microsomes (12.9%), respectively. Spectroscopic analysis of apigenin with calf-thymus DNA exhibited intercalation as the dominant binding mode to DNA duplex. Apigenin exposure resulted in significant genoprotective effects in H2O2-stressed RWPE-1 cells by reduction in reactive oxygen species levels. In addition, apigenin exposure suppressed the formation of 8-hydroxy-2' deoxyguanosine and protected exposed cells from apoptosis. Our studies demonstrate that apigenin is readily taken up by normal prostatic epithelial cells and prostate cancer cells, and is incorporated into their nuclei, where its intercalation with nucleic acid bases may account for its antioxidant and chemopreventive activities.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Apigenin; Cell Death; Cell Line, Tumor; Cytoprotection; Deoxyguanosine; DNA; DNA Damage; Endocytosis; Epithelial Cells; Humans; Hydrogen Peroxide; Kinetics; Male; Nucleic Acids; Oxidation-Reduction; Prostate; Prostatic Neoplasms; Reactive Oxygen Species; Spectrophotometry, Ultraviolet; Subcellular Fractions

Reactive oxygen species are known to be linked with cell damage leading to carcinogenesis. Augmented levels of oxidative stress biomarkers, such as nuclear factor erythroid 2-related factor 2 (Nrf-2) and 8-hydroxydeoxyguanosine (8-OHDG), have been shown to associate with more aggressive behavior in many malignancies. The aim of this study was to determine whether Nrf-2 and 8-OHDG expression could predict the outcome in radical prostatectomy patients. Samples of 240 prostate cancer patients were analyzed for Nrf-2 and 8-OHDG expression by immunohistochemistry. The results were compared with clinicopathological data, biochemical recurrence-free survival (BFS), prostate cancer-specific survival, and overall survival (OS). Positive expression of 8-OHDG (P < .0001), Nrf-2 in cytoplasm (c-Nrf-2) (P = .015), and Nrf-2 in nucleus (n-Nrf-2) (P = .016) was more abundant in malignant tissue compared with benign, respectively. Elevated level of c-Nrf-2 expression was associated with positive surgical marginal (P = .005), extraprostatic extension (P = .031), biochemical recurrence (BCR) (P = .030), and OS (P = .002); and n-Nrf-2 expression was associated with pathologic stage class (P = .001), Gleason score (P = .026), extraprostatic extension (P = .027), BCR (P = .037), and OS (P < .0001). The increased c-Nrf-2 expression predicted shortened BFS (P = .034) and worse OS (P = .017). In the multivariate analysis, c-Nrf-2 (P = .028 and P = .019) and Gleason score (P = .001 and P = .033) were independent predictors of BFS and OS, respectively. Expression of the analyzed biomarkers was not linked with prostate cancer-specific survival. Expression of 8-OHDG was not associated with any clinicopathological factors or survival. These results reveal that increased c-Nrf-2 expression is a predictor of BFS and OS in conjunction with Gleason score in prostate cancer patients treated with radical prostatectomy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Deoxyguanosine; Disease-Free Survival; Humans; Male; Middle Aged; Neoplasm Grading; NF-E2-Related Factor 2; Prognosis; Prostate; Prostatectomy; Prostatic Neoplasms; Reactive Oxygen Species

The pi-class glutathione S-transferase (GSTP1) actively protect cells from carcinogens and electrophilic compounds. Loss of GSTP1 expression via promoter hypermethylation is the most common epigenetic alteration observed in human prostate cancer. Silencing of GSTP1 can increase generation of reactive oxygen species (ROS) and DNA damage in cells. In this study we investigated whether loss of GSTP1 contributes to increased DNA damage that may predispose men to a higher risk of prostate cancer. We found significantly elevated (103%; P < 0.0001) levels of 8-oxo-2'-deoxogunosine (8-OHdG), an oxidative DNA damage marker, in adenocarcinomas, compared to benign counterparts, which positively correlated (r = 0.2) with loss of GSTP1 activity (34%; P < 0.0001). Silencing of GSTP1 using siRNA approach in normal human prostate epithelial RWPE1 cells caused increased intracellular production of ROS and higher susceptibility of cells to H2 O2 -mediated oxidative stress. Additionally, human prostate carcinoma LNCaP cells, which contain a silenced GSTP1 gene, were genetically modified to constitutively express high levels of GSTP1. Induction of GSTP1 activity lowered endogenous ROS levels in LNCaP-pLPCX-GSTP1 cells, and when exposed to H2 O2 , these cells exhibited significantly reduced production of ROS and 8-OHdG levels, compared to vector control LNCaP-pLPCX cells. Furthermore, exposure of LNCaP cells to green tea polyphenols caused reexpression of GSTP1, which protected the cells from H2 O2 -mediated DNA damage through decreased ROS production compared to nonexposed cells. These results suggest that loss of GSTP1 expression in human prostate cells, a process that increases their susceptibility to oxidative stress-induced DNA damage, may be an important target for primary prevention of prostate cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Catechin; Cell Line; Deoxyguanosine; DNA Damage; Enzyme Activation; Epithelial Cells; Gene Expression Regulation, Neoplastic; Glutathione S-Transferase pi; Guanosine Triphosphate; Humans; Hydrogen Peroxide; Male; Oxidative Stress; Prostate; Prostatic Neoplasms; Reactive Oxygen Species

Docetaxel (DTX) is one of the most important anticancer drugs; however, the severity of its adverse effects detracts from its practical use in the clinic. Magnetic nanoparticles of Fe3O4 (MgNPs-Fe3O4) can enhance the delivery and efficacy of anticancer drugs. We investigated the effects of MgNPs-Fe3O4 or DTX alone, and in combination with prostate cancer cell growth in vitro, as well as with the mechanism underlying the cytotoxic effects. MgNPs-Fe3O4 caused dose-dependent increases in reactive oxygen species levels in DU145, PC-3, and LNCaP cells; 8-hydroxydeoxyguanosine levels were also elevated. MgNPs-Fe3O4 alone reduced the viability of LNCaP and PC-3 cells; however, MgNPs-Fe3O4 enhanced the cytotoxic effect of a low dose of DTX in all three cell lines. MgNPs-Fe3O4 also augmented the percentage of DU145 cells undergoing apoptosis following treatment with low dose DTX. Expression of nuclear transcription factor κB in DU145 was not affected by MgNPs-Fe3O4 or DTX alone; however, combined treatment suppressed nuclear transcription factor κB expression. These findings offer the possibility that MgNPs-Fe3O4-low dose DTX combination therapy may be effective in treating prostate cancer with limited adverse effects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Deoxyguanosine; DNA; Docetaxel; Humans; Magnetite Nanoparticles; Male; NF-kappa B; Prostatic Neoplasms; Reactive Oxygen Species; Taxoids

To understand the association between markers of oxidative stress, levels of vascular endothelial growth factor (VEGF), and cell proliferation index in relation to disease progression, clinical stage, and cytologic grade in pathophysiology of prostate carcinoma.. Case control study comprised of 40 prostate carcinoma patients along with 40 age- and sex-matched healthy subjects as controls. Levels of 8-hydroxy-2-deoxy guanosine, protein carbonyl, and malondialdehyde along with total antioxidant status were measured to study the oxidative stress status in the study subjects. Angiogenesis was evaluated by studying the VEGF level and cell proliferation index.. The levels of markers of oxidative stress along with VEGF and cell proliferation index were found to be significantly higher with significantly decreased levels of antioxidant activity in the study subjects in comparison with healthy controls. The results indicate oxidative stress, angiogenesis, and cell proliferation activity increase progressively with the increase in staging and progression of disease.. Oxidative stress parameters, angiogenesis, and cell proliferation activity point clearly that with the progression of oxidative stress there is a simultaneous progression of angiogenesis, regulation and control of endothelial cell proliferation in relation to disease progression, clinical stage, and cytologic grade in the pathophysiology of prostate carcinoma.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Analysis of Variance; Antioxidants; Biomarkers, Tumor; Case-Control Studies; Cell Proliferation; Deoxyguanosine; Disease Progression; Humans; Male; Malondialdehyde; Middle Aged; Mitotic Index; Neoplasm Grading; Neoplasm Staging; Neovascularization, Pathologic; Oxidative Stress; Prostatic Neoplasms; Protein Carbonylation; Vascular Endothelial Growth Factor A

Epidemiological studies have demonstrated an inverse relationship between selenium (Se) intake and cancer incidence and/or mortality. However, the molecular mechanisms underlying the cancer chemopreventive activity of Se compounds remain largely unknown. The objective of this study was to investigate the effect of low doses of Se on the stimulation of DNA repair systems in response to four different qualities of DNA damage. P53-proficient LNCaP human prostate adenocarcinoma cells were grown either untreated or in the presence of low concentrations of two Se compounds (30° nM sodium selenite, or 10 μM selenomethionine) and exposed to UVA, H2O2, methylmethane sulfonate (MMS) or UVC. Cell viability as well as DNA damage induction and repair were evaluated by the alkaline Comet assay. Overall, Se was shown to be a very potent protector against cell toxicity and genotoxicity induced by oxidative stress (UVA or H2O2) but not from the agents that induce other types of deleterious lesions (MMS or UVC). Furthermore, Se-treated cells exhibited increased oxidative DNA repair activity, indicating a novel mechanism of Se action. Therefore, the benefits of Se could be explained by a combination of antioxidant activity, the reduction in DNA damage and the enhancement of oxidative DNA repair capacity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Anticarcinogenic Agents; Antioxidants; Cell Line, Tumor; Cell Survival; Deoxyguanosine; DNA Fragmentation; DNA Repair; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Humans; Hydrogen Peroxide; Male; Oxidation-Reduction; Oxidative Stress; Prostatic Neoplasms; Selenomethionine; Sodium Selenite; Thioredoxin-Disulfide Reductase; Ultraviolet Rays

It has been demonstrated in various animal models that the oral administration of green tea (GT) extracts in drinking water can inhibit tumor growth, but the effects of brewed GT on factors promoting tumor growth, including oxidant damage of DNA and protein, angiogenesis and DNA methylation, have not been tested in an animal model. To explore these potential mechanisms, brewed GT was administered instead of drinking water to male severe combined immunodeficiency (SCID) mice with androgen-dependent human LAPC4 prostate cancer cell subcutaneous xenografts. Tumor volume was decreased significantly in mice consuming GT, and tumor size was significantly correlated with GT polyphenol (GTP) content in tumor tissue. There was a significant reduction in hypoxia-inducible factor 1-alpha and vascular endothelial growth factor protein expression. GT consumption significantly reduced oxidative DNA and protein damage in tumor tissue as determined by 8-hydroxydeoxyguanosine/deoxyguanosine ratio and protein carbonyl assay, respectively. Methylation is known to inhibit antioxidative enzymes such as glutathione S-transferase pi to permit reactive oxygen species promotion of tumor growth. GT inhibited tumor 5-cytosine DNA methyltransferase 1 mRNA and protein expression significantly, which may contribute to the inhibition of tumor growth by reactivation of antioxidative enzymes. This study advances our understanding of tumor growth inhibition by brewed GT in an animal model by demonstrating tissue localization of GTPs in correlation with inhibition of tumor growth. Our results suggest that the inhibition of tumor growth is due to GTP-mediated inhibition of oxidative stress and angiogenesis in the LAPC4 xenograft prostate tumor in SCID mice.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antineoplastic Agents, Phytogenic; Camellia sinensis; Deoxyguanosine; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; Humans; Hypoxia-Inducible Factor 1; Macrophages; Male; Mice; Mice, SCID; Neovascularization, Pathologic; Oxidative Stress; Plant Extracts; Polyphenols; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Guanosine derivatives are important for diagnosis of oxidative DNA damage including 8-hydroxy-2'-deoxyguanosine (8-OHdG) as one of the most abundant products of DNA oxidation. This compound is commonly determined in urine, which makes 8-OHdG a good non-invasive marker of oxidation stress. In this study, we optimized and tested the isolation of 8-OHdG from biological matrix by using paramagnetic particles with an antibody-modified surface. 8-OHdG was determined using 1-naphthol generated by alkaline phosphatase conjugated with the secondary antibody. 1-Naphthol was determined by stopped flow injection analysis (SFIA) with electrochemical detector using a glassy carbon working electrode and by stationary electrochemical detection using linear sweep voltammetry. A special modular electrochemical SFIA system which needs only 10  μL of sample including working buffer for one analysis was completely designed and successfully verified. The recoveries in different matrices and analyte concentration were estimated. Detection limit (3 S/N) was estimated as 5  pg/mL of 8-OHdG. This method promises to be very easily modified to microfluidic systems as "lab on valve". The optimized method had sufficient selectivity and thus could be used for determination of 8-OHDG in human urine and therefore for estimation of oxidative DNA damage as a result of oxidation stress in prostate cancer patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Alkaline Phosphatase; Antibodies; Deoxyguanosine; Electrochemical Techniques; Enzyme-Linked Immunosorbent Assay; Flow Injection Analysis; Humans; Magnets; Male; Microfluidic Analytical Techniques; Microspheres; Middle Aged; Naphthols; Oxidative Stress; Prostatic Neoplasms; Robotics

Prostatic oxidative stress (OS) is androgen-regulated and a key event in the development of prostate cancer (PC). Thus, reducing prostatic OS is an attractive target for PC prevention strategies. We sought to determine if the individual's prostatic OS status can be determined by examining the OS in surrogate androgen regulated tissues from the same host.. Adult male rats were divided equally into three groups: (A-) underwent bilateral orchiectomy, (A+) received continuous testosterone supplementation or (C) were eugonadal. Serum testosterone, 8-hydroxy-2-deoxyguanosine (8-OHdG) and anti-oxidative capacity (AOC) were determined after 72 hrs and the prostate, salivary glands and the hair follicles' Dermal Papillary Cells (DPC) from each animal were harvested, embedded into tissue microarray and examined for the expression of 8-OHdG by immuno-staining. Multi-variate regression was used to analyze inter-individual differences in OS staining within each androgen group and if there was a correlation between serum testosterone, 8-OHdG or AOC and Prostatic OS in tissues of same host. At the group level, 8-OHdG staining intensity directly correlated with serum testosterone levels in all three target tissues (p>0.01, Mann-Whitney Test). Although different levels of prostatic OS were noted between rats with similar serum testosterone levels and similar systemic OS measurements (p<0.01), there were no intra-individual differences between the OS status of the prostate and DPC (p<0.05).. The level of prostatic OS is correlated with the OS of hair follicles and salivary glands, but not systemic OS. Moreover, systemic AOC negatively correlates with both prostatic and hair follicle OS. This suggests that hair follicle and salivary gland OS can serve as surrogate markers for the efficiency of OS reduction. This has tremendous potential for the rational evaluation of patient response to prevention strategies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Biomarkers; Biomarkers, Tumor; Deoxyguanosine; Hair Follicle; Immunohistochemistry; Male; Oxidative Stress; Prostate; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Salivary Glands; Testosterone

Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) represents a non-invasive biomarker for oxidative stress and may be useful for monitoring chemotherapeutic and chemopreventive interventions associated with cancer-related alterations in oxidative stress. We describe the development and validation of two separate liquid chromatography/tandem mass spectrometry (LC/MS/MS) selected reaction monitoring (SRM) methods for the determination of 8-oxodG and creatinine in both murine and human urine using stable isotope labelled internal standards. Levels of 8-oxodG were normalised to creatinine. The LC/MS/MS methods were applied to two chemoprevention studies utilising tea polyphenols in humans and TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice. Patients with benign prostatic hyperplasia received 1 g/day of green tea polyphenols (GTP), 1 g/day of black tea theaflavins (BTT) or no treatment for 4 weeks. TRAMP mice received GTP (0.05% in drinking water) for 4 or 25 weeks. Prostate pathology in TRAMP mice was not affected by GTP. Levels of 8-oxodG were not altered by tea polyphenols in either mice or humans. In TRAMP mice, urinary 8-oxodG levels were elevated with increasing age (p < 0.0001) but not changed by the presence of prostate tumours. In conclusion, the LC/MS/MS SRM methods described here are ideally suited for the accurate determination of 8-oxodG and creatinine in urine samples from both clinical and pre-clinical studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Creatinine; Deoxyguanosine; Humans; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Prostatic Neoplasms; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tea; Urinalysis

Angiotensin II has been shown to be a cytokine especially acting as a growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of angiotensin II seems to be similar in prostate cancer, as we previously reported. In the present study, we explored the biological role of angiotensin II in oxidative stress of prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related proteins (p47phox, manganese superoxide dismutase 2, glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with angiotensin II and/or an angiotensin II receptor type 1 blocker, candesartan. To examine DNA damage induced by angiotensin II, 8-hydroxy-2'-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint proteins including p53, Chk2, and cdc2. Immunocytochemical studies of inducible nitric oxide synthase and superoxide anion radical (O(2)(-)) were done in LNCaP cells stimulated with angiotensin II. The phosphorylation of Akt was induced by angiotensin II treatment and inhibited by candesartan, as well as by LY294002, an inhibitor of phosphoinositide 3-kinase. Oxidative stress-related proteins were up-regulated by angiotensin II and inhibited by pretreatment with candesartan or catalase. The level of 8-hydroxy-2'-deoxyguanosine was increased by angiotensin II and conversely decreased by candesartan. Immunocytochemical studies showed that angiotensin II enhanced an inflammatory marker, inducible nitric oxide synthase, and the production of O(2)(-) radical. The hypothesis that angiotensin II has the potential to induce oxidative stress, which may be implicated in carcinogenesis of the prostate gland through long-term exposure to chronic inflammation is proposed.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Cell Cycle Proteins; Cell Line, Tumor; Deoxyguanosine; DNA Damage; Humans; Immunohistochemistry; Male; Microscopy, Confocal; Models, Biological; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Superoxides; Time Factors

Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administration of testosterone plus 17beta-estradiol to Noble rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2'-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/nitrosative stress in epithelium. We concluded that the oxidative/nitrosative damage resulting from the testosterone-plus-17beta-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alterations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cell Transformation, Neoplastic; Cyclooxygenase 2; Deoxyguanosine; Epithelial Cells; Estradiol; Gonadal Steroid Hormones; Lasers; Male; Microdissection; NADH, NADPH Oxidoreductases; Nitric Oxide Synthase; Oxidation-Reduction; Oxidative Stress; Prostate; Prostatic Neoplasms; Rats; Rats, Inbred Strains; RNA, Messenger; Testosterone

As part of a systematic study of the effects of phytochemicals beyond antioxidation on cancer prevention, we investigated whether naringenin (NR), a citrus flavonoid, stimulates DNA repair following oxidative damage in LNCaP human prostate cancer cells. The 8-hydroxydeoxyguanosine (8-OH-dG) to deoxyguanosine (dG) ratio was measured after cells were treated with 200 micromol/L of ferrous sulfate in serum-free medium followed by NR exposure for 24 h in growth medium. The results demonstrated that exposure to 10-80 micromol/L of NR led to a significant decrease in the ratio of 8-OH-dG to 10(6) dG. Because cells were treated with NR after ferrous sulfate was removed, we conclude that we demonstrated an effect on DNA repair beyond antioxidation. In support of this conclusion, we determined the induction of mRNA expression over time after oxidative stress followed by NR administration of three major enzymes in the DNA base excision repair (BER) pathway: 8-oxoguanine-DNA glycosylase 1 (hOGG1), apurinic/apyrimidinic endonuclease and DNA polymerase beta (DNA poly beta). hOGG1 and DNA poly beta mRNA expression in cells after 24-h exposure to NR was increased significantly compared with control cells without NR. The intracellular concentration of NR after exposure to 80 micromol/L was 3 pmol/mg protein, which is physiologically achievable in tissues. In conclusion, the cancer-preventive effects of citrus fruits demonstrated in epidemiological studies may be due in part to stimulation of DNA repair by NR, which by stimulating BER processes may prevent mutagenic changes in prostate cancer cells.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Cell Line, Tumor; Citrus; Deoxyguanosine; DNA Glycosylases; DNA Polymerase beta; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; Ferrous Compounds; Flavanones; Gene Expression; Humans; Male; Oxidative Stress; Prostatic Neoplasms; RNA, Messenger

Animal and epidemiological studies point to a cancer preventive/therapeutic role for tomato products and its antioxidant, lycopene. It is hypothesized that lycopene will behave as an antioxidant at low concentrations and as a prooxidant at high concentrations in LNCaP human prostate cancer cell culture systems. We characterized the antioxidant, and prooxidant effects of a hexane extract of tomato paste (TP) and water solubilized lycopene at different concentrations using a prostate cancer cell line. Placebo (5% triglyceride, Roche Inc.) was used as a control. After 6, 24 hr and 48 hr incubation, LNCaP cells were harvested and used for each measurement. Cellular proliferation was determined using the MTT colorimetric assay. Lycopene and TP hexane extract inhibited cell growth in a dose-dependent (0.1-50 microM lycopene) manner and growth inhibition was 55% and 35% at 1 microM lycopene and TP hexane extract, respectively after 48 hr incubation. The levels of 8-hydroxydeoxyguanosine/deoxyguanosine (an oxidative DNA damage product) was significantly increased starting at 5 microM lycopene from both TP hexane extract and pure lycopene after 24 and 48 hr incubation with no protection at the lower concentrations. Malondialdehyde formation (a lipid peroxidation product measured by HPLC separation of the MDA-TBA adduct) was significantly reduced at low concentrations (0.1-1 microM) of lycopene in all treatments. Clinically relevant concentrations of lycopene and the tomato fraction containing lycopene significantly reduced LNCaP cancer cell survival which can only be partially explained by increased DNA damage at high lycopene concentrations (> 5 microM). Low concentrations of lycopene acted as a lipid antioxidant but did not protect DNA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Carotenoids; Cell Proliferation; Deoxyguanosine; DNA, Neoplasm; Hexanes; Humans; Lipid Peroxidation; Lycopene; Male; Malondialdehyde; Oxidants; Plant Extracts; Prostatic Neoplasms; Solanum lycopersicum; Thiobarbiturates

We evaluated the significance of oxidative DNA damage in patients with prostate cancer based on the measurement of urinary 8-OHdG (8-hydroxy-2'-deoxyguanosine) and analyzed changes in urinary 8-OHdG before and after initial treatment.. A total of 82 patients with prostate cancer were included in this study. Of these 82 patients 42 underwent radical prostatectomy and the remaining 40 received hormonal therapy as initial treatment. Urinary 8-OHdG and creatinine (Cr), and serum prostate specific antigen (PSA) in these 82 patients were assessed before and 2 months after the initiation of treatment.. The ratio of urinary 8-OHdG-to-Cr (8-OHdG/Cr) in patients with prostate cancer was significantly higher than in age matched healthy controls. Only age was significantly associated with 8-OHdG/Cr in prostate cancer cases among several clinicopathological factors, including serum PSA clinical T stage, metastasis and Gleason score. There was no significant difference in urinary 8-OHdG/Cr in 42 patients before and after radical prostatectomy, while urinary 8-OHdG/Cr in 40 patients after hormonal therapy was significantly lower than before hormonal therapy. In addition, changes in PSA after initial treatment were not related to changes in urinary 8-OHdG/Cr in either treatment group.. These findings suggest that oxidative stress may be involved in an early event in prostate cancer development and androgen suppression is capable of decreasing oxidative stress. Accordingly androgen withdrawal therapy combined with antioxidative agents may inhibit the progression of prostate cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Creatinine; Deoxyguanosine; DNA Damage; Humans; Male; Oxidative Stress; Prostatic Neoplasms

Recent studies reported that oxidative stress is one of the major factors associated with the progression of prostate cancer through the accumulation of DNA damage. In the present study, we investigated the effect of oxidative stress on cell injury using androgen-dependent human prostate cancer LNCaP cells overexpressing clusterin, which has been shown to play crucial roles in the acquisition of resistance to several apoptotic stimuli.. We introduced clusterin cDNA into LNCaP cells which do not express a detectable level of clusterin expression, and generated a clusterin-overexpressing cell line (LNCaP/Cl) and a control vector only-transfected cell line (LNCaP/Co). The effects of hydrogen peroxide (H2O2) treatment on the LNCaP sublines with and without the addition of dihydrotestosterone (DHT) were analyzed using the in vitro mitogenic assay and lipid peroxidation assay, and morphological changes in the LNCaP sublines after H2O2 treatment were examined by staining with Hoechst 33258. The degrees of DNA damage induced by H2O2 into the LNCaP sublines were evaluated by the measurement of 8-hydroxy-2'-deoxyguanosine (8-OHdG) level.. H2O2-induced apoptosis in LNCaP/Cl was significantly suppressed compared with that in LNCaP/Co through the inhibition of membrane damage; however, the measurement of 8-OHdG level demonstrated that DNA damage was more intensively accumulated in LNCaP/Cl cells than LNCaP/Co cells. Furthermore, DHT suppressed the incidence of apoptotic cell death and enhanced the formation of 8-OHdG in both LNCaP/Cl and LNCaP/Co cells after H2O2 treatment in a dose-dependent manner.. These findings suggest that clusterin may contribute to conferring resistance to oxidative stress-mediated cellular injury on prostate cancer cells, especially in the presence of androgen.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Androgens; Apoptosis; Clusterin; Deoxyguanosine; Dihydrotestosterone; DNA Damage; DNA, Complementary; Gene Expression; Glycoproteins; Humans; Hydrogen Peroxide; Lipid Peroxidation; Male; Molecular Chaperones; Neoplasms, Hormone-Dependent; Oxidative Stress; Prostatic Neoplasms; Transfection; Tumor Cells, Cultured

8-hydroxydeoxyguanosine (8-OHdG) is the most frequently detected and studied DNA lesion. Upon DNA repair, 8-OHdG is excreted in the urine. Urinary 8-OHdG is now considered as a biomarker of generalized, cellular oxidative stress and is linked to degenerative diseases including cancer.. We developed a competitive enzyme-linked immunosorbent assay (ELISA) for urinary 8-OHdG by coating BSA conjugated 8-hydroxyguanine (8-OHG) on a microplate. Urine specimens containing 8-OHdG and monoclonal anti-8-OHdG antibody were incubated together in the microwell. Final quantification of bound anti-8-OHdG antibody was estimated by the addition of HRP-conjugated sheep-anti-mouse antibody.. The concentration range of the calibration curve was 0-60 ng/ml. The sensitivity of the assay was 0.5 ng/ml. The within-day precision and day-to-day precision were <10%. The ELISA correlated well with a commercial kit (r=0.9). Our assay measured not only 8-OHdG but also 8-OHG and 8-hyroxyguanine in urine. Increased urinary concentration of 8-OHdG and its analogs were detected in both patients with bladder cancer (70.5+/-38.2 ng/mg creatinine) and prostate cancer (58.8+/-43.4 ng/mg creatinine) as compared to the healthy control (36.1+/-24.5 ng/mg creatinine).. Our preliminary data suggest that the competitive ELISA for 8-OHdG and its analogs appears to be a simple method for quantifying the extent of oxidative stress and may have potential for identifying cancer risk.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Calibration; Chromatography, Gel; Deoxyguanosine; DNA; Enzyme-Linked Immunosorbent Assay; Guanosine; Humans; Male; Oxidative Stress; Prostatic Neoplasms; Reagent Kits, Diagnostic; Reproducibility of Results; Urinary Bladder Neoplasms

Prostate cancer continues to be the most frequently diagnosed cancer in men in the United States. Despite aggressive intervention, a significant number of men with prostate cancer will not be cured of their disease and will face the possibility of metastatic disease. Thus, development of potent prevention strategies to diminish or eliminate this threat is in order. Cellular exposure to chronic oxidative stress may be 1 possible etiologic factor in the development of many cancers, including prostate cancer. Oxygen radicals can attack DNA directly and result in the accumulation of potentially promutagenic oxidized DNA bases such as 8-hydroxydeoxyguanosine. In addition, chronic oxidant stress may also result in lipid peroxidation and the subsequent generation of a range of reactive products that can damage DNA. Disruption of certain genes may result in cellular tolerance to oxidative genomic injury. GSTP1 is an enzyme that helps catalyze the conjugation reaction between potentially damaging electrophiles and glutathione. Inactivation of GSTP1 has been documented to occur in nearly 100% of human prostate cancers; it is also frequently inactivated in prostatic intraepithelial neoplasia lesions. This inactivation may leave the cell vulnerable to oxidative DNA damage and/or tolerant to accumulation of oxidized DNA base adducts. These base adducts can be measured by several quantitative methods, such as gas chromatography-mass spectrometry with selected ion monitoring. These sophisticated methods can be readily integrated into prostate cancer chemoprevention studies of new and developing prevention agents by providing quantitative assessment of oxidative DNA damage before and after administration of these candidate chemopreventive drugs. The combination of genetic information, state-of-the-art assessment tools, and novel agents will allow rational, directed prostate cancer chemoprevention studies to be performed and, together, will help determine the role of chronic oxidative stress in the carcinogenic process of prostate cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; DNA Adducts; DNA Damage; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Isoenzymes; Male; Oxidative Stress; Prostate; Prostatic Neoplasms; Tumor Cells, Cultured

Human prostate tissues are vulnerable to oxidative DNA damage. The risk of prostate cancer is lower in men reporting higher consumption of tomato products, which contain high levels of the antioxidant lycopene. We examined the effects of consumption of tomato sauce-based pasta dishes on lycopene uptake, oxidative DNA damage, and prostate-specific antigen (PSA) levels in patients already diagnosed with prostate cancer.. Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for the 3 weeks (30 mg of lycopene per day) preceding their scheduled radical prostatectomy. Serum and prostate lycopene concentrations, serum PSA levels, and leukocyte DNA oxidative damage (ratio of 8-hydroxy-2'-deoxyguanosine [8-OHdG] to 2'-deoxyguanosine [dG]) were assessed before and after the dietary intervention. DNA oxidative damage was assessed in resected prostate tissue from study participants and from seven randomly selected prostate cancer patients. All statistical tests were two-sided.. After the dietary intervention, serum and prostate lycopene concentrations were statistically significantly increased, from 638 nM (95% confidence interval [CI] = 512 to 764 nM) to 1258 nM (95% CI = 1061 to 1455 nM) (P<.001) and from 0.28 nmol/g (95% CI = 0.18 to 0.37 nmol/g) to 0.82 nmol/g (95% CI = 0.57 to 1.11 nmol/g) (P <.001), respectively. Compared with preintervention levels, leukocyte oxidative DNA damage was statistically significantly reduced after the intervention, from 0.61 8-OHdG/10(5) dG (95% CI = 0.45 to 0.77 8-OHdG/10(5) dG) to 0.48 8-OHdG/ 10(5) dG (95% CI = 0.41 to 0.56 8-OHdG/10(5) dG) (P =.005). Furthermore, prostate tissue oxidative DNA damage was also statistically significantly lower in men who had the intervention (0.76 8-OHdG/10(5) dG [95% CI = 0.55 to 0.96 8-OHdG/10(5) dG]) than in the randomly selected patients (1.06 8-OHdG/10(5) dG [95% CI = 0.62 to 1.51 8-OHdG/10(5) dG]; P =.03). Serum PSA levels decreased after the intervention, from 10.9 ng/mL (95% CI = 8.7 to 13.2 ng/mL) to 8.7 ng/mL (95% CI = 6.8 to 10.6 ng/mL) (P<.001).. These data indicate a possible role for a tomato sauce constituent, possibly lycopene, in the treatment of prostate cancer and warrant further testing with a larger sample of patients, including a control group.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Age Factors; Aged; Carotenoids; Chromatography, High Pressure Liquid; Deoxyguanosine; Diet Therapy; DNA; DNA Damage; Electrochemistry; Humans; Leukocytes; Lycopene; Male; Middle Aged; Oxidative Stress; Oxygen; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Solanum lycopersicum; Time Factors

The risk for prostate cancer seems to be reduced by certain antioxidant compounds (vitamins E and A, and selenium).. Antioxidant enzymes and oxidative damage products were localized in normal prostatic epithelium and malignant glands in primary and metastatic prostatic adenocarcinomas, using well-characterized antibodies and immunoperoxidase techniques.. Antioxidant enzymes and four markers of oxidative damage were compared in basal and secretory cells of normal prostatic epithelium and prostate adenocarcinoma cells, and each cell type had unique patterns of enzymes and oxidative damage products. One marker of oxidative damage, a fluorophore derived from 4-hydroxy-2-nonenal-lysine adduction, was found in secretory cells of normal but not malignant epithelium, demonstrating a different oxidative metabolism in normal vs. malignant prostate epithelium. Metastatic lesions from primary prostate cancer had higher levels of manganese superoxide dismutase and nuclear oxidative damage products than did primary tumors.. Antioxidant enzymes and oxidative damage products are modulated in metastatic compared to primary prostate cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Antibodies, Monoclonal; Antioxidants; Bone Neoplasms; Catalase; Deoxyguanosine; Glutathione Peroxidase; Humans; Immunoenzyme Techniques; Lipofuscin; Male; Prostate; Prostatic Neoplasms; Reactive Oxygen Species; Superoxide Dismutase; Tyrosine

Various markers of radiation-induced DNA damage including DNA oxidation were investigated in peripheral lymphocytes of 23 cancer patients prior to and one week after receiving radiotherapy with a cumulative dose of 54-70 Gy. Exposure to ionizing radiation nonsignificantly increased the ratio 2'deoxy-7-dihydro-8-oxoguanosine/2'deoxyguanosine (8-oxodG/dG) from 1.73 x 10(-5) to 3.33 x 10(-5). Frequencies of micronuclei significantly (p = 0.0003) increased from 6.4 to 38.9 per 1000 cells. The frequency of hypoxanthine-guanine-phosphoribosyltransferase (HPRT) mutant lymphocytes measured as 6-thioguanine resistant variant cells by 5-bromodeoxyuridine labeling, was elevated eight-fold, from 4.7 x 10(-6) to 36.2 x 10(-6) (p = 0.008) after termination of the radiotherapy, thus showing a clear response to the radiation treatment. No correlation between levels of oxidative DNA damage and frequencies of HPRT mutant lymphocytes or micronuclei could be established.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Antioxidants; Biomarkers; Breast Neoplasms; Bromodeoxyuridine; Deoxyguanosine; DNA Damage; Female; Head and Neck Neoplasms; Humans; Hypoxanthine Phosphoribosyltransferase; Male; Micronucleus Tests; Middle Aged; Neoplasms; Oxidation-Reduction; Prostatic Neoplasms; Smoking