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Approaches and Methods to Measure Oxidative Stress in Clinical Samples: Research Applications in the Cancer Field

Meghri Katerji, Maria Filippova, Penelope Duerksen-Hughes

Oxidative Medicine and Cellular Longevity · 2019 · Review

doi:10.1155/2019/1279250

Abstract

Reactive oxygen species (ROS) are common by-products of normal aerobic cellular metabolism and play important physiological roles in intracellular cell signaling and homeostasis. The human body is equipped with antioxidant systems to regulate the levels of these free radicals and maintain proper physiological function. However, a condition known as oxidative stress (OS) occurs, when ROS overwhelm the body’s ability to readily detoxify them. Excessive amounts of free radicals generated under OS conditions cause oxidative damage to proteins, lipids, and nucleic acids, severely compromising cell health and contributing to disease development, including cancer. Biomarkers of OS can therefore be exploited as important tools in the assessment of disease status in humans. In the present review, we discuss different approaches used for the evaluation of OS in clinical samples. The described methods are limited in their ability to reflect on OS only partially, revealing the need of more integrative approaches examining both pro- and antioxidant reactions with higher sensitivity to physiological/pathological alternations. We also provide an overview of recent findings of OS in patients with different types of cancer. Identification of OS biomarkers in clinical samples of cancer patients and defining their roles in carcinogenesis hold great promise in promoting the development of targeted therapeutic approaches and diagnostic strategies assessing disease status. However, considerable data variability across laboratories makes it difficult to draw general conclusions on the significance of these OS biomarkers. To our knowledge, no adequate comparison has yet been performed between different biomarkers and the methodologies used to measure them, making it difficult to conduct a meta-analysis of findings from different groups. A critical evaluation and adaptation of proposed methodologies available in the literature should therefore be undertaken, to enable the investigators to choose the most suitable procedure for each chosen biomarker.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen that play several beneficial roles for the organism. At low/moderate concentrations, they are needed for physiological activities such as intracellular cell signaling and homeostasis, cell death, immune defense against pathogens, and induction of mitogenic response. These free radicals are produced endogenously as a natural by-product of the normal cellular metabolism of oxygen. Additionally, they can be induced by exogenous sources such as UV light, ionizing radiation, lifestyle, diet, stress, and smoking. Maintaining equilibrium between the reducing and oxidizing states is crucial for proper physiological functions; therefore, living organisms are equipped with antioxidant defense systems, consisting of both enzymatic and nonenzymatic antioxidants, to regulate the levels of these free radicals.

An imbalance between the production of ROS and the ability of the antioxidant systems to readily detoxify these reactive intermediates results in oxidative stress. Free radicals generated in excessive and uncontrollable amounts under oxidative stress conditions cause damage to DNA, proteins, and lipids, which can severely compromise cell health and contribute to disease development. Indeed, in the past years, considerable research has demonstrated that oxidative stress is involved in the natural process of aging as well as a wide variety of human diseases, including neurodegenerative disorders, multiple sclerosis, cardiovascular disease, rheumatoid arthritis, and cancer. Consistent with this relationship between oxidative stress and human disease, numerous studies have suggested that an increase in dietary antioxidant intake reduces the risk for coronary heart disease, Alzheimer's disease, Parkinson disease, ischemic stroke, and asthma.

Biomarkers of oxidative stress are therefore important tools in the assessment both of disease status and of the health-enhancing effects of antioxidants in humans. In this review, we aim to discuss different methods and approaches used for the evaluation of oxidative stress in clinical samples, as well as to review recent findings of oxidative stress in patients with different types of cancer.

2.1. Direct Measurement of Reactive Oxygen Species

Reactive oxygen species (ROS) are the key molecules responsible for the deleterious effects of oxidative stress. Direct measurement of their cellular levels is therefore one approach to determine oxidative stress conditions.

One way to estimate the cellular levels of ROS is through the use of fluorogenic probes. Hydrogen peroxide (H2O2), hydroxyl radicals (OH−), and peroxyl radicals (ROO−) can be measured following staining with 5-(and -6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (DCFDA). This membrane-permeable probe diffuses into the cells where it becomes hydrolyzed by intracellular esterase to DCFH. The latter remains trapped within the cells and reacts with H2O2, generating the fluorescent 2′,7′-dichlorofluorescein (DCF). Therefore, the amount of peroxide produced by the cells can be estimated by the fluorescence intensity of DCF (λexcitation = 488 nm and λemission = 530 nm) as analyzed by flow cytometry or by employing a fluorescence plate reader. On the other hand, superoxide molecules (O2−) can be detected following staining with another fluorescent probe, dihydroethidium (DHE). The sodium borohydride-reduced form of ethidium bromide is also permeable to viable cells. Inside the cells, DHE is directly oxidized to ethidium bromide by the superoxide anion, which then fluoresces. The red fluorescence, measured using an excitation of 488 nm and an emission of 585 nm, is therefore considered to be proportional to the intracellular superoxide anion levels. Another way to quantify ROS molecules such as hydroperoxides (R-OOH), particularly in serum, is by assessing the derivatives of reactive oxygen metabolites (D-Roms) test, as described by Trotti et al.. In this assay, a small amount of patient serum is dissolved in an acetate-buffered solution (pH 4.8). Transition metal ions (Fe2+, Fe3+), liberated from the proteins in the acidic medium, react with hydroperoxide groups converting them into alkoxy (R-O•) and peroxy (R-OO•) radicals by way of the Fenton reaction. These newly formed radicals become trapped chemically with a chromogen (N,N-diethyl-para-phenylendiamine) leading to the formation of the corresponding radical cation. The concentrations of these newly formed radicals, which are directly proportional to those of the peroxides present in serum, are then determined by spectrophotometric procedures at an absorption of 505 nm.

2.2. Assessment of Oxidative Damage

Direct measurement of ROS levels with high accuracy and precision is difficult due to their short lifespan and rapid reactivity with redox state regulating components. While peroxyl radicals and hydrogen peroxide are relatively stable molecules (with half-lives of seconds to minutes), hydroxyl radicals are very reactive (having a half-life of less than a nanosecond). Therefore, indirect measurement of ROS by examining the oxidative damage these radicals cause to the lipids, proteins, and nucleic acids of the cells is a promising alternative approach to assess oxidative stress in clinical samples.

2.2.1. Protein Damage

Protein carbonyl (PC) content is a commonly used marker of oxidative modification of proteins, providing significant evidence of oxidative stress in clinical samples. PCs are generated due to the oxidation of protein backbones and amino acid residues such as proline, arginine, lysine, and threonine by ROS molecules. The oxidized proteins can be measured using the 2,4-dinitrophenylhydrazine (DNPH) method as described by Levine et al., and simplified by Mesquita et al.. In this assay, DNPH reacts with PCs, forming a Schiff base to produce dinitrophenylhydrazone products, the levels of which can be analyzed spectrophotometrically at 375 nm and correlated to the levels of oxidized proteins. Alternatively, PC contents can be identified by 2D gel electrophoresis and western blot, or by OxyBlot according to Butterfield et al..

The detection of advanced oxidation protein products (AOPP), according to Witko-Sarsat et al., is another approach to assess protein oxidation in clinical samples. AOPP, also defined as dityrosine containing cross-linked protein products, are generated through the reaction of plasma proteins with chlorinated oxidants such as chloramines. In this method, plasma or serum of patients, calibrated with chloramine-T, is mixed with potassium iodide and acetic acid and the absorbance is spectrophotometrically read at 340 nm.

2.2.2. Lipid Damage

Lipid peroxidation has been commonly used as an indicator of ROS-mediated damage to cell membranes. Malondialdehyde (MDA) is one of the best studied end-products of peroxidation of polyunsaturated fatty acids in clinical samples and is frequently used to estimate oxidative stress conditions. The levels of MDA can be measured using thiobarbituric acid reactive substances (TBARS) as described by Donnan, Yagi, Mihara and Uchiyama, Buege and Aust, Ohkawa et al., or Yoshioka et al.. In all these methods, MDA reacts with TBARS in acidic medium at 100°C to generate a pink/red-colored product which can be extracted with butanol and measured using a spectrophotometer at an absorbance of 520-535 nm or by a fluorimeter at λexcitation = 515 nm and λemission = 555 nm. The TBARS method is rapid and easy; however, aldehydes other than MDA may also react with TBARS, producing derivatives that absorb light in the same wavelength range. Alternatively, plasma MDA can be measured using high-performance liquid chromatography (HPLC) employing a C18 reversed-phase column as described by Victorino et al. or by gas chromatography-mass spectrometry (GC-MS) on a capillary column following transmethylation with sodium methoxide. While this method determines MDA levels more reproducibly and reliably, the individual sample processing makes it time-consuming, labor-intensive, and impractical.

Other lipid peroxidation markers include 8-iso-prostaglandin F2α (8-iso-PGF2α), 4-hydroxy-2-nonenal (4-HNE), conjugated dienes (CD), and lipid hydroperoxides (LOOH), providing different reliable approaches for the identification of oxidative damage to the cell's lipids. 8-Iso-PGF2α, generated as a result of nonenzymatic peroxidation of arachidonic acid in membrane phospholipids, can be measured using rapid ultra-high-performance liquid chromatography-tandem mass spectrometry, noting the limitations of being labor-intensive and requiring specialized and expensive instrumentation. Unsaturated hydroxyalkenal 4-HNE can be investigated in tissues, preferably using immunohistochemistry (IHC), or HPLC. CDs, produced as a consequence of free radical-induced autoxidation of polyunsaturated fatty acids (PUFAs), can be detected according to Suryanarayana Rao and Recknagel, which follows the maximal absorption of UV light at 233 nm by these compounds. Finally, LOOHs, which are the primary oxidation products of PUFAs, can be determined by the ferrous oxidation xylenol orange (FOX) assay, based on the ability of LOOH to oxidize ferrous iron in the presence of xylenol orange, leading to the formation of a colored ferric-xylenol orange complex, with an absorbance at 560 nm.

Oxidized levels of low-density lipoproteins (LDL) are also sometimes measured in human serum or plasma as established biosensors of oxidative stress, using a sandwich ELISA based on the proprietary mouse monoclonal antibody 4E6, which is directed against a conformational epitope in oxidized ApoB-100. However, this method may fall short on antibody specificity for oxLDL as native LDL may also be detected.

2.2.3. DNA Damage

8-Hydroxy-2′-deoxyguanosine (8-OHdG) is one of the major oxidative modifications in DNA that is generated by hydroxylation of the deoxyguanosine residues. 8-OHdG residues can be excised from the DNA by enzymatic repair systems, leading to their circulation in the blood and subsequent excretion in the urine. Levels of 8-OHdG in blood and/or urine of patients can therefore be measured as a marker of oxidative DNA damage. 8-OHdG is frequently examined using HPLC coupled with an electrochemical detector (ECD) based on the procedures elaborated by Shigenaga et al., Toyokuni et al., or Helbock et al.. In spite of its sensitivity and accuracy, the HPLC-ECD method is not very convenient for analyzing 8-OHdG contents in clinical samples because of its cost, technical involvement, and low throughput. Alternative and simpler ways to measure this DNA damage marker include the enzyme-linked immunosorbent assay (ELISA) and immunohistochemical analysis. 8-oxodG can also be identified by OxyDNA-FITC conjugate binding followed by analysis by flow cytometry for fluorescence at λexcitation = 495 nm and λemission = 515 nm.

Thymidine glycol (TG) is another principal DNA lesion caused by oxidative stress. TG is a more specific marker for oxidative DNA damage because thymidine, unlike guanosine, is not incorporated into RNA. Moreover, TG is sustained in tissues while 8-OHdG is rapidly excised from DNA and excreted in urine. Therefore, TG is an appropriate marker for oxidative DNA damage in tissue specimens. Accumulation of TG in tissues can be examined immunohistochemically using the streptavidin-biotin-peroxidase complex method.

Single- or double-stranded breaks within the DNA are also generated during oxidative stress conditions. These oxidative DNA lesions can be identified using the comet assay, which is based on the ability of cleaved DNA fragments to migrate out of the nucleus when an electric field is applied, unlike the undamaged DNA which migrates slower and remains within the nucleoid. Assessment of the DNA “comet” tail shape and migration pattern can therefore be used to evaluate DNA damage within cells.

More generally, various modified DNA bases in clinical samples can also be measured using gas chromatography-mass spectrometry with selected ion monitoring (GC/MS-SIM) as described by Dizdaroglu. Here, the quantification of these products is done by isotope-dilution mass spectrometry using their stable isotope-labeled analogues as internal standards.

It is worth mentioning that the DNA base modifications detected with all these methods, although very important, do not provide information as to whether the damage is in active genes or in quiescent DNA. However, it seems likely that the “exposed” and active DNA would be more sensitive to oxidative damage than that packaged into condensed chromatin.

Alternatively, DNA repair enzymes, such as human 8-oxoguanine-DNA-glycosylase (hOGG) and apurinic/apyrimidinic endonuclease (APE), which repair the endogenous DNA damage induced by increased ROS levels, can be evaluated to estimate oxidative damage in clinical samples. Their levels can be determined by IHC analysis or HPLC while the activity of the hOGG enzyme can be assessed according to the method of Yamamoto et al., which uses a double-stranded 22 bp oligonucleotide substrate containing one 8-OHdG paired with deoxycytidine at the complementary strand and labeled with FITC.

2.3. Assessment of Antioxidant Status

The human body is equipped with an antioxidant system that serves to counterbalance the deleterious effects of oxidative free radicals. When the balance between antioxidants and ROS species, referred to as redox homeostasis, is disturbed, oxidative stress can occur. The disturbance of this prooxidant and antioxidant balance can be a result of increased free radical production, antioxidant enzyme inactivation, or excessive antioxidant consumption. Assessment of the antioxidant status can thereby be correlated to the extent of oxidative stress in clinical samples.

Redox homeostasis is regulated by two arms of antioxidant machineries: enzymatic components and nonenzymatic, low molecular compounds. Several approaches have been developed to measure the different activities or levels of these antioxidants. Alternatively, the total antioxidant status can be evaluated to assess the oxidative state of clinical samples.

2.3.1. Enzymatic Antioxidants

(1) Superoxide Dismutase. Superoxide dismutase (SOD) is a family of antioxidant enzymes that regulate ROS levels by catalyzing the conversion of superoxide to hydrogen peroxide and molecular oxygen.

Their total activity can be determined using a method described by McCord and Fridovich or Misra and Fridovich. The basis of this method is the ability of SOD to inhibit the autoxidation of adrenaline to adrenochrome in a basic medium, which can be measured at an absorption of λ = 480 nm. Another method to directly measure the activity of SOD has been established by Marklund and Marklund and described by Roth and Gilbert and is based on a similar principle. Instead of epinephrine autoxidation, their method conversely investigates the ability of SOD to inhibit the autoxidation of pyrogallol into a yellow solution that can be measured at an absorbance of 420 nm.

Alternatively, SOD activity can be measured using indirect methods developed by Nishikimi et al. & Kakkar et al. or Oyanagui (1984) & Sun et al. (1988). The principle of this indirect method is that superoxide radicals, generated by the NADH/D-amino acid oxidase-phenazine methosulfate (PMS) system or the xanthine-xanthine oxidase system, respectively, cause the reduction of tetrazolium salts such as 2-(4-idophenyl) 3-(4-nitrophenol)-5-phenyltetrazolium (INT), 3′-{1-[(phenylamino)-carbonyl]-3,4-tetrazolium}-bis (4-methoxy-6-nitro)benzenesulfonic acid (XTT), or nitro blue tetrazolium (NBT), into blue formazan which can be measured spectrophotometrically at 470-560 nm. The SOD in the samples competes for the generated superoxide radicals, thereby inhibiting the reaction of tetrazolium reduction. In all the methods discussed above, a unit of SOD is generally defined as the amount of the enzyme which causes inhibition of the reaction (autoxidation of adrenaline, autoxidation of pyrogallol, or tetrazolium reduction).

It is worth noting that these methods can also be applied following a separation step in sample preparation to determine the different activities of the three SOD isoforms (cytosolic Cu/Zn-SOD, mitochondrial MnSOD, and extracellular EC-SOD). Due to its affinity to heparin, EC-SOD can be separated from the intracellular isoforms by passing the samples over a concanavalin A sepharose column. On the other hand, applying differential centrifugation to the samples results in a mitochondrial pellet and cytosolic supernatant, which can be used to assess the separate activities of MnSOD and Cu/Zn-SOD, respectively. The selective measurement of MnSOD activity can also be achieved by the addition of sodium cyanide to the samples to inhibit the Cu/Zn-SOD isoform.

(2) Catalase. Catalase is a ubiquitously expressed antioxidant enzyme that is responsible for the degradation of hydrogen peroxide into water and oxygen. Numerous methods have been designed to assess the activity of this antioxidant in biological samples. A quantitative spectrophometric method, developed by Beers and Sizer and described by Nelson and Kiesow or Aebi, follows the breakdown of hydrogen peroxide catalyzed by catalase, by observing the decrease in ultraviolet absorbance of a hydrogen peroxide solution at λ = 240 nm as a function of time. Another simple colorimetric assay based on the utilization of hydrogen peroxide by catalase using the K2Cr2O7/acetic acid reagent has been described by Sinha. When heated in the presence of hydrogen peroxide, the dichromate in acetic acid reduces to chromic acetate, which can be measured colorimetrically at 610 nm. In both these methods, the catalase activity is determined by the disappearance of hydrogen peroxide and each unit is therefore defined as the amount that degrades 1 μmol of hydrogen peroxide per minute. Alternatively, the activity of the catalase enzyme can be determined using another spectrophotometric assay developed by Goth, which measures the stable complex formation of hydrogen peroxide with ammonium molybdate at an absorbance of 405 nm.

In contrast to the previously discussed assays, the method developed by Johansson and Håkan Borg determines the activity of catalase using its peroxidatic function of alcohol oxidation. In this method, the formaldehyde, generated by the reaction of catalase with methanol in the presence of an optimal concentration of hydrogen peroxide, is measured spectrophotometrically at λ = 550 nm with purpald reagent (4-amino-3-hydrazino-5-mercapto-1,2,4-triazole) as a chromagen.

(3) Glutathione Peroxidase. Glutathione peroxidase (GPx) is another antioxidant enzyme that catalyzes the reduction of hydrogen peroxide and lipid peroxides to water and their corresponding lipid alcohols via the oxidation of reduced glutathione (GSH) into glutathione disulfide (GSSG). Its activity can be assessed by the method of Rotruck et al., as described by Hafeman et al., in which the samples are incubated with hydrogen peroxide in the presence of glutathione for a particular time period. The amount of utilized hydrogen peroxide is then determined by directly estimating GSH content using Ellman's reagent, 5,5′-dithiobisnitrobenzoic acid (DTNB) (discussed in Section ). Another method developed by Kokatnur and Jelling and later described by Paglia and Valentine and Pleban et al. relies on a similar principle, with GPx catalyzing the oxidation of glutathione by cumene hydroperoxide (for selenium-independent GPx) or hydrogen peroxide (for selenium-dependent GPx). However, in this method, the oxidized glutathione is later reduced by exogenous glutathione reductase causing the coenzyme of the reaction, NADPH, to become oxidized into NADP+. The change in the absorbance can then be read spectrophometrically at λ = 340 nm.

(4) Glutathione S-Transferase. Glutathione S-transferases (GSTs) are members of the multigene family of isoenzymes that are ubiquitously expressed in humans. In addition to their catalytic role in conjugating GSH to a variety of harmful electrophilic compounds for detoxification, a number of GST isoenzymes reduce lipid hydroperoxides through their selenium-independent GPx activity and detoxify lipid peroxidation end-products such as 4-HNE. Their activity is most commonly determined by the method of Habig et al., which is based on the ability of GST to conjugate 1-chloro-2,4-dinitrobenzene (CDNB) to reduced glutathione. The conjugation is accompanied by an increase in absorbance at 340 nm which can be measured spectrophometrically to directly estimate the level of GST activity in clinical samples.

2.3.2. Nonenzymatic Antioxidants

(1) Glutathione. Inside the cell, free glutathione can exist as the reduced GSH and oxidized GSSG forms, although it is primarily maintained in the former state by glutathione reductase. GSH is the most abundant intracellular low-molecular-weight thiol and plays a critical role in metabolic protective functions, including hydroperoxide reduction, xenobiotic detoxification, and free radical scavenging. The levels of GSH are commonly determined by the method developed by Ellman and described by Beutler et al., Sedlak and Lindsay, or Hu, based on the ability of the Ellman reagent, DTNB, to react with compounds containing sulfhydryl groups, yielding a mixed disulfide (GS-TNB) and 2-nitro-5-thiobenzoic acid (TNB). The levels of the latter are quantified spectrophometrically by measuring the absorbance of the anion (TNB2-) at 412 nm using a molar extinction coefficient of 14,150 M−1 cm−1. This method has been modified by Tietze using an enzymatic recycling procedure by glutathione reductase to enhance the sensitivity of the assay and to measure instead the total glutathione content of the biological samples. In this method, the NADPH-dependent glutathione reductase of the recycling system subsequently reduces the generated GS-TNB, releasing a second TNB molecule and recycling GSH, thereby amplifying the response. In addition, any GSSG, present in the samples or formed during the reaction, is also reduced to GSH by glutathione reductase. Therefore, the glutathione concentration of the sample measured at an absorbance of 415 nm would account for both GSH and GSSG levels.

Alternatively, the level of GSH can be determined using the GSH-400 method, based on a two-step chemical reaction followed by a spectrophotometric detection. First, 4-chloro-7-trifluoromethylbenzopyridine reacts with all mercaptans present in the sample to form substitution products (thioethers). Then, the passage through an alkaline medium gives rise to a specific β-elimination reaction of the thioether obtained with glutathione, leading to the formation of a chromophoric thione with an absorbance of 400 nm.

Fluorometric assays have also been developed for glutathione analysis offering high specificity and specificity. The most frequently used probe, ortho-phthalaldehyde (OPA) or its analogue 2,3-naphthalenedicarboxaldehyde, reacts with GSH to form a highly fluorescent product with Ex/Em = 340/420 nm. Other fluorescent probes, such as monochlorobimane (MCB) and monobromobimane (MBB), used less frequently, also form stable fluorescent adducts with GSH, which can be determined at Ex/Em = 394/490 nm. In comparison with OPA, MCB and MBB have the substantial advantage of penetrating into the cell to react directly with cellular thiols, preventing possible GSH oxidation after cell lysis and allowing analysis by flow cytometry and fluorescence microscopy.

(2) Vitamin A. Vitamin A refers to a group of fat-soluble retinoids (retinol, retinal, and retinyl esters) and provitamin A carotenoids (most notably β-carotene) that function as important dietary antioxidants, due to their ability to scavenge and directly neutralize free radicals. The levels of retinoids and carotenoids are typically measured in plasma/serum or tissue samples to assess vitamin A inadequacy using atmospheric pressure chemical ionization (APCI) liquid chromatography/mass spectrometry or reversed-phase HPLC.

(3) Vitamin C. Water-soluble vitamin C (ascorbic acid), primarily found in the cytosol and extracellular fluid, plays a protective effect in reducing oxidative damage by reacting with ROS molecules such as aqueous peroxyl radicals. The total ascorbic acid level is commonly estimated by the method developed by Roe and Keuther. This method involves the oxidation of ascorbic acid into dehydroascorbic acid by Cu2+, followed by its coupling with 2,4-dinitrophenylhydrazine (DNPH). The resulting derivative is then treated with strong acid leading to the production of an orange-red product, which can be measured spectrophometrically at 520 nm. Ascorbic acid can also be measured using the method developed by Zannoni et al. In this method, ferric iron is reduced by ascorbic acid, producing ferrous iron, which then forms a red-colored complex with 2,2′-dipyridyl, displaying an absorbance at 520 nm. It is worth noting that incubation of the samples with dithiothreitol prior to performing this assay, as suggested by Masato, would reduce dehydroascorbic acid into ascorbic acid, enabling the determination of total ascorbic acid in clinical samples. Alternatively, the levels of vitamin C can be determined using reversed-phase HPLC.

(4) Vitamin E. Vitamin E (α-tocopherol) is a lipid-soluble vitamin which acts as a lipid peroxyl radical scavenger, preventing lipid peroxidation chain reactions in the cell membranes.

Its level can be measured by the method of Emmerie and Engel, later described by Hashim and Schuttringer and Baker et al., and is based on the reduction of ferric ions to ferrous ions by α-tocopherol. Similar to the method by Zannoni et al. (discussed in Section 3), the ferrous ions are then coupled with 2,2′-dipyridyl, which can be detected colorimetrically at 520 nm. The method of Desai also involves the reduction of ferric ions by vitamin E, but the formation of a pink-colored complex is achieved with batophenanthroline orthophosphoric acid, and the absorbance is read at 536 nm.

Vitamin E levels in serum can also be estimated using fluorometry by the method of Hansen and Warwick. Following the precipitation of serum proteins by alcohol, vitamin E can be extracted into hexane level and quantified at λexcitation = 295 nm and λemission = 340 nm. Alternatively, tocopherols can be analyzed by gas chromatography-mass spectrometry (GC-MS) on a SPB1 column using a selected ion monitoring technique or by reversed-phase HPLC.

2.3.3. Total Antioxidant Capacity

Until recently, investigating the status of antioxidants has been carried out by measuring the levels or activities of each separately. However, measurement of the overall effect of antioxidants can be quite useful in assessing the oxidative state in clinical samples due to the various interactions between the different antioxidants. Several methods that are less time-consuming and labor-intensive have therefore been developed to determine the total antioxidant status (TAS) in clinical samples.

The 2,2-diphenyl-1-picryl-hydrazyl (DPPH) reduction assay is a method that uses free radical traps to assess the antioxidant capacity of the samples. DPPH is a stable free radical due to the delocalization of the spare electron over the molecule as a whole, with a deep violet color characterized by an absorption band at 520 nm. When DPPH is mixed with an antiradical compound that can neutralize it, it becomes colorless. Therefore, the decrease in optical density of DPPH radicals is monitored to evaluate the antioxidant potential of the samples.

The 2,2′-azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid) (ABTS) assay, developed by Erel, similarly uses a strongly colored stable radical compound to evaluate the antioxidant state of samples. Here, ABTS is first oxidized by metmyoglobin and hydrogen peroxide into its radical cation form (ABTS•+), a blue-green chromophore with an absorption at 750 nm. When antioxidants are added, ABTS•+ is reduced to ABTS and becomes decolorized again. Therefore, this method also follows the discoloration of the stable radical spectrophotometrically to measure the relative antioxidant ability of the samples. This assay is often referred to as Trolox equivalent antioxidant capacity (TEAC) method, because the reaction rate is commonly calibrated with a water-soluble analogue of vitamin E, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), as an antioxidant standard. The ABTS assay has an advantage over other techniques in that it is freely soluble in both organic and aqueous solvents so it is applicable for both hydrophilic and lipophilic antioxidants.

The total radical-trapping antioxidant parameter (TRAP) assay is another free radical trapping method which has been widely applied to evaluate the antioxidant capacity particularly in plasma. In this assay, thermal decomposition of the water-soluble azo compound 2,2′-azobis(2-methylpropionamidine) dihydrochloride (ABAP) generates peroxyl radicals at a known steady rate, which is monitored through a linear decrease in R-phycoerythrin (R-PE) fluorescence over time using a luminescence spectrometer (λexcitation = 495 nm and λemission = 575 nm). When the sample is added to the reaction mixture, the antioxidants provide protection for the fluorescence decay of R-PE. The length of the lag phase is therefore used to directly estimate the total antioxidant capacity. This method is relatively more complex and time-consuming than the others are.

The ferric-reducing antioxidant power (FRAP) assay is a simpler and faster method to assess the antioxidative potential of plasma; however, this method cannot detect antioxidants that act by radical quenching. The colorimetric assay is based on the ability of antioxidants to reduce the ferric tripyridyltriazine (Fe3+-TPTZ) complex to the ferrous form at low pH. The end-product (Fe2+-TPTZ) has an intense blue color with absorption at 593 nm which can be monitored using a diode-array spectrophotometer to estimate the antioxidant capacity of the samples.

The biological antioxidant potential (BAP) test is another assay based on the ability of antioxidants to reduce ferric ions to ferrous ions. However, in this method, ferric ions are bound to a chromogenic thiocyanate derivative substrate, which becomes decolorized when the ferric ions are reduced to ferrous ions by the antioxidants of the serum sample. This reduction is therefore quantified to estimate the antioxidant capacity of the sample by measuring the absorbance change at 505 nm.

As for the method developed by Koracevic et al., a standardized solution of the Fe-EDTA complex reacts with hydrogen peroxide by a Fenton-type reaction leading to the formation of hydroxyl radicals which degrade sodium benzoate solution resulting in the release of colored TBARS. Addition of antioxidants inhibits the production of TBARS, and the inhibition of color development is detected spectrophotometrically at 532 nm to estimate the total antioxidant status in the clinical samples.

3. Oxidative Stress in Clinical Samples of Cancer Patients

ROS is a contributing factor in the natural process of aging as well as in various pathological diseases including cancer. Oxidative stress has been reported in almost all types of cancers, promoting many aspects of tumor development and progression. During the process of carcinogenesis, an increase in ROS levels can occur due to elevated metabolic activity, oncogene activation, increased cellular receptor signaling, or mitochondrial dysfunction. Overproduction of ROS can also be induced exogenously by carcinogenic insults such as cigarette smoke, heavy metals, ionizing radiation, and asbestos. Alternatively, oxidative stress observed in cancer cells can arise from low levels or inactivation of antioxidant defense mechanisms as a result of mutations in tumor suppressor genes. For instance, mutant BRCA1 and p53 have been shown to attenuate the activation and function of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that stimulates a stress response pathway by inducing expression of ROS-detoxifying enzymes.

The free radicals, generated during oxidative stress conditions, can consequently act as secondary messengers in intracellular signaling pathways involved in cell cycle progression and proliferation, cell survival and apoptosis, cell migration and angiogenesis, tissue invasion and metastasis, and tumor stemness, thereby affecting all characters of oncogenic phenotype of cancer cells. In addition to these oxidative stress-mediated signaling events, high levels of ROS can also lead to nonspecific damage of macromolecules such as nucleic acids, proteins, and lipids, often creating more free radicals, and triggering a chain of destruction, to promote oncogenic transformation. ROS can cause individual DNA base changes or gross chromosomal alterations, thereby inducing mutagenesis and genomic instability. The cells harboring DNA mutations typically undergo apoptosis if they are unable to completely repair these DNA lesions; however, under certain circumstances, these cells escape programmed cell death, giving rise to transformed progeny. The mutagenic effects of ROS are not limited to DNA damage, but can also involve an attack of ROS molecules on proteins and lipids. For instance, oxidative damage to the cells' lipids initiates lipid peroxidation, leading to the generation of a range of mutagenic products that could alter cellular functions and enhance cancer initiation or progression. On the other hand, ROS-induced protein damage to DNA repair enzymes has been suggested as an explanation for the increased susceptibility of mutations which contribute to the process of carcinogenesis.

Identification of oxidative stress biomarkers in clinical samples of cancer patients and defining their roles in cancer initiation and progression holds great promise in promoting the development of targeted therapeutic approaches and diagnostic strategies evaluating disease status. While literature records of direct measurement of ROS levels in clinical samples are limited, significant amount of data do exist regarding oxidative damage to the cell's biomolecules (DNA, lipids, and proteins) as well as on enzymatic, nonenzymatic, and total antioxidant status in clinical samples of cancer patients. In the tables below, we summarize some of these findings in 10 different types of cancer. Table 1 outlines findings regarding oxidative damage to DNA, lipids, and proteins in clinical samples of cancer patients, while Tables 2, 3, and 4 summarize data related to enzymatic antioxidant activities, nonenzymatic antioxidant levels, and total antioxidant status, respectively. We have particularly selected publications that report quantitative values of the oxidant/antioxidant markers.

4. Conclusion

Oxidative stress is implicated in the natural process of aging as well as in a variety of disease states. A detailed understanding regarding the link between oxidative stress and pathogenesis can be exploited to assess disease status as well as to develop preventive and therapeutic strategies in humans. In this review, three approaches were suggested to assess oxidative stress in clinical samples: (1) direct measurement of ROS levels, (2) detection of the resulting oxidative damage to biomolecules (DNA, lipids, and proteins), and (3) determination of antioxidant status (enzymatic antioxidant activities, nonenzymatic antioxidant levels, or total antioxidant capacity).

Direct ROS determination is a valuable and promising oxidative stress biomarker that can reflect on disease status. However, as we noted earlier, their measurement in biological systems is a complex task given the short half-life and high reactivity of these species. On the other hand, “footprints” of oxidative stress are extremely stable and provide a more reliable approach to evaluate oxidative stress in clinical samples. While some of these modifications only reflect the local degree of oxidative stress, others have a direct effect on the function of target molecules. This functional significance or the causal role of oxidative modifications further highlights the clinical applicability of these oxidative stress markers. However, sample processing should be performed with caution to ensure their stability and to avoid the possibility that biomolecules may become oxidatively damaged during their isolation. As for the correlation of the antioxidant status to the state of oxidative stress in clinical samples, the measurement of individual antioxidant levels/activities could yield conflicting results. For instance, some papers report low antioxidant status in cancer samples, explaining it as a loss of their protective capacity due to high oxidative stress, while others interpret the findings of high levels/activities of the antioxidants as an adaptive response mechanism to detoxify oxidative stress-related harmful metabolites. To overcome such biases, it is advisable to determine the total antioxidant status by evaluating all antioxidants simultaneously without excluding their interactions with each other.

The choice of the oxidative stress biomarkers and the methods used to measure them in order to assess oxidative status in clinical samples should be decided based on the aim of the study and its design, as well as on the clinical relevance in the selected subjects. No single parameter has yet been recommended as a gold standard for defining redox status in clinical samples. Furthermore, the individual markers described above only partially reflect on oxidative status. Therefore, an integrative approach examining both pro- and antioxidant reactions has been recently suggested to obtain a comprehensive score with higher sensitivity to physiological and pathological alternations. Global redox status indexes such as OXY-SCORE or oxidative-INDEX, computed by subtracting the antioxidant capacity from ROS levels/ROS-induced damage, or oxidative stress index (OSI), which is the ratio of total oxidant status to total antioxidant status, reflect simultaneously on oxidative and antioxidant status in clinical samples and provide a better and more powerful index in the evaluation of overall oxidative stress in clinical samples and the establishment of a definitive relationship between oxidative stress and disease status.

As a final note, to our knowledge, no adequate comparison has yet been performed between different biomarkers and the methodologies used to measure them, making it difficult if not impossible to make a reliable comparison of findings from different groups. A critical evaluation and adaptation of proposed methodologies available in the literature should therefore be undertaken prior to carrying out a proposed study, so as to enable the investigators to choose the most suitable procedure for each chosen biomarker. In addition, such a comparison will enable careful meta-analysis of multiple scientific studies related to oxidative stress.

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    Ock C. Y., Kim E. H., Choi D. J., Lee H. J., Hahm K. B., Chung M. H. 8-Hydroxydeoxyguanosine: not mere biomarker for oxidative stress, but remedy for oxidative stress-implicated gastrointestinal diseases. World Journal of Gastroenterology. 2012;18(4):302-308.

    Not in our library10.3748/wjg.v18.i4.302

  93. 93.

    Akçay T., Saygılı I., Andican G., Yalçın V. Increased formation of 8-hydroxy-2′-deoxyguanosine in peripheral blood leukocytes in bladder cancer. Urologia Internationalis. 2003;71(3):271-274.

    Not in our library10.1159/000072677

  94. 94.

    Kondo S., Toyokuni S., Iwasa Y., et al. Persistent oxidative stress in human colorectal carcinoma, but not in adenoma. Free Radical Biology & Medicine. 1999;27(3-4):401-410.

    Not in our library10.1016/s0891-5849(99)00087-8

  95. 95.

    Kondo S., Toyokuni S., Tanaka T., et al. Overexpression of the hOGG1 gene and high 8-hydroxy-2′-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: regulation mechanism of the 8-OHdG level in DNA. Clinical Cancer Research. 2000;6(4):1394-1400.

    Not in our library

  96. 96.

    Płachetka A., Adamek B., Strzelczyk J. K., et al. 8-Hydroxy-2′-deoxyguanosine in colorectal adenocarcinoma--is it a result of oxidative stress? Medical Science Monitor. 2013;19:690-695.

    Not in our library10.12659/msm.883999

  97. 97.

    Shigenaga M. K., Park J. W., Cundy K. C., Gimeno C. J., Ames B. N. In vivo oxidative DNA damage: measurement of 8-hydroxy-2′-deoxyguanosine in DNA and urine by high-performance liquid chromatography with electrochemical detection. Methods in Enzymology. 1990;186:521-530.

    Not in our library10.1016/0076-6879(90)86146-m

  98. 98.

    Toyokuni S., Tanaka T., Hattori Y., et al. Quantitative immunohistochemical determination of 8-hydroxy-2′-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model. Laboratory Investigation. 1997;76(3):365-374.

    Not in our library

  99. 99.
    DNA oxidation matters: The HPLC–electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine · 1998
    Not checked
  100. 100.

    Chiou C. C., Chang P. Y., Chan E. C., Wu T. L., Tsao K. C., Wu J. T. Urinary 8-hydroxydeoxyguanosine and its analogs as DNA marker of oxidative stress: development of an ELISA and measurement in both bladder and prostate cancers. Clinica Chimica Acta. 2003;334(1-2):87-94.

    Not in our library10.1016/s0009-8981(03)00191-8

  101. 101.

    Pylväs M., Puistola U., Laatio L., Kauppila S., Karihtala P. Elevated serum 8-OHdG is associated with poor prognosis in epithelial ovarian cancer. Anticancer Research. 2011;31(4):1411-1415.

    Not in our library

  102. 102.

    Soini Y., Haapasaari K. M., Vaarala M. H., Turpeenniemi-Hujanen T., Kärjä V., Karihtala P. 8-Hydroxydeguanosine and nitrotyrosine are prognostic factors in urinary bladder carcinoma. International Journal of Clinical and Experimental Pathology. 2011;4(3):267-275.

    Not in our library

  103. 103.

    Karihtala P., Soini Y., Vaskivuo L., Bloigu R., Puistola U. DNA adduct 8-hydroxydeoxyguanosine, a novel putative marker of prognostic significance in ovarian carcinoma. International Journal of Gynecological Cancer. 2009;19(6):1047-1051.

    Not in our library10.1111/igc.0b013e3181ad0f0d

  104. 104.

    Nishida N., Arizumi T., Takita M., et al. Reactive oxygen species induce epigenetic instability through the formation of 8-hydroxydeoxyguanosine in human hepatocarcinogenesis. Digestive Diseases. 2013;31(5-6):459-466.

    Not in our library10.1159/000355245

  105. 105.

    Tanaka S., Miyanishi K., Kobune M., et al. Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Journal of Gastroenterology. 2013;48(11):1249-1258.

    Not in our library10.1007/s00535-012-0739-0

  106. 106.

    Dizdaroglu M. Quantitative determination of oxidative base damage in DNA by stable isotope-dilution mass spectrometry. FEBS Letters. 1993;315(1):1-6.

    Not in our library10.1016/0014-5793(93)81120-o

  107. 107.

    Chaisiriwong L., Wanitphakdeedecha R., Sitthinamsuwan P., et al. A case-control study of involvement of oxidative DNA damage and alteration of antioxidant defense system in patients with basal cell carcinoma: modulation by tumor removal. Oxidative Medicine and Cellular Longevity. 2016;2016:12.

    Not in our library10.1155/2016/5934024

  108. 108.

    Li D., Zhang W., Zhu J., et al. Oxidative DNA damage and 8-hydroxy-2-deoxyguanosine DNA glycosylase/apurinic lyase in human breast cancer. Molecular Carcinogenesis. 2001;31(4):214-223.

    Not in our library10.1002/mc.1056

  109. 109.

    Park Y. J., Choi E. Y., Choi J. Y., Park J. G., You H. J., Chung M. H. Genetic changes of hOGG1 and the activity of oh8Gua glycosylase in colon cancer. European Journal of Cancer. 2001;37(3):340-346.

    Not in our library10.1016/s0959-8049(00)00388-9

  110. 110.

    Yamamoto F., Kasai H., Bessho T., et al. Ubiquitous presence in mammalian cells of enzymatic activity specifically cleaving 8-hydroxyguanine-containing DNA. Japanese Journal of Cancer Research. 1992;83(4):351-357.

    Not in our library10.1111/j.1349-7006.1992.tb00114.x

  111. 111.

    McCord J. M., Fridovich I. Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). Journal of Biological Chemistry. 1969;244(22):6049-6055.

    Not in our library

  112. 112.

    Misra H. P., Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. The Journal of Biological Chemistry. 1972;247(10):3170-3175.

    Not in our library

  113. 113.

    Marklund S., Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. European Journal of Biochemistry. 1974;47(3):469-474.

    Not in our library10.1111/j.1432-1033.1974.tb03714.x

  114. 114.

    Roth E. F., Gilbert H. S. The pyrogallol assay for superoxide dismutase: absence of a glutathione artifact. Analytical Biochemistry. 1984;137(1):50-53.

    Not in our library10.1016/0003-2697(84)90344-0

  115. 115.

    Nishikimi M., Appaji Rao N., Yagi K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochemical and Biophysical Research Communications. 1972;46(2):849-854.

    Not in our library10.1016/s0006-291x(72)80218-3

  116. 116.

    Kakkar P., Das B., Viswanathan P. N. A modified spectrophotometric assay of superoxide dismutase. Indian Journal of Biochemistry & Biophysics. 1984;21(2):130-132.

    Not in our library

  117. 117.

    Oyanagui Y. Reevaluation of assay methods and establishment of kit for superoxide dismutase activity. Analytical Biochemistry. 1984;142(2):290-296.

    Not in our library10.1016/0003-2697(84)90467-6

  118. 118.

    Sun Y., Oberley L. W., Li Y. A simple method for clinical assay of superoxide dismutase. Clinical Chemistry. 1988;34(3):497-500.

    Not in our library

  119. 119.

    Grace Nirmala J., Narendhirakannan R. T. Detection and genotyping of high-risk HPV and evaluation of anti-oxidant status in cervical carcinoma patients in Tamil Nadu State, India--a case control study. Asian Pacific Journal of Cancer Prevention. 2011;12(10):2689-2695.

    Not in our library

  120. 120.

    Margaret A. L., Syahruddin E., Wanandi S. I. Low activity of manganese superoxide dismutase (MnSOD) in blood of lung cancer patients with smoking history: relationship to oxidative stress. Asian Pacific Journal of Cancer Prevention. 2011;12(11):3049-3053.

    Not in our library

  121. 121.

    Güner G., İşlekel H., Oto Ö., Hazan E., Açikel Ü. Evaluation of some antioxidant enzymes in lung carcinoma tissue. Cancer Letters. 1996;103(2):233-239.

    Not in our library10.1016/0304-3835(96)04226-7

  122. 122.

    Jaruga P., Zastawny T. H., Skokowski J., Dizdaroglu M., Olinski R. Oxidative DNA base damage and antioxidant enzyme activities in human lung cancer. FEBS Letters. 1994;341(1):59-64.

    Not in our library10.1016/0014-5793(94)80240-8

  123. 123.

    Strzelczyk J. K., Wielkoszyński T., Krakowczyk Ł., et al. The activity of antioxidant enzymes in colorectal adenocarcinoma and corresponding normal mucosa. Acta Biochimica Polonica. 2012;59(4):549-556.

    Not in our library

  124. 124.

    Marklund S. L. Analysis of extracellular superoxide dismutase in tissue homogenates and extracellular fluids. Methods in Enzymology. 1990;186:260-265.

    Not in our library10.1016/0076-6879(90)86117-e

  125. 125.

    Marklund S. L. Superoxide dismutase isoenzymes in tissues and plasma from New Zealand black mice, nude mice and normal BALB/c mice. Mutation Research. 1985;148(1-2):129-134.

    Not in our library10.1016/0027-5107(85)90216-7

  126. 126.

    Mattiazzi M., D'Aurelio M., Gajewski C. D., et al. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. The Journal of Biological Chemistry. 2002;277(33):29626-29633.

    Not in our library10.1074/jbc.m203065200

  127. 127.

    Dieterich S., Bieligk U., Beulich K., Hasenfuss G., Prestle J. Gene expression of antioxidative enzymes in the human heart: increased expression of catalase in the end-stage failing heart. Circulation. 2000;101(1):33-39.

    Not in our library10.1161/01.cir.101.1.33

  128. 128.

    Iqbal J., Whitney P. Use of cyanide and diethyldithiocarbamate in the assay of superoxide dismutases. Free Radical Biology & Medicine. 1991;10(1):69-77.

    Not in our library10.1016/0891-5849(91)90023-v

  129. 129.

    Djordjevic V. B. Free radicals in cell biology. International Review of Cytology. 2004;237:57-89.

    Not in our library10.1016/s0074-7696(04)37002-6

  130. 130.

    Beers R. F., Sizer I. W. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. The Journal of Biological Chemistry. 1952;195(1):133-140.

    Not in our library

  131. 131.

    Nelson D. P., Kiesow L. A. Enthalpy of decomposition of hydrogen peroxide by catalase at 25° C (with molar extinction coefficients of H2O2 solutions in the UV). Analytical Biochemistry. 1972;49(2):474-478.

    Not in our library10.1016/0003-2697(72)90451-4

  132. 132.

    Aebi H. Catalase in vitro. Methods in Enzymology. 1984;105:121-126.

    Not in our library10.1016/s0076-6879(84)05016-3

  133. 133.

    Sinha A. K. Colorimetric assay of catalase. Analytical Biochemistry. 1972;47(2):389-394.

    Not in our library10.1016/0003-2697(72)90132-7

  134. 134.

    Goth L. A simple method for determination of serum catalase activity and revision of reference range. Clinica Chimica Acta. 1991;196(2-3):143-151.

    Not in our library10.1016/0009-8981(91)90067-m

  135. 135.

    Johansson L. H., Håkan Borg L. A. A spectrophotometric method for determination of catalase activity in small tissue samples. Analytical Biochemistry. 1988;174(1):331-336.

    Not in our library10.1016/0003-2697(88)90554-4

  136. 136.

    Arthur J. R. The glutathione peroxidases. Cellular and Molecular Life Sciences. 2000;57(13-14):1825-1835.

    Not in our library10.1007/pl00000664

  137. 137.

    Rotruck J. T., Pope A. L., Ganther H. E., Swanson A. B., Hafeman D. G., Hoekstra W. G. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973;179(4073):588-590.

    Not in our library10.1126/science.179.4073.588

  138. 138.

    Hafeman D. G., Sunde R. A., Hoekstra W. G. Effect of dietary selenium on erythrocyte and liver glutathione peroxidase in the rat. The Journal of Nutrition. 1974;104(5):580-587.

    Not in our library10.1093/jn/104.5.580

  139. 139.

    Ellman G. L. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics. 1959;82(1):70-77.

    Not in our library10.1016/0003-9861(59)90090-6

  140. 140.

    Kokatnur V. R., Jelling M. Iodometric determination of peroxygen in organic compounds. Journal of the American Chemical Society. 1941;63(5):1432-1433.

    Not in our library10.1021/ja01850a082

  141. 141.

    Paglia D. E., Valentine W. N. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. The Journal of Laboratory and Clinical Medicine. 1967;70(1):158-169.

    Not in our library

  142. 142.

    Pleban P. A., Munyani A., Beachum J. Determination of selenium concentration and glutathione peroxidase activity in plasma and erythrocytes. Clinical Chemistry. 1982;28(2):311-316.

    Not in our library

  143. 143.

    Czeczot H., Scibior D., Skrzycki M., Podsiad M. Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellular carcinoma. Acta Biochimica Polonica. 2006;53(1):237-242.

    Not in our library

  144. 144.

    Hubatsch I., Ridderstrom M., Mannervik B. Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation. The Biochemical Journal. 1998;330(1):175-179.

    Not in our library10.1042/bj3300175

  145. 145.

    Chasseaud L. F. The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Advances in Cancer Research. 1979;29:175-274.

    Not in our library10.1016/s0065-230x(08)60848-9

  146. 146.

    Habig W. H., Pabst M. J., Jakoby W. B. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. Journal of Biological Chemistry. 1974;249(22):7130-7139.

    Not in our library

  147. 147.

    Lu S. C. Regulation of glutathione synthesis. Molecular Aspects of Medicine. 2009;30(1-2):42-59.

    Not in our library10.1016/j.mam.2008.05.005

  148. 148.

    Wu G., Fang Y. Z., Yang S., Lupton J. R., Turner N. D. Glutathione metabolism and its implications for health. The Journal of Nutrition. 2004;134(3):489-492.

    Not in our library10.1093/jn/134.3.489

  149. 149.

    Beutler E., Duron O., Kelly B. M. Improved method for the determination of blood glutathione. The Journal of Laboratory and Clinical Medicine. 1963;61:882-888.

    Not in our library

  150. 150.

    Sedlak J., Lindsay R. H. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Analytical Biochemistry. 1968;25(1):192-205.

    Not in our library10.1016/0003-2697(68)90092-4

  151. 151.

    Hu M.-L. [41] Measurement of protein thiol groups and glutathione in plasma. Methods in Enzymology. 1994;380-385.

    Not in our library10.1016/s0076-6879(94)33044-1

  152. 152.

    Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Analytical Biochemistry. 1969;27(3):502-522.

    Not in our library10.1016/0003-2697(69)90064-5

  153. 153.

    Eiberger W., Volkmer B., Amouroux R., Dhérin C., Radicella J. P., Epe B. Oxidative stress impairs the repair of oxidative DNA base modifications in human skin fibroblasts and melanoma cells. DNA Repair. 2008;7(6):912-921.

    Not in our library10.1016/j.dnarep.2008.03.002

  154. 154.

    Boutolleau D., Lefévre G., Etienne J. Determination of glutathione with the GSH-400 method: value of derivative spectrophotometry. Annales de Biologie Clinique. 1997;55(6):592-596.

    Not in our library

  155. 155.

    Cohn V. H., Lyle J. A fluorometric assay for glutathione. Analytical Biochemistry. 1966;14(3):434-440.

    Not in our library10.1016/0003-2697(66)90286-7

  156. 156.

    White C. C., Viernes H., Krejsa C. M., Botta D., Kavanagh T. J. Fluorescence-based microtiter plate assay for glutamate–cysteine ligase activity. Analytical Biochemistry. 2003;318(2):175-180.

    Not in our library10.1016/s0003-2697(03)00143-x

  157. 157.

    Hissin P. J., Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Analytical Biochemistry. 1976;74(1):214-226.

    Not in our library10.1016/0003-2697(76)90326-2

  158. 158.

    Sun L., Li X., Li G., Dai B., Tan W. Actinidia chinensis planch. improves the indices of antioxidant and anti-inflammation status of type 2 diabetes mellitus by activating Keap1 and Nrf2 via the upregulation of microRNA-424. Oxidative Medicine and Cellular Longevity. 2017;2017:14.

    Not in our library10.1155/2017/7038789

  159. 159.

    Ramírez-Ortega D., Ramiro-Salazar A., González-Esquivel D., Ríos C., Pineda B., Pérez de la Cruz V. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid enhance the toxicity induced by copper in rat astrocyte culture. Oxidative Medicine and Cellular Longevity. 2017;2017:12.

    Not in our library10.1155/2017/2371895

  160. 160.

    Katerji M., Barada K., Jomaa M., et al. Chemosensitivity of U251 cells to the co-treatment of D-penicillamine and copper: possible implications on Wilson disease patients. Frontiers in Molecular Neuroscience. 2017;10:10-10.

    Not in our library10.3389/fnmol.2017.00010

  161. 161.

    Čapek J., Hauschke M., Brůčková L., Roušar T. Comparison of glutathione levels measured using optimized monochlorobimane assay with those from ortho-phthalaldehyde assay in intact cells. Journal of Pharmacological and Toxicological Methods. 2017;88(Part 1):40-45.

    Not in our library10.1016/j.vascn.2017.06.001

  162. 162.

    Hennekens C. H., Mayrent S. L., Willett W. Vitamin A, carotenoids, and retinoids. Cancer. 1986;58(8 Supplement):1837-1841.

    Not in our library10.1002/1097-0142(19861015)58:8+<1837::aid-cncr2820581409>3.0.co;2-x

  163. 163.

    Zhu D., Wang Y., Pang Y., et al. Quantitative analyses of beta-carotene and retinol in serum and feces in support of clinical bioavailability studies. Rapid Communications in Mass Spectrometry. 2006;20(16):2427-2432.

    Not in our library10.1002/rcm.2601

  164. 164.

    Gackowski D., Kruszewski M., Jawien A., Ciecierski M., Olinski R. Further evidence that oxidative stress may be a risk factor responsible for the development of atherosclerosis. Free Radical Biology and Medicine. 2001;31(4):542-547.

    Not in our library10.1016/s0891-5849(01)00614-1

  165. 165.

    Kaplan L. A., Miller J. A., Stein E. A., Stampfer M. J. [15] Simultaneous, high-performance liquid chromatographic analysis of retinol, tocopherols, lycopene, and α- and β-carotene in serum and plasma. Methods in Enzymology. 1990;155-167.

    Not in our library10.1016/0076-6879(90)89286-q

  166. 166.

    Miller K. W., Lorr N. A., Yang C. S. Simultaneous determination of plasma retinol, α-tocopherol, lycopene, α-carotene, and β-carotene by high-performance liquid chromatography. Analytical Biochemistry. 1984;138(2):340-345.

    Not in our library10.1016/0003-2697(84)90819-4

  167. 167.

    Nelis H. J. C. F., De Leenheer A. P. Isocratic nonaqueous reversed-phase liquid chromatography of carotenoids. Analytical Chemistry. 2002;55(2):270-275.

    Not in our library10.1021/ac00253a021

  168. 168.

    Taibi G., Nicotra C. M. A. Development and validation of a fast and sensitive chromatographic assay for all-trans-retinol and tocopherols in human serum and plasma using liquid–liquid extraction. Journal of Chromatography B. 2002;780(2):261-267.

    Not in our library10.1016/s1570-0232(02)00529-9

  169. 169.

    Suntres Z. E. Liposomal antioxidants for protection against oxidant-induced damage. Journal of Toxicology. 2011;2011:16.

    Not in our library10.1155/2011/152474

  170. 170.

    Roe J. H., Kuether C. A. The determination of ascorbic acid in whole blood and urine through the 2, 4-dinitrophenylhydrazine derivative of dehydroascorbic acid. Journal of Biological Chemistry. 1943;147(2):399-407.

    Not in our library

  171. 171.

    Battisti V., Maders L. D. K., Bagatini M. D., et al. Oxidative stress and antioxidant status in prostate cancer patients: relation to Gleason score, treatment and bone metastasis. Biomedicine & Pharmacotherapy. 2011;65(7):516-524.

    Not in our library10.1016/j.biopha.2011.06.003

  172. 172.

    Zannoni V., Lynch M., Goldstein S., Sato P. A rapid micromethod for the determination of ascorbic acid in plasma and tissues. Biochemical Medicine. 1974;11(1):41-48.

    Not in our library10.1016/0006-2944(74)90093-3

  173. 173.

    Masato O. An improved method for determination of l-ascorbic acid and l-dehydroascorbic acid in blood plasma. Clinica Chimica Acta. 1980;103(3):259-268.

    Not in our library10.1016/0009-8981(80)90144-8

  174. 174.

    Gackowski D., Banaszkiewicz Z., Rozalski R.?., Jawien A., Olinski R. Persistent oxidative stress in colorectal carcinoma patients. International Journal of Cancer. 2002;101(4):395-397.

    Not in our library10.1002/ijc.10610

  175. 175.

    Grammenandi K., Kyriazi M., Katsarou-Katsari A., et al. Low-molecular-weight hydrophilic and lipophilic antioxidants in nonmelanoma skin carcinomas and adjacent normal-looking skin. Skin Pharmacology and Physiology. 2017;29(6):324-331.

    Not in our library10.1159/000453456

  176. 176.

    Ivanović D., Popović A., Radulović D., Medenica M. Reversed-phase ion-pair HPLC determination of some water-soluble vitamins in pharmaceuticals. Journal of Pharmaceutical and Biomedical Analysis. 1999;18(6):999-1004.

    Not in our library10.1016/s0731-7085(98)00109-5

  177. 177.

    Schleich T., Rodemeister S., Venturelli S., Sinnberg T., Garbe C., Busch C. Decreased plasma ascorbate levels in stage IV melanoma patients. Metabolism and Nutrition in Oncology. 2015;1(1):e2-e6.

    Not in our library10.1055/s-0033-1348256

  178. 178.

    Emmerie A., Engel C. Colorimetric determination of α-tocopherol (vitamin E). Recueil des Travaux Chimiques des Pays-Bas. 1938;57(12):1351-1355.

    Not in our library10.1002/recl.19380571207

  179. 179.

    Hashim S. A., Schuttringer G. R. Rapid determination of tocopherol in macro- and microquantities of plasma. Results obtained in various nutrition and metabolic studies. American Journal of Clinical Nutrition. 1966;19(2):137-145.

    Not in our library10.1093/ajcn/19.2.137

  180. 180.

    Baker H., Frank O., DeAngelis B., Feingold S. Plasma tocopherol in man at various times after ingesting free or acetylated tocopherol. Nutrition Reports International. 1980;21(4):531-536.

    Not in our library

  181. 181.

    Desai I. D. Vitamin E analysis methods for animal tissues. Methods in Enzymology. 1984;105:138-147.

    Not in our library10.1016/s0076-6879(84)05019-9

  182. 182.

    Hansen L. G., Warwick W. J. A fluorometric micromethod for serum vitamin A. American Journal of Clinical Pathology. 1968;50(4_ts):525-529.

    Not in our library10.1093/ajcp/50.4_ts.525

  183. 183.

    Badjatia N., Satyam A., Singh P., Seth A., Sharma A. Altered antioxidant status and lipid peroxidation in Indian patients with urothelial bladder carcinoma. Urologic Oncology. 2010;28(4):360-367.

    Not in our library10.1016/j.urolonc.2008.12.010

  184. 184.

    Cao G., Prior R. L. Comparison of different analytical methods for assessing total antioxidant capacity of human serum. Clinical Chemistry. 1998;44, 6, Part 1:1309-1315.

    Not in our library

  185. 185.

    Alam M. N., Bristi N. J., Rafiquzzaman M. Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi Pharmaceutical Journal. 2013;21(2):143-152.

    Not in our library10.1016/j.jsps.2012.05.002

  186. 186.

    Bartosz G. Total antioxidant capacity. Advances in Clinical Chemistry. 2003;37:219-292.

    Not in our library10.1016/s0065-2423(03)37010-6

  187. 187.

    Blois M. S. Antioxidant determinations by the use of a stable free radical. Nature. 1958;181(4617):1199-1200.

    Not in our library10.1038/1811199a0

  188. 188.

    Erel O. A new automated colorimetric method for measuring total oxidant status. Clinical Biochemistry. 2005;38(12):1103-1111.

    Not in our library10.1016/j.clinbiochem.2005.08.008

  189. 189.

    Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clinical Biochemistry. 2004;37(4):277-285.

    Not in our library10.1016/j.clinbiochem.2003.11.015

  190. 190.

    Arnao M. B., Cano A., Hernández-Ruiz J., García-Cánovas F., Acosta M. Inhibition by L-ascorbic acid and other antioxidants of the 2.2′-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) oxidation catalyzed by peroxidase: a new approach for determining total antioxidant status of foods. Analytical Biochemistry. 1996;236(2):255-261.

    Not in our library10.1006/abio.1996.0164

  191. 191.

    Miller N. J., Rice-Evans C. A. Spectrophotometric determination of antioxidant activity. Redox Report. 2016;2(3):161-171.

    Not in our library10.1080/13510002.1996.11747044

  192. 192.

    Wang D., Feng J. F., Zeng P., Yang Y. H., Luo J., Yang Y. W. Total oxidant/antioxidant status in sera of patients with thyroid cancers. Endocrine-Related Cancer. 2011;18(6):773-782.

    Not in our library10.1530/erc-11-0230

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    Be F., de Castro L. L., Aguiar J. R., et al. Antioxidant capacity total in non-melanoma skin cancer and its relationship with food consumption of antioxidant nutrients. Nutrición Hospitalaria. 2015;31(4):1682-1688.

    Not in our library10.3305/nh.2015.31.4.8331

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    Ghiselli A., Serafini M., Natella F., Scaccini C. Total antioxidant capacity as a tool to assess redox status: critical view and experimental data. Free Radical Biology & Medicine. 2000;29(11):1106-1114.

    Not in our library10.1016/s0891-5849(00)00394-4

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    Wayner D. D. M., Burton G. W., Ingold K. U., Locke S. Quantitative measurement of the total, peroxyl radical-trapping antioxidant capability of human blood plasma by controlled peroxidation. The important contribution made by plasma proteins. FEBS Letters. 1985;187(1):33-37.

    Not in our library10.1016/0014-5793(85)81208-4

  196. 196.

    Benzie I. F., Strain J. J. Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration. Methods in Enzymology. 1999;299:15-27.

    Not in our library10.1016/s0076-6879(99)99005-5

  197. 197.

    Dohi K., Satoh K., Ohtaki H., et al. Elevated plasma levels of bilirubin in patients with neurotrauma reflect its pathophysiological role in free radical scavenging. In Vivo. 2005;19(5):855-860.

    Not in our library

  198. 198.

    Koracevic D., Koracevic G., Djordjevic V., Andrejevic S., Cosic V. Method for the measurement of antioxidant activity in human fluids. Journal of Clinical Pathology. 2001;54(5):356-361.

    Not in our library10.1136/jcp.54.5.356

  199. 199.

    Liou G.-Y., Storz P. Reactive oxygen species in cancer. Free Radical Research. 2010;44(5):479-496.

    Not in our library10.3109/10715761003667554

  200. 200.

    Storz P. Reactive oxygen species in tumor progression. Frontiers in Bioscience. 2005;10(1-3):1881-1896.

    Not in our library10.2741/1667

  201. 201.
    Reactive oxygen species: role in the development of cancer and various chronic conditions. · 2006
    No notice
  202. 202.

    Reuter S., Gupta S. C., Chaturvedi M. M., Aggarwal B. B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biology & Medicine. 2010;49(11):1603-1616.

    Not in our library10.1016/j.freeradbiomed.2010.09.006

  203. 203.
    Inhibition of cancer antioxidant defense by natural compounds · 2016
    No notice
  204. 204.

    Gorrini C., Baniasadi P. S., Harris I. S., et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. The Journal of Experimental Medicine. 2013;210(8):1529-1544.

    Not in our library10.1084/jem.20121337

  205. 205.

    Kalo E., Kogan-Sakin I., Solomon H., et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. Journal of Cell Science. 2013;125(22):5578-5586.

    Not in our library10.1242/jcs.106815

  206. 206.
    Oxidative Stress, Prooxidants, and Antioxidants: The Interplay · 2014
    No notice
  207. 207.

    Wiseman H., Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. The Biochemical Journal. 1996;313(1):17-29.

    Not in our library10.1042/bj3130017

  208. 208.

    Visconti R., Grieco D. New insights on oxidative stress in cancer. Current Opinion in Drug Discovery & Development. 2009;12(2):240-245.

    Not in our library

  209. 209.
    DNA repair mechanisms in cancer development and therapy · 2015
    No notice
  210. 210.
    Oxidative Stress and Lipid Peroxidation Products in Cancer Progression and Therapy · 2012
    No notice
  211. 211.

    Cejas P., Casado E., Belda-Iniesta C., et al. Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain). Cancer Causes & Control. 2004;15(7):707-719.

    Not in our library10.1023/b:caco.0000036189.61607.52

  212. 212.

    McAdam E., Brem R., Karran P. Oxidative stress–induced protein damage inhibits DNA repair and determines mutation risk and therapeutic efficacy. Molecular Cancer Research. 2016;14(7):612-622.

    Not in our library10.1158/1541-7786.mcr-16-0053

  213. 213.

    Opanuraks J., Boonla C., Saelim C., et al. Elevated urinary total sialic acid and increased oxidative stress in patients with bladder cancer. Asian Biomedicine. 2010;4(5):703-710.

    Not in our library10.2478/abm-2010-0092

  214. 214.

    Sönmez H., Ozturk Z., Ekmekci H., Baloglu H., Kökoglu E. TBARS, carnitine, and reduced glutathione levels in human bladder carcinoma. Biochemistry. 2003;68(3):346-348.

    Not in our library10.1023/a:1023018620047

  215. 215.
    Long interspersed nuclear element-1 hypomethylation and oxidative stress: correlation and bladder cancer diagnostic potential. · 2012
    Not checked
  216. 216.

    Matsui A., Ikeda T., Enomoto K., et al. Increased formation of oxidative DNA damage, 8-hydroxy-2′-deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes. Cancer Letters. 2000;151(1):87-95.

    Not in our library10.1016/s0304-3835(99)00424-3

  217. 217.

    Gupta R. K., Patel A. K., Kumari R., et al. Interactions between oxidative stress, lipid profile and antioxidants in breast cancer: a case control study. Asian Pacific Journal of Cancer Prevention. 2012;13(12):6295-6298.

    Not in our library10.7314/apjcp.2012.13.12.6295

  218. 218.

    Kumaraguruparan R., Subapriya R., Kabalimoorthy J., Nagini S. Antioxidant profile in the circulation of patients with fibroadenoma and adenocarcinoma of the breast. Clinical Biochemistry. 2002;35(4):275-279.

    Not in our library10.1016/s0009-9120(02)00310-7

  219. 219.

    Kumaraguruparan R., Kabalimoorthy J., Nagini S. Correlation of tissue lipid peroxidation and antioxidants with clinical stage and menopausal status in patients with adenocarcinoma of the breast. Clinical Biochemistry. 2005;38(2):154-158.

    Not in our library10.1016/j.clinbiochem.2004.10.012

  220. 220.

    Bhattacharjee J., Jogdand S., Shinde R. K., Goswami S. Assessment of oxidative stress in breast cancer patients: a hospital based study. International Journal of Basic & Clinical Pharmacology. 2018;7(5):p. 966.

    Not in our library10.18203/2319-2003.ijbcp20181644

  221. 221.

    Aryal B., Rao V. A. Specific protein carbonylation in human breast cancer tissue compared to adjacent healthy epithelial tissue. PLoS One. 2018;13(3, article e0194164).

    Not in our library10.1371/journal.pone.0194164

  222. 222.

    Romano G., Sgambato A., Mancini R., et al. 8-Hydroxy-2′-deoxyguanosine in cervical cells: correlation with grade of dysplasia and human papillomavirus infection. Carcinogenesis. 2000;21(6):1143-1147.

    Not in our library10.1093/carcin/21.6.1143

  223. 223.

    Looi M. L., Mohd Dali A. Z. H., Md Ali S. A., Wan Ngah W. Z., Mohd Yusof Y. A. Oxidative damage and antioxidant status in patients with cervical intraepithelial neoplasia and carcinoma of the cervix. European Journal of Cancer Prevention. 2008;17(6):555-560.

    Not in our library10.1097/cej.0b013e328305a10b

  224. 224.

    Manju V., Kalaivani Sailaja J., Nalini N. Circulating lipid peroxidation and antioxidant status in cervical cancer patients: a case-control study. Clinical Biochemistry. 2002;35(8):621-625.

    Not in our library10.1016/s0009-9120(02)00376-4

  225. 225.

    Gautam S., Bhatt M. L. B., Mehrotra S., et al. Implication of therapeutic intervention on putative oxidative stress markers in cervical cancer. Journal of Dental and Medical Sciences. 2017;16(2):86-89.

    Not in our library

  226. 226.

    Suzuki K., Ito Y., Wakai K., et al. Serum oxidized low-density lipoprotein levels and risk of colorectal cancer: a case-control study nested in the Japan Collaborative Cohort Study. Cancer Epidemiology Biomarkers &amp;amp; Prevention. 2004;13(11):p. 1781.

    Not in our library

  227. 227.

    Rainis T., Maor I., Lanir A., Shnizer S., Lavy A. Enhanced oxidative stress and leucocyte activation in neoplastic tissues of the colon. Digestive Diseases and Sciences. 2007;52(2):526-530.

    Not in our library10.1007/s10620-006-9177-2

  228. 228.

    Yeh C.-C., Lai C. Y., Hsieh L. L., Tang R., Wu F. Y., Sung F. C. Protein carbonyl levels, glutathione S -transferase polymorphisms and risk of colorectal cancer. Carcinogenesis. 2010;31(2):228-233.

    Not in our library10.1093/carcin/bgp286

  229. 229.

    RafiqKhan M., Sellappa S. Serum malondialdehyde levels in lung cancer patients. Journal of Applied Biology & Biotechnology. 2013;1(4):32-34.

    Not in our library

  230. 230.

    Jüngst C., Cheng B., Gehrke R., et al. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology. 2004;39(6):1663-1672.

    Not in our library10.1002/hep.20241

  231. 231.

    Lin C. C., Yin M. C. B vitamins deficiency and decreased anti-oxidative state in patients with liver cancer. European Journal of Nutrition. 2007;46(5):293-299.

    Not in our library10.1007/s00394-007-0665-8

  232. 232.

    Yuan J. M., Grouls M., Carmella S. G., et al. Prediagnostic levels of urinary 8-epi-prostaglandin F2α and prostaglandin E2 metabolite, biomarkers of oxidative damage and inflammation, and risk of hepatocellular carcinoma. Carcinogenesis. 2019;(article bgy180).

    Not in our library10.1093/carcin/bgy180

  233. 233.

    Poungpairoj P., Whongsiri P., Suwannasin S., Khlaiphuengsin A., Tangkijvanich P., Boonla C. Increased oxidative stress and RUNX3 hypermethylation in patients with hepatitis B virus-associated hepatocellular carcinoma (HCC) and induction of RUNX3 hypermethylation by reactive oxygen species in HCC cells. Asian Pacific Journal of Cancer Prevention. 2015;16(13):5343-5348.

    Not in our library10.7314/apjcp.2015.16.13.5343

  234. 234.

    Pylvas-Eerola M., Karihtala P., Puistola U. Preoperative serum 8-hydroxydeoxyguanosine is associated with chemoresistance and is a powerful prognostic factor in endometrioid-type epithelial ovarian cancer. BMC Cancer. 2015;15(1):p. 493.

    Not in our library10.1186/s12885-015-1504-6

  235. 235.

    Xu X., Wang Y., Guo W., et al. The significance of the alteration of 8-OHdG in serous ovarian carcinoma. Journal of Ovarian Research. 2013;6(1):p. 74.

    Not in our library10.1186/1757-2215-6-74

  236. 236.

    Bandebuche S. Oxidative stress and antioxidant status in patients of ovarian cancer. Biomedical Research. 2011;22(2).

    Not in our library

  237. 237.

    Didžiapetrienė J., Bublevič J., Smailytė G., Kazbarienė B., Stukas R. Significance of blood serum catalase activity and malondialdehyde level for survival prognosis of ovarian cancer patients. Medicina. 2014;50(4):204-208.

    Not in our library10.1016/j.medici.2014.09.001

  238. 238.

    Mohan S. K., Priya V. Changes in lipid peroxidation, glutathione, ascorbic acid, vitamin E and antioxidant enzymes in patients with ovarian cancer. Acta Medica Academica. 2008;38(1):p. 5.

    Not in our library

  239. 239.

    Miyake H., Hara I., Kamidono S., Eto H. Oxidative DNA damage in patients with prostate cancer and its response to treatment. The Journal of Urology. 2004;171(4):1533-1536.

    Not in our library10.1097/01.ju.0000116617.32728.ca

  240. 240.

    Srivastava D. S. L., Mittal R. D. Free radical injury and antioxidant status in patients with benign prostate hyperplasia and prostate cancer. Indian Journal of Clinical Biochemistry. 2005;20(2):162-165.

    Not in our library10.1007/bf02867419

  241. 241.

    Gadjeva V., Dimov A., Georgieva N. Influence of therapy on the antioxidant status in patients with melanoma. Journal of Clinical Pharmacy and Therapeutics. 2008;33(2):179-185.

    Not in our library10.1111/j.1365-2710.2008.00909.x

  242. 242.

    Bisevac J. P., Djukic M., Stanojevic I., et al. Association between oxidative stress and melanoma progression. Journal of Medical Biochemistry. 2018;37(1):12-20.

    Not in our library10.1515/jomb-2017-0040

  243. 243.

    Tabur S., Aksoy Ş. N., Korkmaz H., Ozkaya M., Aksoy N., Akarsu E. Investigation of the role of 8-OHdG and oxidative stress in papillary thyroid carcinoma. Tumor Biology. 2015;36(4):2667-2674.

    Not in our library10.1007/s13277-014-2889-6

  244. 244.

    Sadani G. R., Nadkarni G. D. Role of tissue antioxidant defence in thyroid cancers. Cancer Letters. 1996;109(1-2):231-235.

    Not in our library10.1016/s0304-3835(96)04484-9

  245. 245.

    Erdamar H., Çimen B., Gülcemal H., Saraymen R., Yerer B., Demirci H. Increased lipid peroxidation and impaired enzymatic antioxidant defense mechanism in thyroid tissue with multinodular goiter and papillary carcinoma. Clinical Biochemistry. 2010;43(7-8):650-654.

    Not in our library10.1016/j.clinbiochem.2010.02.005

  246. 246.

    Kosova F., Çetin B., Akıncı M., et al. Advanced oxidation protein products, ferrous oxidation in xylenol orange, and malondialdehyde levels in thyroid cancer. Annals of Surgical Oncology. 2007;14(9):2616-2620.

    Not in our library10.1245/s10434-007-9425-5

  247. 247.

    Senthil N., Manoharan S. Lipid peroxidation and antioxidants status in patients with papillary thyroid carcinoma in India. Asia Pacific Journal of Clinical Nutrition. 2004;13(4):391-395.

    Not in our library

  248. 248.

    Koduru B., Tejaswini, Thakur A., et al. Indicators of oxidative stress in thyroid cancer. Indian Journal of Biochemistry & Biophysics. 2010;47(2):121-123.

    Not in our library

  249. 249.

    Moustafa S. R. Association of superoxide dismutase, glutathione peroxidase, catalse, and xanthine oxidase with incidence of bladder cancer. Cancer Research Journal. 2015;3(2):17-27.

    Not in our library10.11648/j.crj.20150302.11

  250. 250.

    Hasan H. R., Mathkor T. H., Al-Habal M. H. Superoxide dismutase isoenzyme activities in plasma and tissues of Iraqi patients with breast cancer. Asian Pacific Journal of Cancer Prevention. 2012;13(6):2571-2576.

    Not in our library10.7314/apjcp.2012.13.6.2571

  251. 251.

    Pirinççi N., Geçit I., Güneş M., et al. Serum adenosine deaminase, catalase and carbonic anhydrase activities in patients with bladder cancer. Clinics. 2012;67(12):1443-1446.

    Not in our library10.6061/clinics/2012(12)15

  252. 252.

    Simic T., Mimic-Oka J., Savic-Radojevic A., et al. Glutathione S-transferase T1-1 activity upregulated in transitional cell carcinoma of urinary bladder. Urology. 2005;65(5):1035-1040.

    Not in our library10.1016/j.urology.2005.01.005

  253. 253.

    Saygili E. I., Akcay T., Konukoglu D., Papilla C. Glutathione and glutathione-related enzymes in colorectal cancer patients. Journal of Toxicology and Environmental Health. Part A. 2003;66(5):411-415.

    Not in our library10.1080/15287390306448

  254. 254.

    Zabłocka-Słowińska K., Płaczkowska S., Prescha A., et al. Serum and whole blood Zn, Cu and Mn profiles and their relation to redox status in lung cancer patients. Journal of Trace Elements in Medicine and Biology. 2018;45:78-84.

    Not in our library10.1016/j.jtemb.2017.09.024

  255. 255.

    Oh I.-J., Kim H. E., Song S. Y., et al. Diagnostic value of serum glutathione peroxidase 3 levels in patients with lung cancer. Thoracic Cancer. 2014;5(5):425-430.

    Not in our library10.1111/1759-7714.12113

  256. 256.

    Gupta K. B., Tandon S., Garg V., Lal H. Plasma glutathione-S-transferase activity in lung malignancy. Indian Journal of Tuberculosis. 2000;47(4):227-228.

    Not in our library

  257. 257.

    Ferruzzi E., Franceschini R., Cazzolato G., et al. Blood glutathione as a surrogate marker of cancer tissue glutathione S-transferase activity in non-small cell lung cancer and squamous cell carcinoma of the head and neck. European Journal of Cancer. 2003;39(7):1019-1029.

    Not in our library10.1016/s0959-8049(03)00122-9

  258. 258.
    Role of superoxide dismutase in hepatitis B virus-related hepatocellular carcinoma · 2016
    Not checked
  259. 259.

    Arslan A., Demir H., Arslan H. Investigating catalase and carbonic anhydrase enzyme activities and levels of certain trace elements and heavy metals in patients with primary and metastatic hepatic carcinoma. Journal of Cancer Therapy. 2013;4(8):1373-1381.

    Not in our library10.4236/jct.2013.48163

  260. 260.

    Agnani D., Camacho-Vanegas O., Camacho C., et al. Decreased levels of serum glutathione peroxidase 3 are associated with papillary serous ovarian cancer and disease progression. Journal of Ovarian Research. 2011;4(1):p. 18.

    Not in our library10.1186/1757-2215-4-18

  261. 261.

    Asen A., Tanya T., Dincheva V., et al. Preliminary study of erythrocyte glutathione-s-transferase activity in patients with skin melanoma. Trakia Journal of Sciences. 2012;10(Supplement 1):88-94.

    Not in our library

  262. 262.

    Dinçer Y., Akçay T., Çelebi N., Uslu İ., Özmen Ö., Hatemi H. Glutathione S-transferase and O6-methylguanine DNA methyl transferase activities in patients with thyroid papillary carcinoma. Cancer Investigation. 2002;20(7-8):965-971.

    Not in our library10.1081/cnv-120005912

  263. 263.

    Matuszewski M., Szymańska B., Długosz A., Małkiewicz B., Dembowski J., Piwowar A. Preliminary evaluation of the diagnostic usefulness of uroplakin 2 with an assessment of the antioxidant potential of patients with bladder cancer. BioMed Research International. 2018;2018:9.

    Not in our library10.1155/2018/8693297

  264. 264.

    Liang D., Lin J., Grossman H. B., et al. Plasma vitamins E and A and risk of bladder cancer: a case–control analysis. Cancer Causes & Control. 2008;19(9):981-992.

    Not in our library10.1007/s10552-008-9165-2

  265. 265.

    Dorjgochoo T., Gao Y. T., Chow W. H., et al. Plasma carotenoids, tocopherols, retinol and breast cancer risk: results from the Shanghai Women Health Study (SWHS). Breast Cancer Research and Treatment. 2009;117(2):381-389.

    Not in our library10.1007/s10549-008-0270-4

  266. 266.

    Singh P., Kapil U., Shukla N. K., Deo S., Dwivedi S. N. Association between breast cancer and vitamin C, vitamin E and selenium levels: results of a case-control study in India. Asian Pacific Journal of Cancer Prevention. 2005;6(2):177-180.

    Not in our library

  267. 267.

    Nagata C., Shimizu H., Yoshikawa H., et al. Serum carotenoids and vitamins and risk of cervical dysplasia from a case–control study in Japan. British Journal of Cancer. 1999;81(7):1234-1237.

    Not in our library10.1038/sj.bjc.6690834

  268. 268.

    Kabat G. C., Kim M. Y., Sarto G. E., Shikany J. M., Rohan T. E. Repeated measurements of serum carotenoid, retinol and tocopherol levels in relation to colorectal cancer risk in the Women’s Health Initiative. European Journal of Clinical Nutrition. 2012;66(5):549-554.

    Not in our library10.1038/ejcn.2011.207

  269. 269.

    Klarod K., Hongsprabhas P., Khampitak T., et al. Serum antioxidant levels and nutritional status in early and advanced stage lung cancer patients. Nutrition. 2011;27(11-12):1156-1160.

    Not in our library10.1016/j.nut.2010.12.019

  270. 270.

    Ramatullah M., Rafique M., Khan M. N., Islam S. N. Serum vitamin e, c and a level in lung cancer: a case control study. European Scientific Journal. 2013;9(30).

    Not in our library

  271. 271.

    Yuan J. M., Gao Y. T., Ong C. N., Ross R. K., Yu M. C. Prediagnostic level of serum retinol in relation to reduced risk of hepatocellular carcinoma. Journal of the National Cancer Institute. 2006;98(7):482-490.

    Not in our library10.1093/jnci/djj104

  272. 272.

    Jeong N. H., Song E. S., Lee J. M., et al. Plasma carotenoids, retinol and tocopherol levels and the risk of ovarian cancer. Acta Obstetricia et Gynecologica Scandinavica. 2009;88(4):457-462.

    Not in our library10.1080/00016340902807215

  273. 273.

    Gann P. H., Ma J., Giovannucci E., et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Research. 1999;59(6):1225-1230.

    Not in our library

  274. 274.

    Karagas M. R., Greenberg E. R., Nierenberg D., et al. Risk of squamous cell carcinoma of the skin in relation to plasma selenium, alpha-tocopherol, beta-carotene, and retinol: a nested case-control study. Cancer Epidemiology, Biomarkers & Prevention. 1997;6(1):25-29.

    Not in our library

  275. 275.

    Maria Zowczak-Drabarczyk M., Murawa D., Kaczmarek L., Połom K., Litwiniuk M. Total antioxidant status in plasma of breast cancer patients in relation to ERβ expression. Contemporary Oncology. 2013;17(6):499-503.

    Not in our library10.5114/wo.2013.38782

  276. 276.

    Genet S., Gamini M., Metwally T. Deranged antioxidant status and oxidative stress in patients with cervical cancer receiving radiotherapy. Reactive Oxygen Species. 2018;5(13):68-77.

    Not in our library10.20455/ros.2018.807

  277. 277.
    Significance of Serum Total Oxidant/Antioxidant Status in Patients with Colorectal Cancer. · 2017
    Not checked
  278. 278.

    Camuzcuoglu H., Arioz D. T., Toy H., Kurt S., Celik H., Aksoy N. Assessment of preoperative serum prolidase activity in epithelial ovarian cancer. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2009;147(1):97-100.

    Not in our library10.1016/j.ejogrb.2009.07.012

  279. 279.

    Aldemir M. Evaluation of oxidative stress status and antioxidant capacity in patients with localized prostate cancer and benign prostatic hyperplasia. Journal of Clinical and Analytical Medicine. 2015;6(4):479-482.

    Not in our library10.4328/jcam.2209

  280. 280.
    Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans · 2017
    No notice
  281. 281.

    Vassalle C. An easy and reliable automated method to estimate oxidative stress in the clinical setting. Methods in Molecular Biology. 2008;477:31-39.

    Not in our library10.1007/978-1-60327-517-0_3

  282. 282.

    Veglia F., Cavalca V., Tremoli E. OXY-SCORE: a global index to improve evaluation of oxidative stress by combining pro- and antioxidant markers. Methods in Molecular Biology. 2010;594:197-213.

    Not in our library10.1007/978-1-60761-411-1_14

  283. 283.

    Veglia F., Cighetti G., de Franceschi M., et al. Age- and gender-related oxidative status determined in healthy subjects by means of OXY-SCORE, a potential new comprehensive index. Biomarkers. 2008;11(6):562-573.

    Not in our library10.1080/13547500600898623

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