8-hydroxy-2--deoxyguanosine and Carcinoma--Squamous-Cell

The development and establishment of oral squamous cell carcinoma are confined to carcinogenesis, which involves oxidative stress via oxygen-free radical production as a hydroxyl radical (HO•), considered the most important cause of oxidative damage to basic biomolecules since it targets DNA strands. 8-Hydroxy-2´-deoxyguanosine (8-OHdG) is considered a free radical with a promutagenic capacity due to its ability to pair with adenosine instead of cytosine during replication.. We collected 30 paraffin-embedded tissue samples of OSCC from patients treated between 2013 and 2018. We recorded risk habits, disease stage, disease free survival and death with at least 3 years of follow-up. 8-Hydroxyguanosine was evaluated by immunohistochemistry and subsequently classified as weak-moderate or strong positive expression. Additionally, we noted whether it was expressed in the cytoplasm and/or nucleus.. Most of the cases expressed 8-OHdG with a strong intensity (80%). All neoplastic cells were preferentially stained in only the cytoplasm (70.0%), but nuclear positivity was found in 30%, independent of the intensity. Based on the location in the cytoplasm and/or nucleus, tumors >4 cm showed a high frequency (95.5%) of 8-OHdG expression in only the cytoplasm, with a significant difference (p value 0.001). Additionally, overall survival was affected when immunoexpression was present in the cytoplasm and nucleus because all deaths were in this group were statistically significant (p value = 0.001).. All tumors showed DNA oxidative damage, and 8-OHdG was preferentially expressed in the cytoplasm. This finding was associated with tumor size and, when present in the nucleus, might also be related to death.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Carcinoma, Squamous Cell; Deoxyguanosine; DNA Damage; Free Radicals; Humans; Mouth Neoplasms; Oxidative Stress

Squamous Cell Carcinoma is almost always preceded by potentially malignant disorders in the oral cavity before malignant transformation. Characterization of  8-OHdG from the saliva offers a relatively non-invasive, simple and efficient methodology for monitoring oxidative stress in subjects of Premalignant oral disorders (PMOD) and Oral Squamous Cell Carcinoma (OSCC). Hence the aim of the current study is to estimate the levels of salivary 8-hydroxydeoxyguanosine (8-OHdG) as a potential DNA Damage Biomarker in OSMF and OSCC patients in comparison to healthy individuals to assess disease progression from potentially malignant oral disorder to frank malignancy.. The study was conducted among 90 patients [Oral Squamous cell carcinoma (n=30) and Oral Submucous Fibrosis (n=30) and healthy gender and age matched controls (n=30)]. 4ml of unstimulated saliva was collected from each of the subjects and was subjected to Sandwich ELISA for the quantification of salivary 8-OHdG. Statistical analysis was done using ANOVA, and p value was set at ≤0.05.. The mean age of OSCC patients were 56.8±11.8 years. Smoking was the most prevalent adverse habit among this group (66.6%) followed by Smokeless tobacco chewers (40%). The mean age of OSMF patients was 46.2± 9.8 years. Smokeless tobacco was the most predominant habit among the OSMF patients (83.33%) followed by smoking (33.33%). The mean OHdG levels among the controls was 6.59±1.47 (ng/dl) and almost doubled in patients of OSMF 13.89±1.96(ng/dL) and further raised in OSCC patients 19.96 ± 2.11 (ng/dL). These levels showed a highly significant difference (p <0.0001) in mean on comparison by using one-way ANOVA. Pearson correlation between the groups were also statistically significant (p=0.000).. There were significant differences in the concentration of salivary 8-OHdG between healthy controls, OSMF, and OSCC patients. Hence, 8-OHdG can be used as a novel biomarker of DNA damage to assess disease progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Case-Control Studies; Cell Transformation, Neoplastic; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mouth Neoplasms; Prognosis; Saliva

8-Hydroxy-2'-deoxyguanosine is a biomolecule associated with DNA damage. We evaluated oxidative stress and DNA damage in patients with laryngeal cancer by measuring 8-hydroxy-2'-deoxyguanosine levels.. This study enrolled 117 subjects, including 64 controls and 53 patients who had benign vocal cord lesions or laryngeal cancer. The benign excised lesions, tumor tissue, noncancerous laryngeal tissue, blood, and urine were subjected to high-performance liquid chromatography, and 8-hydroxy-2'-deoxyguanosine levels were compared between groups.. Blood and urine 8-hydroxy-2'-deoxyguanosine levels in patients with laryngeal carcinoma were significantly higher than in the controls ( P = .00002, P = .00001). The 8-hydroxy-2'-deoxyguanosine level was significantly higher in tumor tissues than in non-tumor tissue and benign vocal cord lesion tissues ( P = .00002, P = .000001).. We determined that laryngeal cancer was associated with oxidative stress, which may be quantified by measuring 8-hydroxy-2'-deoxyguanosine. For a patient with a suspicious laryngeal lesion, 8-hydroxy-2'-deoxyguanosine levels in blood and urine can provide advance information about the likely diagnosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Carcinoma, Squamous Cell; Case-Control Studies; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA; DNA Damage; Female; Head and Neck Neoplasms; Humans; Laryngeal Neoplasms; Laryngectomy; Male; Middle Aged; Oxidative Stress; Smoking; Squamous Cell Carcinoma of Head and Neck

MutT homolog-1 (MTH1) is a pyrophosphatase that acts on oxidized nucleotides and hydrolyzes 8-oxo-2'-deoxyguanosine triphosphate in deoxynucleoside triphosphate pool to prevent its incorporation into nuclear and mitochondrial DNA, result in reduce cytotoxicity in tumor cells. MTH1 is overexpressed in various cancers and is considered as a therapeutic target. Environmental factors such as cigarette smoking and alcohol consumption are critical risk factors for the development and progression of esophageal squamous cell carcinoma (ESCC), suggesting that oxidative stress contributes to the pathogenesis of ESCC. We examined the expression of MTH1 and the accumulation of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in 84 patients with ESCC who underwent curative resection without neoadjuvant therapy. MTH1 mRNA level was quantified by performing quantitative reverse transcription-PCR. Immunohistochemical analysis of paraffin-embedded cancer tissues was performed to determine MTH1 protein expression and 8-oxo-dG accumulation. MTH1 mRNA expression was higher in cancerous tissues than in the corresponding normal epithelium (P < 0.0001). Immunohistochemical analysis showed that high MTH1 expression was significantly associated with deeper tumor invasion and venous invasion, advanced cancer stage, and poor overall survival (P = 0.0021) and disease-specific survival (P = 0.0013) compared with low MTH1 expression. Furthermore, high MTH1 expression was an independent predictor of poor disease-specific survival (P = 0.0121). In contrast, 8-oxo-dG accumulation was not associated with any clinicopathological factor and poor prognosis. These results suggest that MTH1 overexpression is a predictor of ESCC progression and poor prognosis and that MTH1 can serve as a therapeutic target for treating patients with ESCC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Carcinoma, Squamous Cell; Cell Line, Tumor; Deoxyguanosine; DNA Repair Enzymes; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Male; Middle Aged; Neoplasm Invasiveness; Phosphoric Monoester Hydrolases; Prognosis; Survival Analysis; Treatment Outcome; Up-Regulation

Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose-dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0-2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed-onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers.

Topics: 8-Hydroxy-2'-Deoxyguanosine; A549 Cells; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cats; Cell Line, Tumor; Cell Survival; Deoxyguanosine; Female; HEK293 Cells; Humans; Mouth Neoplasms; NAD(P)H Dehydrogenase (Quinone); Quinones

The objectives of this study are to analyze oxidative DNA and lipid damage using salivary 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDA), and vitamins C and E in oral lichen planus lesions, oral leukoplakia, oral submucous fibrosis, oral squamous cell carcinoma (SCC), and controls and to determine the value of salivary biomarkers in the diagnosis of oral pre-cancer and cancer patients.. Unstimulated saliva was collected from a group of patients diagnosed with 40 oral squamous cell carcinoma (OSCC), 40 oral lichen planus lesions, 40 oral leukoplakia, 40 oral submucous fibrosis, and from a control group of healthy age- and gender-matched individuals. Salivary 8-OHdG, MDA, and vitamins C and E were measured.. Squamous cell carcinoma and pre-cancer patients showed significantly higher levels of salivary 8-OHdG and MDA and lower levels of vitamins C and E when compared to levels in healthy normal subjects. The specificity and sensitivity of the combination of 8-OHdG, MDA, vitamin C, and vitamin E are high for the diagnosis of oral pre-cancer and SCC compared to an individual biomarker approach using either 8-OHdG, MDA, or vitamin C and vitamin E independently.. This study indicates the presence of oxidative DNA and lipid damage in pre-cancerous and SCC patients. It is postulated that the mechanism may have a significant link to carcinogenesis in oral cancer. Detection of salivary 8-OHdG, MDA, vitamin C, and vitamin E can act as suitable diagnostic biomarkers of oral pre-cancer and cancer.. Of clinical importance is that salivary 8-OHdG, MDA, vitamin C, and vitamin E could play a significant role in oral cancer and pre-cancer patients and could therefore be useful for diagnosis in patients with oral lichen planus lesions, oral leukoplakia, oral submucous fibrosis, and oral squamous cell carcinoma.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Ascorbic Acid; Biomarkers; Biopsy; Carcinoma, Squamous Cell; Case-Control Studies; Deoxyguanosine; Female; Free Radicals; Humans; Leukoplakia, Oral; Lichen Planus, Oral; Male; Malondialdehyde; Middle Aged; Mouth Neoplasms; Oral Submucous Fibrosis; Precancerous Conditions; Risk Factors; Saliva; Sensitivity and Specificity; Vitamin E

Chronic inflammation is associated with increased risk of cancer development, whereas the link between chronic inflammation and esophageal carcinogenesis is still obscure heretofore. This study aimed to investigate the relationship between chronic inflammation and DNA damage, as well as the possible role of DNA damage in esophageal carcinogenic process. Endoscopic esophageal biopsies from 109 individuals from Chaoshan littoral, a high-risk region for esophageal squamous cell carcinoma (ESCC), were examined to evaluate the association between chronic inflammation and histological severity, while additional 204 esophageal non-tumor samples from patients with ESCC were collected. Immunohistochemistry was performed to detect the oxidative DNA damage and DNA double-strand breaks (DSBs). Significantly positive correlation was observed between degree of chronic inflammation and esophageal precursor lesions (rs = 0.37, P < 0.01). Immunohistochemical analysis showed that oxidative DNA damage level was positively correlated with the degree of chronic inflammation (rs = 0.21, P < 0.05). Moreover, the level of oxidative DNA damage positively correlated with histological severity (rs = 0.49, P < 0.01). We found that the extent of DSBs was progressively increased with inflammation degree (P < 0.01) and the progression of precancerous lesions (P < 0.001). Collectively, these findings provide evidence linking chronic inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Carcinogenesis; Carcinoma, Squamous Cell; Chronic Disease; Deoxyguanosine; Disease Progression; DNA Damage; Esophageal Neoplasms; Esophagus; Female; Genomic Instability; Histones; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged

Both internal and external oxidative stresses act on DNA and can induce carcinogenesis. 8-hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and it leads to transversion mutations and carcinogenesis. 8-OHdG is excision-repaired by 8-OHdG DNA glycosylase (OGG1). The purpose of this study is to clarify the effect of oxidative DNA damage and repair enzymes on esophageal carcinogenesis. The levels of 8-OHdG and OGG1 were immunohistochemically evaluated in resected specimens, including squamous cell carcinoma (SCC) in 97 patients with esophageal cancer. Higher levels of 8-OHdG in normal esophageal epithelium were associated with a higher smoking index (P = 0.0464). The 8-OHdG level was higher in cancerous areas than in normal epithelia (P = 0.0061), whereas OGG1 expression was weaker in cancerous areas than in normal epithelia (P < 0.0001). An increase of OGG1 expression in normal epithelium was observed as 8-OHdG levels increased (P = 0.0011). However, this correlation was not observed in cancerous areas. High OGG1 expression in the cytoplasm was related to deeper tumors (P = 0.0023), node metastasis (P = 0.0065) and stage (P = 0.0019). Oxidative DNA damage, which is attributable to smoking as well as disturbances in DNA repair systems, appears to be closely related to esophageal carcinogenesis and its progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Carcinoma, Squamous Cell; Deoxyguanosine; DNA Damage; DNA Glycosylases; DNA Repair Enzymes; Epithelium; Esophageal Neoplasms; Esophagus; Female; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Oxidative Stress; Smoking

Overexpression of peroxiredoxin 1 (Prx1) has been observed in numerous cancers including oral squamous cell carcinoma (OSCC). The precise molecular mechanism of up-regulation of Prx1 in carcinogenesis, however, is still poorly understood. The objective of this study is to investigate the relationship between Prx1 and hypoxia, and potential mechanism(s) of Prx1 in OSCC cell line SCC15 and xenograft model. We treated wild-type and Prx1 knockdown SCC15 cells with transient hypoxia followed by reoxygenation. We detected the condition of hypoxia, production of reactive oxygen species (ROS), and expression and/or activity of Prx1, heme oxygenase 1 (HO-1) and nuclear factor-kappa B (NF-κB). We found that hypoxia induces ROS accumulation, up-regulates Prx1, increases NF-κB translocation and DNA binding activity, and down-regulates HO-1 in vitro. In Prx1 knockdown cells, the expression level of HO-1 was increased, while NFκB translocation and DNA binding activity were decreased after hypoxia or hypoxia/reoxygenation treatment. Moreover, we mimicked the dynamic oxygenation tumor microenvironment in xenograft model and assessed the above indices in tumors with the maximal diameter of 2 mm, 5 mm, 10 mm or 15 mm, respectively. Our data showed that tumor hypoxic condition and expression of Prx1 are significantly associated with tumor growth. The expression of HO-1 and NF-κB, and NF-κB DNA binding activity were significantly elevated in 15 mm tumors, and the level of 8-hydroxydeoxyguanosine was increased in 10 mm and 15 mm tumors, compared to those in size of 2 mm. The results from this study provide experimental evidence that overexpression of Prx1 is associated with hypoxia, and Prx1/NF-κB/HO-1 signaling pathway may be involved in oral carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Carcinogenesis; Carcinoma, Squamous Cell; Deoxyguanosine; Gene Expression Regulation, Neoplastic; Heme Oxygenase-1; Homeodomain Proteins; Humans; Hypoxia; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Neoplasm Transplantation; NF-kappa B; Oxygen; Protein Transport; Reactive Oxygen Species; Signal Transduction; Tumor Burden; Tumor Microenvironment

Esophageal cancer is characterized by increased oxidative stress and the production of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is one of the main mutagenic modifications of DNA. We analyzed the predictive value of 8-OHdG expression on postoperative survival of patients with esophageal cancer with univariate and multivariate analysis. The high levels of 8-OHdG are associated with significantly shorter survival time by log-rank test using Kaplan-Meier methods. Moreover, the level of 8-OHdG expression was identified as an independent predictor for esophageal cancer outcome using Cox proportional hazards model analysis (relative risk, 0.294; 95% confidence interval, 0.178-0.487; P = .000). These results suggest that oxidative damage marker of 8-OHdG is a useful prognostic marker in esophageal cancer. The analysis of 8-OHdG levels can help in the identification of patient subgroups that are at high risk for poor disease outcomes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; China; Deoxyguanosine; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Postoperative Period; Survival Analysis; Treatment Outcome

The aim of this study was to evaluate oxidative stress status in the saliva of patients with oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC).. Thirty-two patients with OLP, 26 patients with OSCC, and 30 non-involved subjects were enrolled in this study. The study was conducted at the Cancer Department, Clinic of Oral Medicine, Tehran University of Medical Sciences. The unstimulated whole saliva malondialdehyde (MDA), as an indicator of lipid peroxidation, the total antioxidant capacity (TAC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were assayed by thiobarbituric acid, ferric reducing antioxidant potential (FRAP), and ELISA method, respectively. The TAC/MDA ratio was used as an index of oxidative stress status. Data were analyzed by ANOVA followed by the Tukey's post hoc test.. There were no significant differences in saliva TAC and MDA levels between OLP and control, and also between OLP and OSCC patients. MDA and 8-OHdG were significantly higher but TAC was lower in OSCC patients than control. TAC/MDA ratio was significantly lower in patients with OSCC than both OLP patients and control. TAC/MDA ratio was significantly lower but 8-OHdG was higher in patients with OLP compared to control. This suggests that patients with OLP and OSCC are more susceptible to an imbalance of antioxidant-oxidative stress status.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers; Carcinoma, Squamous Cell; Case-Control Studies; Deoxyguanosine; DNA Damage; Female; Free Radicals; Humans; Lichen Planus, Oral; Male; Malondialdehyde; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Oxidative Stress; Precancerous Conditions; Predictive Value of Tests; Reference Values; Risk Assessment; Saliva; Salivary Proteins and Peptides; Statistics, Nonparametric

To determine the possible role of oxidants and antioxidants in the pathogenesis of in laryngeal squamous cell carcinoma.. Our study involved patients with newly diagnosed laryngeal cancer (n = 29) and same age- and sex-matched healthy individuals (n = 21). Serum malondialdehyde (MDA) and paraoxonase (PON1) levels were measured by colorimetric methods and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) was measured using enzyme-linked immunosorbent assay in fasting blood samples of participants.. The levels of 8-OH-dG (control, 4.61 ± 1.27 ng/mL; patient, 11.70 ± 2.44 ng/mL; P < 0.001) and MDA (control, 4.16 ± 1.02 nmol/mL; patient, 8.74 ± 1.65 nmol/mL; P < 0.001) were significantly higher, and those of PON1 (control, 170.86 ± 72.46 U/mL; patient, 80.44 ± 29.81 U/mL; P < 0.001) were significantly lower in patients. There were no statistically significant differences in the 8-OH-dG, MDA levels, and PON1 activity in relation to T (tumor) staging of differentiation and different smoking/drinking status. There was a statistically significant difference in MDA levels (10.24 ± 0.64 nmol/mL) only in stage II laryngeal cancer. There were a statistically significant positive correlation between serum MDA and 8-OH-dG (r = 0.887, P < 0.001), a statistically significant negative correlation between serum MDA and serum PON1 (r = -0.477, P < 0.01), and a statistically significant negative correlation between serum 8-OH-dG and serum PON1 in patients (r = -0.420, P < 0.05).. We conclude that, in patients with laryngeal squamous cell carcinoma, the oxidant/antioxidant balance was impaired in favor of lipid peroxidation and DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Alcohol Drinking; Aryldialkylphosphatase; Carcinoma, Squamous Cell; Case-Control Studies; Cholesterol, HDL; Colorimetry; Deoxyguanosine; DNA Damage; Enzyme-Linked Immunosorbent Assay; Free Radical Scavengers; Humans; Indicators and Reagents; Laryngeal Neoplasms; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Neoplasm Staging; Oxidative Stress; Serum Albumin; Smoking; Spectrophotometry; Thiobarbituric Acid Reactive Substances

The hamster buccal pouch (HBP) carcinogenesis model is one of the most well characterized animal systems for analyzing the development of oral squamous cell carcinoma (OSCC), a common malignancy worldwide. HBP carcinomas that closely mimic human OSCC are useful in understanding the molecular mechanisms of neoplastic transformation. The present study is a comparative evaluation of markers of carcinogen activation, oxidative stress, cell proliferation, apoptosis, invasion, and angiogenesis in human and hamster OSCCs. Enhanced expression of CYP1A1 and CYP1B1 isoforms in both human and hamster oral tumours was associated with significantly increased expression of 8-hydroxy 2-deoxyguanosine (8-OHdG) indicating oxidative DNA damage. Analysis of markers of cell survival and proliferation revealed increased expression of PCNA, GST-P, and NF-kappaB with downregulation of p21, p53 and IkappaB in both human and hamster OSCCs. In addition, both human and hamster oral carcinomas displayed invasive, and angiogenic properties as revealed by dysregulated cytokeratin expression, downregulation of RECK, and increased expression of uPA, MMP-2 and-9, HIF-1alpha, and VEGF. The results reveal aberrant expression of multiple molecules in key signaling pathways in both human OSCCs and HBP carcinomas rendering the HBP model as an important tool for monitoring oral oncogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Animals; Apoptosis; Aryl Hydrocarbon Hydroxylases; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Proliferation; Cheek; Cricetinae; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Deoxyguanosine; DNA Damage; Humans; India; Male; Mesocricetus; Middle Aged; Models, Animal; Mouth Neoplasms; Oxidative Stress

Cigarette smoke is strongly associated with NSCLC, but the carcinogenesis of NSCLC is poorly understood.. To discover the role of oxidative stress and anti-oxidative defense in NSCLC, we measured NADPH oxidase (NOX) activity, myeloperoxidase activity, 8-OHdG, and glutathione content from lung specimens. These came from 32 patients: 22 NSCLC patients and ten controls without cancer.. In NSCLC patients, NOX activity was significantly higher both in the malignant (p = 0.001) and non-malignant (p = 0.044) samples from NSCLC patients, than in the control specimens. Myeloperoxidase activity was lower (p = 0.001) and glutathione content (p = 0.009) higher in malignant tissue. No significant difference was observable in 8-OHdG content between patient groups.. Increase in NOX activity in the malignant tissues was independent of smoking history and myeloperoxidase activity, suggesting its independent role in NSCLC pathogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antioxidants; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Case-Control Studies; Deoxyguanosine; Female; Glutathione; Humans; Lung Neoplasms; Male; Middle Aged; NADPH Oxidases; Oxidative Stress; Peroxidase; Smoking; Young Adult

Free radicals that induced lipid peroxidation and DNA damage have been implicated in many diseases including cancer. Cellular antioxidant defense plays an important role in neoplastic disease to counteract oxidative damage. This study aims to investigate the status of oxidative damage by measuring plasma malondialdehyde (MDA) level and urinary 8-hydroxydeoxyguanosine (8-OHdG), and the level of antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase in patients with cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC) of the cervix. Urinary 8-OHdG was measured by an enzyme-linked immunosorbent assay kit. MDA and antioxidant enzyme activities were determined by high-performance liquid chromatography and spectrophotometry, respectively. Eighty patients with CIN and SCC of the cervix were recruited and compared with normal controls. Urinary 8-OHdG/creatinine ratio did not show any significant changes in any disease status studied as compared with controls (P=0.803). Plasma MDA was found to be increased in CIN and SCC patients when compared with controls (P=0.002). Glutathione peroxidase activity was increased (P=0.0001) whereas superoxide dismutase and catalase activity was decreased (P=0.019 and 0.0001, respectively) in both CIN and SCC patients when compared with controls. Urinary 8-OHdG may not be a good marker for enhanced oxidative stress in cervical cancer. Oxidative damage as demonstrated by the level of MDA is markedly increased in CIN and SCC patients with changes of enzymatic antioxidants observed.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Carcinoma, Squamous Cell; Case-Control Studies; Catalase; DNA Damage; Female; Glutathione Peroxidase; Guanine; Hemoglobins; Humans; Malondialdehyde; Oxidative Stress; Superoxide Dismutase; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Evaluation of oxidative stress and diagnostic utility of its markers in oesophageal squamous cell carcinoma (OSCC).. Serum 8-hydroxydeoxyguanosine, thiobarbituric acid-reactive substances (TBARS) and total antioxidant status (TAS) were measured in OSCC (n=75), non-malignant oesophageal diseases (n=30), and healthy subjects (n=79). Three months following oesophagectomy the measurements were repeated.. Exclusively in OSCC, 8-hydroxydeoxyguanosine and TBARS were elevated. TAS was reduced in non-malignancies compared to controls, and in OSCC compared to non-malignancies and controls. Only 8-hydroxydeoxyguanosine was associated with disease progression, lymph node involvement in particular. All indices were good indicators of cancer presence (ROC analysis) and normalized following oesophagectomy. A positive linear relationship between 8-hydroxydeoxyguanosine and TBARS, and negative non-linear between TAS and both 8-hydroxydeoxyguanosine and TBARS was demonstrated.. OSCC is associated with oxidative stress, attenuated following oesophagectomy. Consumption of serum antioxidants prevents accumulation of oxidatively modified molecules in non-malignancies. High accuracy of oxidative stress markers in indicating cancer presence warrants further investigation on their possible application as discriminatory markers and in monitoring treatment efficacy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Biomarkers; Biomarkers, Tumor; Carcinoma, Squamous Cell; Deoxyguanosine; Diagnosis, Differential; Esophageal Diseases; Esophageal Neoplasms; Humans; Lymphatic Metastasis; Neoplasm Staging; Oxidative Stress; Radiography; Thiobarbituric Acid Reactive Substances

To cast light on mechanisms underlying development of urothelial carcinomas (UCs) of the urinary bladder associated with Schistosomiasis, we immunohistochemically analyzed the relationship between oxidative stress markers, DNA single strand breaks (ssDNA) which could also measure the levels of base damage and apoptosis in DNA, and expression of DNA repair genes with levels of nitric oxide synthases in bladder carcinomas of Egyptian patients with or without Schistosoma hematobium infection. Marked elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels was found in squamous cell carcinomas and UCs associated with Schistosomiasis when compared with non-Schistosomal carcinomas. This was accompanied by strong over expression of the DNA-repair genes, 8-oxoguanine-DNA-glycosylase and apurinic/apyrimidinic endonuclease, as well as increased formation levels of ssDNA. Expression levels of inducible nitric oxide synthase (iNOS) which is known to be indirectly related to oxidative stress was higher in Schistosomal than in the non-Schistosomal carcinomas. However, expression of endothelial nitric oxide synthase was slightly stronger in non-Schistosomal than in the Schistosomal carcinomas. In conclusion, these findings suggest a strong correlation between Schistosoma haematobium infection and increased levels of oxidative stress accompanied by a continuous DNA damage and repair in UCs, all directly correlating with elevated iNOS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Biomarkers, Tumor; Carcinoma; Carcinoma, Squamous Cell; Deoxyguanosine; DNA Damage; DNA Repair; Egypt; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Schistosomiasis haematobia; Up-Regulation; Urinary Bladder Neoplasms; Urothelium

Renal transplant patients are at a greatly increased risk of skin malignancy, particularly squamous cell carcinoma (SCC), a tumor closely associated with UV exposure. There is also significant interindividual skin cancer risk among transplant patients, with evidence suggesting that this derives from variation in response to oxidative stress. Our aim was to assess urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), by liquid chromatography-tandem mass spectrometry, in renal transplant patients with and without SCC. The relationships between SCC and urinary 8-oxodG were analyzed by conditional logistic regression and those between 8-oxodG and other candidate variables by linear regression, correcting for the effect of SCC. In SCC patients, urinary 8-oxodG was significantly elevated (p=0.03), both pre- and post-tumor development, compared to non-SCC transplant patients. Secondary analyses indicated that 8-oxodG was related to current heavy smoking (p=0.02) and darker skin type (p=0.02), but not measures of previous chronic sun exposure or current age and gender. Although subject numbers were limited, immunosuppression with azathioprine was positively associated with 8-oxodG in all patients combined (p=0.02). These results demonstrate, for the first time, that a subpopulation of renal transplant patients is under greater oxidative burden, and it is this population that is particularly predisposed to skin cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Azathioprine; Carcinoma, Squamous Cell; Case-Control Studies; Deoxyguanosine; Female; Heliotherapy; Humans; Immunosuppressive Agents; Individuality; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Oxidative Stress; Smoking

Oxidative stress is connected with activation of somatic mutations and rates of cell proliferation existing in cancer tissue. High level of reactive oxygen species is a mutagenic factor for DNA damage. Antioxidants are the components of the cellular defense mechanism against reactive oxygen molecules. The aim of our study was to analyze DNA peroxidation products' concentration and total antioxidant level in serum of the patients with esophageal squamous cell carcinoma before and after esophagectomy. We examined these parameters as markers of cancer development.. We tested 18 patients (2 woman and 16 men, mean age 59.4 years) with esophageal squamous cell cancer before and after esophagectomy and 12 healthy people as a control group. Concentrations of 8-OHdG and enzymatic antioxidants level were analyzed in serum. Data were statistically analyzed by Mann-Whitney test.. We observed statistically significant higher concentrations of 8-OHdG and significant lower levels of enzymatic antioxidants in the patients with cancer in comparison to the control group. After esophagectomy we observed normalization of these parameters. In four patients the level of total antioxidants was low and 8-OHdG concentration was high during the whole time of treatment. These patients had disease progression.. Estimation of serum 8-OHdG concentration and total antioxidant status may be helpful for monitoring cancer therapy in patients with esophageal squamous cell cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antioxidants; Carcinoma, Squamous Cell; Deoxyguanosine; DNA Damage; Esophageal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Models, Biological; Mutation; Reactive Oxygen Species; Treatment Outcome

Vulvar cancer represents an important medical problem worldwide whose incidence is increasing at an alarming rate in young females. Several factors have been linked to vulvar cancer development, but its exact pathogenesis remains to be determined. Vulvar tumorigenesis proceeds through intermediate dysplastic lesions, known as vulvar intraepithelial neoplasias, frequently associated with non-neoplastic epithelial disorders of the vulva, such as lichen sclerosus and squamous cell hyperplasia. In this study, the expression of the CDK inhibitor p27Kip1 and the extent of endogenous oxidative DNA damage were evaluated in vulvar specimens, including normal tissues, lichen sclerosus, squamous cell hyperplasia, vulvar intraepithelial neoplasias and invasive squamous cell carcinomas. We found that p27Kip1 was constantly expressed in normal vulvar epithelium cells while a progressive significant reduction in the percentage of p27Kip1-positive cells was observed in vulvar intraepithelial neoplasias (77%) and in invasive carcinomas (64%). Mean percentage of positive cells in invasive carcinomas, but not in vulvar intraepithelial neoplasias, was also significantly lower than squamous cell hyperplasia lesions (78%) while lichen sclerosus displayed a percentage of positive cells (45%) significantly lower than both vulvar intraepithelial neoplasias and invasive carcinomas. 8-hydroxydeoxyguanosine (8-OHdG) is considered a sensitive biomarker for oxidative stress. We observed a progressive significant increase in the levels of 8-OHdG and in the percentage of positive cells from normal vulvar epithelium to vulvar intraepithelial neoplasias (25%) and to invasive carcinomas (64%). Squamous cell hyperplasia displayed an intermediate percentage of positive cells comparable to vulvar intraepithelial neoplasias 2 but significantly higher than vulvar intraepithelial neoplasias 1 and lower than invasive carcinomas. Lichen sclerosus staining was significantly lower than carcinomas but higher than vulvar intraepithelial neoplasias and squamous cell hyperplasia. These results demonstrate that expression of p27Kip1 is downregulated while oxidative DNA damage increases from early non-neoplastic epithelial alterations through vulvar intraepithelial neoplasias to invasive vulvar carcinomas. Thus, both parameters might play an important role in the development of this cancer and their study might contribute to our understanding of human vulvar carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Deoxyguanosine; DNA Damage; Female; Humans; Hyperplasia; Immunohistochemistry; Lichen Sclerosus et Atrophicus; Middle Aged; Oxidative Stress; Vulva; Vulvar Neoplasms

Oxidative DNA damage plays an important role in carcinogens-induced carcinogenesis. 8-hydoxy-2deoxy-guanosine (8-OH-dG), a biomarker of oxidative DNA damage, plays important roles in initiation, progression, and prognosis of lung cancer, and closely relates with mutations of k-ras and p53 genes in carcinogenesis of lung tissue. This study was to detect protein expressions of 8-OH-dG, k-ras, and p53 genes in lung cancer tissues, and to analyze their values in distinguished diagnosis of lung cancer.. Protein levels of 8-OH-dG, k-ras, and p53 in pleural effusion cells from 53 patients with lung cancer, and 53 patients with other benign lung diseases were detected by immunocytochemistry.. Positive rates of 8-OH-dG, k-ras, and p53 protein in cancer group were significantly higher than those in benign disease group [75.5% (40/53) vs. 15.1% (8/53), P < 0.01; 64.2% (34/53) vs. 3.8% (2/53), P < 0.01; and 69.8% (37/53) vs. 18.9% (10/53), P < 0.01; respectively]. Protein levels of 8-OH-dG, k-ras, and p53 protein in cancer group were 1.68+/-1.21, 1.32+/-1.06, and 1.57+/-1.15,respectively. Rank correlation analysis showed that protein expression of 8-OH-dG positively correlated with those of k-ras (RS=0.643, P < 0.01), and p53 (RS=0.827, P < 0.01)u protein expression of k-ras positively correlated with that of p53 (RS=0.897, P < 0.01).. Protein expressions of 8-OH-dG, k-ras, and p53 are up-regulated in pleural effusion cells of lung cancer, and have mutual relations. They may be used as reference markers in diagnosing and screening for lung cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Deoxyguanosine; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, ras; Humans; Lung Neoplasms; Pleural Effusion, Malignant; ras Proteins; Tumor Suppressor Protein p53; Up-Regulation

Polymorphic genes for the peroxide scavenger glutathione peroxidase I (GPX1) and 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase/apurinic (AP) lyase (hOGG1) map to loci on chromosome 3p which are subject to frequent loss of heterozygosity (LOH) in lung tumours. Levels of the pro-mutagenic, oxidative DNA lesion 8-OHdG, were measured in 37 paired normal and tumorous lung specimens using HPLC with electrochemical detection. Lung tumours were also analysed for 3p LOH by fluorescent PCR with Genescan analysis. No significant difference was observed between 8-OHdG levels in tumour [7.7 +/- 6.7 (mean +/- SE) 8-OHdG/10(6) 2'-deoxyguanosine (dG)] and normal (8.1 +/- 8.8 8-OHdG/10(6) dG) lung tissue. Adduct levels in normal lung tissue DNA were not associated with constitutive hOGG1 genotype although there was a trend towards lower 8-OHdG levels in individuals possessing the ALA6 GPX1 polymorphism. Lung tumours exhibiting 3p LOH (40%) contained higher levels of 8-OHdG adducts (10.9 +/- 2.6 8-OHdG/10(6) dG) (P = 0.05) and lower GPX1 enzyme activity [45.5 nmol glutathione (GSH)/min/mg] (P = 0.09) when compared with tumours without LOH at these sites (5.55 +/- 0.87 8-OHdG/10(6) dG and 63.6 nmol GSH/min/mg, respectively). In conclusion, tumours with 3p LOH at loci associated with hOGG1 and GPX1 appear to have compromised oxidative defence mechanisms as measured by reduced GPX1 enzyme activity and elevated 8-OHdG levels and this may affect the prognosis of lung cancer patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Amino Acid Substitution; Carcinoma, Squamous Cell; Chromosomes, Human, Pair 3; Deoxyguanosine; DNA Adducts; DNA-Formamidopyrimidine Glycosylase; DNA, Neoplasm; Female; Genotype; Glutathione Peroxidase; Humans; Isoenzymes; Loss of Heterozygosity; Lung Neoplasms; Male; N-Glycosyl Hydrolases; Neoplasm Proteins; Oxidative Stress; Polymorphism, Genetic; Smoking

The objective of this study is to investigate if 8-methoxy-psoralen (8-MOP) plus ultraviolet A (UVA) radiation (PUVA) induces oxidative DNA damage. When calf thymus DNA was incubated with 8-MOP and irradiated with UVA (335-400 nm), the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was substantially increased by approximately 6-fold. Formation of 8-OHdG proportionally correlated with both UVA fluence and 8-MOP concentrations. Human epidermoid carcinoma cells were incubated with 10 microg 8-MOP per milliliter, followed by irradiation of 25 kJ/m2 UVA. The level of 8-OHdG increased by nearly 3-fold in PUVA-treated cells compared to 8-MOP and UVA controls. The formation of 8-OHdG correlated with DNA fragmentation as determined by spectrofluorometry. To investigate the reactive oxygen species (ROS) involved in PUVA-induced oxidative DNA damage, less or more specific ROS quenchers were added to DNA solution prior to PUVA treatment. The results showed that only sodium azide and genistein significantly quenched PUVA-induced 8-OHdG, whereas catalase, superoxide dismutase, and mannitol exhibited no effect. The quencher study with cultured cells indicated that N-acetyl-cysteine and genistein protected oxidative DNA damage as well as DNA fragmentation by PUVA treatment. Our studies show that PUVA treatment is able to induce the formation of 8-OHdG in purified DNA and cultured cells and suggest that singlet oxygen is the principle reactive oxygen species involved in oxidative DNA damage by PUVA treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Carcinoma, Squamous Cell; Cattle; Deoxyguanosine; DNA; DNA Damage; DNA Fragmentation; Humans; Methoxsalen; Reactive Oxygen Species; Thymus Gland; Tumor Cells, Cultured; Ultraviolet Rays

The objective of this study is to investigate if benzo[a]pyrene (BaP) and ultraviolet (UV) radiation synergistically induce oxidative DNA damage. Calf thymus DNA was incubated with BaP and irradiated with UVB (280-320 nm) and UVA (335-400 nm). BaP substantially enhanced the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) by UVA, but only moderately increased the level of 8-OHdG by UVB. Formation of 8-OHdG proportionally correlated with both UV dose and BaP concentration. Human epidermoid carcinoma cells were incubated with 10 microg of BaP/mL for 24 h and then exposed to 10 kJ/m2 UVB and 25 kJ/m2 UVA. UVB plus BaP did not affect the level of 8-OHdG in cultured cells, whereas UVA plus BaP substantially increased 8-OHdG by over 4-fold compared to BaP and UVA controls. To confirm what reactive oxygen species (ROS) are involved in BaP plus UVA-induced oxidative DNA damage, less or more specific ROS quenchers were added to DNA solution. The results showed that only superoxide dismutase and genistein significantly quenched BaP plus UVA-induced 8-OHdG, whereas catalase, sodium azide, and mannitol exhibited no effect. Our studies suggest that BaP enhances the formation of 8-OHdG in purified DNA and cultured cells by UVA, but not by UVB, and that superoxide anion plays an important role in the synergistic induction of oxidative DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Benzo(a)pyrene; Carcinoma, Squamous Cell; Cattle; Deoxyguanosine; DNA; DNA Damage; Dose-Response Relationship, Drug; Humans; Reactive Oxygen Species; Thymus Gland; Tumor Cells, Cultured; Ultraviolet Rays