Inhibition of oxidative DNA damage, 8-OHdG, and carbonyl contents in smokers treated with antioxidants (vitamin E, vitamin C, beta-carotene and red ginseng).

The chemopreventive effects of antioxidants (vitamin E, beta-carotene, vitamin C and red ginseng) on oxidative DNA and protein (globin) damages were comparatively investigated in the peripheral blood of smokers (> or = 20 cigarettes/day). Smokers showed a lower baseline level of plasma micronutrients (vitamin C and beta-carotene) (P < 0.01) and higher baseline level of oxidative DNA or protein damage than non-smokers (N = 5; P < 0.05). During daily supplementation of antioxidants (200 IU vitamin of E, 9 mg of beta-carotene, 500 mg of vitamin C, or 1.8 g of red ginseng) for 4 weeks, smokers plasma antioxidant concentrations increased linearly, while their mean levels of 8-hydroxydeoxyguanosine (8-OHdG) and carbonyl contents decreased compared with those in smokers supplemented with a placebo (P < 0.05). Levels of urinary and plasma cotinine remained steady in smokers regardless of supplementation with antioxidants. 8-OHdG and carbonyl content decreased in a time-dependent manner (as the total intake dose increased) after supplementation with vitamin E (8-OHdG, 33.8%; carbonyl content, 43.6%) or red ginseng (8-OHdG, 31.7%; carbonyl content, 21.3%). These preliminary data suggest that supplementation with antioxidants might protect smokers from oxidative damages and could reduce cancer risk or other diseases caused by free radicals associated with smoking.     

Antioxidant vitamin supplementation reduces benzo(a)pyrene-DNA adducts and potential cancer risk in female smokers.

BACKGROUND: Elevated benzo(a)pyrene [B(a)P]-DNA adducts have been associated with 3-fold increased risk of lung cancer in current smokers. We assessed the chemopreventive effects of antioxidant supplementation using B(a)P-DNA adducts in leukocytes as an intermediate cancer risk marker.METHODS: Subjects were randomized to a double-blinded placebo-controlled clinical trial of antioxidant vitamin supplementation [500 mg vitamin C and 400 IU vitamin E (dl-alpha-tocopherol) daily] or placebo. Smokers with > or =10 cigarettes per day and serum cotinine > or =25 ng/mL were eligible for the study. B(a)P-DNA adduct level was the outcome. The randomization was stratified by gender and cigarettes per day (< or =20 or >20). Smoking habits and blood samples were collected every 3 months during the 15-month treatment period. Samples were analyzed for B(a)P-DNA adducts (high-performance liquid chromatography), plasma cotinine, vitamin levels, and GSTM1 genotype. The intent-to-treat model adjusted for B(a)P-DNA and cotinine at randomization.RESULTS: Overall and among men, there was no effect of treatment on B(a)P-DNA adduct levels. Among treated women, B(a)P-DNA adducts decreased by 31% compared with women on placebo (P = 0.03). Among treated women with the GSTM1 genotype, there was a 43% decrease in adducts (P = 0.04).CONCLUSION: Our primary hypothesis that the mean level of smoking-related B(a)P-DNA adducts would be lower in all subjects in the vitamin treatment group compared with all placebo-treated subjects was not substantiated. However, oursecondary gender-specific analysis found a significant reduction in B(a)P-DNA adducts in women with vitamin treatment, suggesting that antioxidant supplementation maymitigate some of the procarcinogenic effects of exposuretoB(a)P. The effect in GSTM1-null women suggeststhat certain subgroups may derive more benefit fromsupplementation. Although the results of this trial showthe potential chemopreventive role of antioxidants, thebest way for smokers to reduce their cancer risk remains smoking cessation.     

Oxidative DNA damage and antioxidant vitamin level: comparison among lung cancer patients, healthy smokers and nonsmokers

In the present study, we examined whether the level of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) in leukocyte DNA is higher in lung cancer patients compared to controls. Factors that may influence oxidative stress, such as antioxidant vitamins, were also determined. These parameters were analyzed in 4 groups of subjects: smokers with lung cancer, ex-smokers with lung cancer, healthy smokers with comparable smoking status and healthy nonsmokers. The 8-oxodGuo mean level in leukocytes of lung cancer patients reached values of 9.22/10(6) dGuo molecules (smokers) and 11.16/10(6) dGuo molecules (ex-smokers). These values were significantly higher than in DNA of healthy smokers and nonsmokers, where mean levels reached 6.99/10(6) dGuo molecules and 5.98/10(6) dGuo molecules, respectively. Mean levels of vitamin C in the plasma of controls and lung cancer patients were 56.17 microM (nonsmokers), 26.34 microM (healthy smokers), 23.83 microM (cancer patients, smokers) and 29.19 microM (cancer patients, ex-smokers). The difference between nonsmokers and the 3 other groups was statistically significant. Vitamin E level was significantly reduced in the plasma of cancer patients (smokers 19.94 microM, ex-smokers 19.59 microM) compared to healthy smokers (28.93 microM). No changes in vitamin A concentration were found. Our results suggest that a high level of 8-oxodGuo in leukocyte DNA and a low concentration of vitamin E in the blood may predict lung cancer risk. However, it is also possible that these phenomena may simply result from disease development.     

Induction of preneoplastic lung lesions in guinea pigs by cigarette smoke inhalation and their exacerbation by high dietary levels of vitamins C and E

The development of effective chemopreventive agents against cigarette smoke-induced lung cancer could be greatly facilitated by the availability of suitable laboratory animal models. Here we report that male Hartley guinea pigs treated with cigarette smoke by inhalation twice a day for 28 days developed preneoplastic lung lesions, including bronchial hyperplasia, dysplasia and squamous metaplasia, analogous to those found in human smokers. The lesions were accompanied by increased expression of proliferating cell nuclear antigen and activation of the serine/threonine kinase Akt in the bronchial epithelium. In contrast, no lung lesions were found in guinea pigs ('sham smoked') that were submitted to identical procedures but without cigarettes. Compared with a diet low in vitamin C (50 p.p.m.) and vitamin E (15 p.p.m.), a diet high in vitamin C (4000 p.p.m.) and vitamin E (40 p.p.m.) significantly increased the incidence of these lesions. The inclusion of 1,4-phenylenebis(methylene)selenocyanate (p-XSC), a synthetic chemopreventive organoselenium compound, in the high vitamin C-high vitamin E diet at a level of 15 p.p.m. as selenium appeared to decrease the lesion incidence. Administration of (-)-epigallocatechin gallate, a powerful green tea polyphenolic antioxidant, at 560 p.p.m. in the drinking water had no effect. As in human smokers, levels of ascorbate in blood plasma, lung, liver and the adrenal glands were significantly decreased by cigarette smoke inhalation. These results identify a relevant in vivo laboratory model of cigarette smoke-induced lung cancer, suggest that p-XSC may have activity as a chemopreventive agent against cigarette smoke-induced lung lesions and provide additional evidence that very high dietary levels of certain antioxidants can have co-carcinogenic activity in cigarette smoke-induced lung cancer.     

Long-term cryoconservation and stability of vitamin C in serum samples of the European prospective investigation into cancer and nutrition.

Plasma vitamin C level may be associated with risk of some chronic diseases. The rapid degradability of vitamin C in biological samples necessitates its stabilization with metaphosphoric acid or similar agents. However, in most cohort studies, prospectively collected biological samples are not treated with stabilizing agents before long-term frozen storage and it is not known whether vitamin C can be properly measured in such samples. The objective of this study was to determine the degree of vitamin C degradation in plasma samples stored without stabilization for 7 to 11 years at -196 degrees C. Spearman's correlation coefficients indicate a moderate correlation between baseline and final plasma vitamin C levels in both men (r = 0.57, P < 0.0001) and women (r = 0.52, P < 0.0001). Samples were also categorized based on low or high baseline levels of plasma vitamin C, with the latter category showing the highest rate of loss per year of frozen storage in men (1.96 micromol/L, P value for difference <0.0001; percent loss 24.6%) and women (2.35 micromol/L, P value for difference <0.0001; percent loss 24.2%), as determined by multiple regression analysis adjusted for smoking status, age, and body mass index. In men, both baseline and final plasma vitamin C values were lower in smokers than never smokers, but for both men and women the rate of vitamin C loss during storage was not significantly different between smokers and never smokers. The results of this study show that vitamin C can be measured with reasonable reliability in plasma samples frozen for long periods of time without addition of any stabilizing agents.     

Effects of a 6-month vitamin intervention on DNA damage in heavy smokers.

Because their formation is associated with tumor development in specific tissues, DNA adducts have potential usefulness as intermediate end points in chemoprevention studies. To determine the efficacy of a combination of antioxidant vitamins (vitamins C and E and beta-carotene), a randomized clinical trial was conducted among heavy smokers using DNA damage as the end point. Immunological methods were used to measure polycyclic aromatic hydrocarbon-DNA adducts and oxidative DNA damage (8-oxo or hydroxydeoxyguanosine) in mononuclear and oral cells. A total of 121 subjects were randomized to the 6-month intervention and received either vitamins or placebo. Dropout rates were higher in the placebo than in the vitamin group; 65% of subjects in the vitamin group, but only 47% in the placebo group, provided specimens at 6 months. Plasma levels of all three antioxidants rose significantly in the vitamin group but not in the placebo group. All four measures of DNA damage decreased in both groups; the between-group differences were not statistically significant. These data do not provide clear evidence that antioxidant vitamin intake prevents DNA damage. However, the study demonstrates that DNA damage is a useful end point in chemoprevention trials.     

Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients

Background: Antioxidants protect the body against cellular oxidative damage and thus some of the adverse effects induced by cisplatin and other cytostatic drugs.Patients and methods: The effect of cisplatin-combination chemotherapy on concentrations of plasma antioxidants was studied in 36 cancer patients, including osteosarcoma and testicular carcinoma patients.Results: Eight to 15 days after the start of each cytostatic drug infusion concentrations of various plasma antioxidants were measured and compared to pretreatment values: vitamin C and E, uric acid and ceruloplasmin levels fell significantly (P < 0.01–0.005) and returned to baseline levels before the start of the next chemotherapy cycle. Levels of the antioxidants bilirubin, albumin and the ratio vitamin E/cholesterol + triglycerides measured three weeks after the start of chemotherapy significantly decreased compared to pretreatment levels and remained low thereafter (P < 0.001–0.002). Dietary intake of antioxidants and anthropometric measurements, evaluated in 14 patients did not change during the whole treatment period.Conclusions: Cisplatin-combination chemotherapy induces a fall in plasma antioxidant levels, that may reflect a failure of the antioxidant defense mechanism against oxidative damage induced by commonly used anticancer drugs. This probably results from consumption of antioxidants caused by chemotherapy induced-oxidative stress as well as renal loss of water-soluble, small molecular weight antioxidants such as uric acid.     

Overexpression of HER-2/neu protein attenuates the oxidative systemic profile in women diagnosed with breast cancer

About 20 % of breast cancer patients over-express the human epidermal growth factor receptor-2 (HER2), which is associated with enhanced tumor malignancy. The influence of HER2 overexpression on oxidant/antioxidant parameters in humans remains unknown; therefore, we investigated the oxidative profile in women according to their HER2 status. Fifty-two controls and 52 breast cancer (BC) patients were enrolled. The BC patients were subdivided into HER?, negative for HER2 overexpression, and HER+, positive for HER2 overexpression. Oxidative stress profilling was measured by malondialdehyde (MDA), free 8-isoprostane F2, protein carbonyl content, nitric oxide (NO), total radical antioxidant parameter (TRAP), superoxide dismutase (SOD), catalase activity, and glutathione (GSH) levels. Total thiol content and lipoperoxidation were evaluated in HCC1954 and MCF-7. Cells overexpressing HER2 presented enhanced oxidative stress. Increased erythrocyte lipoperoxidation was found in BC patients, while plasma lipoperoxidation was detected in both the BC and HER? groups. Decreased MDA levels were found in the HER+ group, suggesting that HER2 overexpression may protects against plasma lipoperoxidation. No alteration was found for 8-isoprostane F2, NO, and carbonyl content. TRAP was decreased in BC patients, while HER2 overexpression increased SOD and prevented decreased GSH levels. These data help to understand the HER2 overexpression in oxidative signaling and may enable the development of new strategies for anti-HER2 therapy.     

Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study

Cisplatin-induced toxicities are mainly caused by the formation of free radicals, leading to oxidative organ damage. Plasma concentrations of antioxidants decrease significantly during cisplatin chemotherapy for cancer. Forty-eight cancer patients treated with cisplatin-based chemotherapy were randomised in a double-blind manner to receive either supplementation with vitamin C, vitamin E and selenium dissolved in a beverage or to receive a placebo beverage. Primary outcome measures were the amount of nephrotoxicity and ototoxicity induced by cisplatin. No significant differences were found between the two study groups with respect to these primary outcome measures. However, patients who achieved the highest plasma concentrations of the three antioxidant micronutrients had significantly less loss of high-tone hearing. In addition, significant correlations were found between the reduced/oxidised vitamin C ratio and malondialdehyde (MDA), markers of oxidative stress, and cisplatin-induced ototoxicity and nephrotoxicity. The lack of protection against cisplatin-induced toxicities in patients in the intervention arm may be related to poor compliance and/or inadequate supplementation. Supplementation with a higher dose (intensity) and in combination with other antioxidants should be investigated further.     

Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study

Plasma vitamins C, E, retinol and carotene were measured in 1971–1973 in 2,974 men working in Basel Switzerland. In 1990, the vital status of all participants was assessed. A total of 290 men had died from cancer during the 17 years of follow-up, including 87 with lung cancer, 30 with prostate cancer, 28 with stomach cancer and 22 with colon cancer. Overall mortality from cancer was associated with low mean plasma levels of carotene (adjusted for cholesterol) and of vitamin C. Lung and stomach cancers were associated with a low mean plasma carotene level. After calculation of the relative risk, using the Cox model, with exclusion of mortality during the first 2 years of follow-up, simultaneously low levels of plasma carotene (below quartile I) and lipid-adjusted retinol were related to a significantly increased mortality risk for all cancers and for lung cancer. Simultaneously, low levels of plasma vitamin C and lipid-adjusted vitamin E also were associated with a significantly increased risk for lung cancer. Additionally, low vitamin E levels in smokers were related to an increased risk for prostate cancer. It is concluded that low plasma levels of the vitamins C, E, retinol and carotene are related to increased risk of subsequent overall and lung-cancer mortality and that low levels of vitamin E in smokers are related to an increased risk of prostate-cancer mortality. © 1996 Wiley-Liss, Inc.     

Oxidative DNA damage estimated by 8-hydroxydeoxyguanosine excretion in humans: influence of smoking, gender and body mass index.

Oxidative DNA damage may be implicated in ageing, carcinogenesis and other degenerative diseases. Oxidative DNA damage can be assessed in humans in vivo from the urinary excretion of the DNA-repair product 8-hydroxydeoxyguanosine (8OHdG). We investigated factors influencing the excretion of 8OHdG in 24 h urine from 83 randomly selected healthy subjects (52 women) aged 40-64 years. For 2 weeks prior to urine collection the subjects kept a weighed diet record. 8OHdG was quantified by an automatic three-dimensional HPLC analysis with electrochemical detection. The 8OHdG excretion was 252 +/- 103 (mean +/- SD) pmol kg body weight/24 h with a range from 78 to 527. Multiple regression analysis identified three factors, smoking, body mass index (BMI) and gender, as significant predictors of the 8OHdG excretion. In 30 smokers the 8OHdG excretion was 320 +/- 99 pmol/kg/24 h opposed to 213 +/- 84 pmol/kg/24 h in 53 non-smokers. According to multiple regression analysis smokers excreted 50% (31-69%; 95% confidence interval) more 8OHdG than non-smokers. In 52 women the 8OHdG excretion was 240 +/- 106 pmol/kg/24 h opposed to 271 +/- 96 pmol/kg/24 h in 31 men. According to the multiple regression analysis men excreted 29% (10-48%) more 8OHdG than women. According to multiple regression analysis the 8OHdG excretion decreased with 4% (2-6%) per increment in BMI measured in kg/m2. The dietary distribution of energy demonstrated no important predictive value with respect to 8OHdG excretion. The intake of the antioxidant vitamins C and E and of vitamin A equivalents, including beta-carotene, was not associated with 8OHdG excretion. The results suggest that smoking increases oxidative DNA damage by approximately 50%. This effect implies potential serious health effects adding to the other well-known health hazards of smoking. The higher 8OHdG excretion in men and lean subjects may be related to a higher rate of metabolism with increased availability of reactive oxygen species. The apparent 7-fold individual variation in oxidative DNA damage carries implications regarding the rate of ageing and the risk of cancer and other degenerative diseases. The excretion of 8OHdG into urine offers a valuable tool for testing such hypotheses in humans.     

A prospective cohort study on antioxidant and folate intake and male lung cancer risk.

Many studies have reported inverse associations between vegetable and fruit consumption and lung cancer risk. The aim of the present study was to elucidate the role of several antioxidants and folate in this relationship. In the Netherlands Cohort Study on Diet and Cancer, 58,279 men of ages 55-69 years at baseline in 1986 returned a questionnaire including a 150-item food frequency questionnaire. After 6.3 years of follow-up, 939 male lung cancer cases were registered. A new Dutch carotenoid database was used to estimate intake of alpha-carotene, beta-carotene, lutein + zeaxanthin, beta-cryptoxanthin, and lycopene, completed with the antioxidant vitamins C and E and folate. Using case-cohort analysis, rate ratios were calculated, adjusted for age, smoking, educational level, and family history of lung cancer. Protective effects on lung cancer incidence were found for lutein + zeaxanthin, beta-cryptoxanthin, folate, and vitamin C. Other carotenoids (alpha-carotene, beta-carotene, and lycopene) and vitamin E did not show significant associations. After adjustment for vitamin C, only folate remained inversely associated, and after adjustment for folate, only beta-cryptoxanthin and vitamin C remained significantly associated. Inverse associations were strongest among current smokers and weaker for former smokers at baseline. Inverse associations with carotenes, lutein + zeaxanthin, and beta-cryptoxanthin seemed to be limited to small cell and squamous cell carcinomas. Only folate and vitamin C intake appeared to be inversely related to small cell and squamous cell carcinomas and adenocarcinomas. Folate, vitamin C, and beta-cryptoxanthin might be better protective agents against lung cancer in smokers than alpha-carotene, beta-carotene, lutein + zeaxanthin, and lycopene.     

Epidemiologic assessment of sugars consumption using biomarkers: comparisons of obese and nonobese individuals in the European prospective investigation of cancer Norfolk.

We have previously shown that urinary sugars excretion in 24 h urine collections can serve as an independent biomarker of sugars consumption. In the European Prospective Investigation of Cancer (EPIC) Norfolk study of nutrition and cancer, this biomarker in spot urines has been assessed in a cross-sectional comparison of 404 obese individuals aged 45 to 75 years with a body mass index (BMI) of >30 kg/m(2) and 471 normal weight individuals aged 45 to 75 years with a BMI of <25 kg/m(2). In individuals of normal weight, sucrose, protein, and vitamin C intake were positively and highly significantly related to biomarkers in spot urine or plasma (P < 0.001), but there were no significant associations between biomarkers and food intake reports in the obese. Odds ratios for a BMI of >30 were significantly elevated for urinary sucrose [trend per milligram per liter quintile, 1.13; 95% confidence interval (95% CI), 1.02-1.25; P = 0.016], and the odds ratio for urinary sucrose/fructose ratio was highly significant (trend per quintile, 1.264; 95% CI, 1.142-1.401; P < 0.001). No associations for sugars intake and obesity were found using a food frequency questionnaire, and dietary vitamin C was apparently associated with increased risk (P < 0.001) despite an inverse association for plasma vitamin C. Nutritional biomarkers of consumption can complement existing methods for assessing cancer risk from diet in epidemiologic studies.     

Status of Oxidative Stress and Antioxidant Levels in Smokers with Breast Cancer from Western Nepal

Background: Research indicates that oxidative stress induced by smoking plays a role in breast cancer. Inview of these reports, we aimed to study th relationship between smoking and oxidative stress in breast cancerpatients from the western region of Nepal. Materials and Methods: The study included a control group of 42females (non-smoking healthy women) and a test group sudivided into Group I consisting of 46 female breastcancer patients who were smokers and Group II consisting of 42 non-smoking breast cancer patients. Detailedhistory of the patients was collected with the help of pre-test proforma. Plasma levels of malondialdehyde (MDA),total antioxidant activity (TAA) which represents total dietary antioxidants, vitamin C and α- tocopherol wereestimated by standard methods. Statistical analysis was done using SPSS version 16. Results: The plasma MDA,TAA, vitamin C and α- tocopherol were 1±1.4nmol/ml, 918±207μmol/L, 1±0.24mg/dL and 0.94±0.31mg/dL incontrols, 5±1.2nmol/ml, 458±166 μmol/L, 0.64±0.32mg/dL and 0.5±0.3mg/dL in Group-I and 2.56±1.2nmol/ml,663±178 μmol/L, 0.78±0.2mg/dL and 0.77±0.2mg/dL in Group- II, respectively. Vitamin C, α- tocopherol andTAA (p=0.001) were significantly reduced whereas MDA (p=0.001) was significantly raised in Group-I whencompared to controls and Group-II. Conclusions: We observed a significant rise in oxidative stress and lowlevels of antioxidants in breast cancer patients with smoking habit. It is well known that free radicals facilitatethe progression of breast cancer, possibly increasing the risk of progression to the next stage.     

Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials

PURPOSE: Much debate has arisen about whether antioxidant supplementation alters the efficacy of cancer chemotherapy. Some have argued that antioxidants scavenge the reactive oxygen species integral to the activity of certain chemotherapy drugs, thereby diminishing treatment efficacy. Others suggest antioxidants may mitigate toxicity and thus allow for uninterrupted treatment schedules and a reduced need for lowering chemotherapy doses. The objective of this study is to systematically review the literature in order to compile results from randomized trials that evaluate concurrent use of antioxidants with chemotherapy. DESIGN: MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases were searched. Only randomized, controlled clinical trials that reported survival and/or tumor response were included in the final tally. The literature searches were performed in duplicate following a standardized protocol. No meta-analysis was performed due to heterogeneity of tumor types and treatment protocols used in trials that met the inclusion criteria. RESULTS: Of 845 articles considered, 19 trials met the inclusion criteria. Antioxidants evaluated were: glutathione (7), melatonin (4), vitamin A (2), an antioxidant mixture (2), vitamin C (1), N-acetylcysteine (1), vitamin E (1) and ellagic acid (1). Subjects of most studies had advanced or relapsed disease. CONCLUSION: None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls; however, lack of adequate statistical power was a consistent limitation. Large, well-designed studies of antioxidant supplementation concurrent with chemotherapy are warranted.     

Evaluation of Plasma Non-enzymatic Antioxidants in Breast Cancer Etiology

Objective: Oxidative stress has emerged as a major etiological factor for breast cancer. Diet derivedantioxidants play an important role against oxidative stress and the aim of the present study was to examineroles of non-enzymatic antioxidants in breast cancer in India. Methods: Plasma non-enzymatic antioxidants;beta-carotene, vitamin A, vitamin E and vitamin C were analyzed spectrophotometrically from 70 healthy femalecontrols, 30 patients with benign breast diseases (BBD) and 125 untreated breast cancer patients (BCPT). Results:Plasma vitamin C levels were significantly lower in patients with BBD as compared to the controls (p=0.043).Plasma beta-carotene, vitamin E and vitamin C levels were significantly lower in BCPT as compared to thecontrols (p=0.0001, p=0.040 and p=0.0001, respectively). Plasma vitamin A levels were significantly higher inpatients with BBD and BCPT as compared to the controls (p=0.0001 and p=0.0001; respectively) and in BCPTas compared to patients with BBD (p=0.030). ROC curve analysis revealed that plasma beta-carotene and vitaminA could significantly discriminate between controls and patients with BBD (p=0.016 and p=0.000; respectively).Plasma beta-carotene, vitamin A, vitamin E and vitamin C could significantly discriminate between controlsand BCPT (p=0.000, p=0.000, p=0.001and p=0.001, respectively). Plasma vitamin E levels could significantlydiscriminate between patients with BBD and BCPT (p=0.055). Odds ratio analysis revealed that, increasinglevels of plasma beta-carotene, vitamin E and vitamin C were significantly associated with decreased risk ofbreast cancer (p=0.0001, p=0.003, and p=0.0001; respectively), whereas, increased risk was linked to plasmavitamin A (p=0.001). Conclusions: The trends of the current study provide interesting clues to the etiology ofbreast cancer and suggest significance of interplay of non-enzymatic antioxidants in breast cancer. Further indepthstudy is warranted to elucidate role of these antioxidants as a preventive measure.     

Determinants of plasma ascorbic acid in a healthy male population.

The antioxidant properties of vitamin C may be involved in the prevention of cancer. The correlation between dietary vitamin C intake as estimated by a dietary questionnaire and plasma ascorbic acid (AA) was examined in 68 nonsmoking male volunteers aged 30-59 years. Determinants of plasma AA as well as interrelationships between various antioxidants in plasma were also explored. The determinants of plasma AA were examined by a multiple regression model containing dietary vitamin C, calories, body weight, and amount of beverages consumed. Higher vitamin C intake (P < 0.0002) increased plasma AA, while greater body weight (P < 0.005) decreased plasma AA. A significant correlation (r = 0.43; P < 0.0003) between vitamin C intake and plasma AA was observed. There was a negative correlation between plasma AA and plasma uric acid (r = -0.32; P < 0.007) and positive associations between plasma beta-carotene and plasma alpha-tocopherol (r = 0.39; P < 0.001) and between plasma beta-carotene and plasma glutathione peroxidase (r = 0.32; P < 0.008). Vitamin C supplement users had higher plasma AA compared to nonusers. The relationship between plasma AA and vitamin C intake appears to be curvilinear with the non-supplement users at the linear part of the curve and the supplement users at the plateau. Plasma AA is an appropriate biomarker, in our subjects, of dietary vitamin C except for people consuming large amounts of this vitamin either in their diet or in supplemental form.     

Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours

Vitamin C (ascorbate) is toxic to tumour cells, and has been suggested as an adjuvant cancer treatment. Our goal was to determine if ascorbate, in combination with other antioxidants, could kill cells in the SW620 hollow fibre in vitro solid tumour model at clinically achievable concentrations. Ascorbate anti-cancer efficacy, alone or in combination with lipoic acid, vitamin K3, phenyl ascorbate, or doxorubicin, was assessed using annexin V staining and standard survival assays. 2-day treatments with 10 mM ascorbate increased the percentage of apoptotic cells in SW620 hollow fibre tumours. Lipoic acid synergistically enhanced ascorbate cytotoxicity, reducing the 2-day LC(50)in hollow fibre tumours from 34 mM to 4 mM. Lipoic acid, unlike ascorbate, was equally effective against proliferating and non-proliferating cells. Ascorbate levels in human blood plasma were measured during and after intravenous ascorbate infusions. Infusions of 60 g produced peak plasma concentrations exceeding 20 mM with an area under the curve (24 h) of 76 mM h. Thus, tumoricidal concentrations may be achievable in vivo. Ascorbate efficacy was enhanced in an additive fashion by phenyl ascorbate or vitamin K3. The effect of ascorbate on doxorubicin efficacy was concentration dependent; low doses were protective while high doses increased cell killing.     

Non-steroidal anti-inflammatory drug (NSAID) use and levels of a lipid oxidation marker in plasma and nipple aspirate fluids

Summary Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to reduce cancer risk by inhibiting cyclo-oxygenases, resulting in deceased formation of inflammatory mediators and oxidative stress. We examined whether the level of one oxidative stress marker, 15-F_2t-isoprostane, was affected by NSAID use in plasma and breast nipple aspirate fluids (NAF) of pre-menopausal women who were participating in a dietary intervention trial (n=121). Baseline levels of 15-F_2t-isoprostane were lower in NSAID users than non-users in both NAF and plasma, although the differences did not persist after intervention. Over the duration of the study, information on NSAID use was collected five times, and average 15-F_2t-isoprostane levels in both NAF and plasma exhibited a statistically significant trend for decreases with increased frequency of NSAID use. These results indicate that NSAID use can result in lower levels of 15-F_2t-isoprostane, which may have implications for the effects of NSAID use on breast cancer risk.     

Association of selenium, tocopherols, carotenoids, retinol, and 15-isoprostane F2t in serum or urine with prostate cancer risk: the multiethnic cohort

Objective  We examine the association of antioxidants and 15-isoprostane F_2t with risk of prostate cancer. Methods  We conducted a nested case–control study of serum antioxidant biomarkers (selenium, tocopherols, carotenoids, and retinol) and a urinary oxidation biomarker (15-isoprostane F_2t) with risk of prostate cancer within the Multiethnic Cohort. Demographic, dietary, and other exposure information was collected by self-administered questionnaire in 1993–1996. We compared prediagnostic biomarker levels from 467 prostate cancer cases and 936 cancer free controls that were matched on several variables. Multivariate conditional logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results  We observed that there was no overall association of serum concentrations of antioxidants and urinary concentrations of 15-isoprostane F_2t with risk of prostate cancer or risk of advanced prostate cancer. However, we did observe an inverse association for serum selenium only among African-American men (p trend = 0.02); men in the third tertile of selenium concentrations had a 41% lower risk (95% CI: 0.38–0.93) of prostate cancer when compared to men in the first tertile. Conclusions  Overall, our study found no association of serum antioxidants or 15-isoprostane F_2t with the risk of prostate cancer. The observed inverse association of selenium with prostate cancer in African-Americans needs to be validated in other studies. This work was performed at the Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii.