Reactive oxygen species,antioxidant mechanisms and serum cytokine levels in cancer patients: impact of an antioxidant treatment

Objective. So far, it is not well established whether oxidative stress found in cancer patients results from an increased production of oxidants in the body or from a failure of physiological antioxidant systems. To further investigate this question we have assessed the blood levels of reactive oxygen species as a marker of free radicals producing oxidative stress and the most relevant of the physiological body enzymes counteracting reactive oxygen species, namely glutathione peroxidase and superoxide dismutase. Serum levels of proinflammatory cytokines and IL‐2 were also investigated. All these parameters were studied in relation to the clinically most important index of disease progression, namely Performance Status (ECOG PS). We also tested the reducing ability of different antioxidant agents on reactive oxygen species levels by measuring the increase in glutathione peroxidase activity, and the reduction of serum levels of IL‐6 and TNF. Design, setting and subjects. We carried out an open non randomized study on 28 advanced stage cancer patients (stage III, 10.7%, and stage IV, 89.3%) with tumours at different (8) sites: all were hospitalized in the Medical Oncology Dept, University of Cagliari Interventions. The patients were divided into 5 groups and a different antioxidant treatment was administered to each group. The selected antioxidants were: alpha lipoic acid 200 mg/day orally, N‐acetylcysteine 1800 mg/day i.v. or carboxycysteine‐lysine salt 2.7 g/day orally, amifostine 375 mg/day i.v., reduced glutathione 600 mg/day i.v., vitamin A 30000 IU/day orally plus vitamin E 70 mg/day orally plus Vitamin C 500 mg/day orally. The antioxidant treatment was administered for 10 consecutive days. Results. Our results show that all but one of the antioxidants tested were effective in reducing reactive oxygen species levels and 2 of them (cysteine‐containing compounds and amifostine) had the additional effect of increasing glutathione peroxidase activity. Comprehensively, the “antioxidant treatment” was found to have an effect both on reactive oxygen species levels and glutathione peroxidase activity. The antioxidant treatment also reduced serum levels of IL‐6 and TNF. Patients in both ECOG PS 0‐1 and ECOG PS 2‐3 responded to antioxidant treatment.     

Trace elements and antioxidant enzymes in extremely low birthweight infants

Oxygen radicals are believed to contribute to typical diseases of prematurity, such as bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), retinopathy of prematurity (ROP) and necrotising enterocolitis (NEC). Our aim was to investigate whether these disorders are associated with disturbances in antioxidant enzyme activities and with low trace elements, which are co-factors of antioxidant enzymes. 209 infants with birthweight less than 1000 g were enrolled into a European multicentre randomised erythropoietin (rhEPO) trial; 155 developed one or more of the above mentioned diseases. We analysed Zn, Cu, Fe, Se in plasma and red blood cells (RBCs), superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in RBCs on the 3rd and 68th day of life. Zn, Fe, Se in plasma, and Se in RBCs decreased (p<0.01), and Zn in RBC (p<0.001), CuZn-SOD (p<0.01) and CAT increased (p<0.05), whereas GSH-Px remained unchanged. No differences were observed between the rhEPO and control groups. Antioxidant enzyme activities did not correlate with gestational age. In infants with BPD, IVH, ROP, or NEC, CuZn-SOD and CAT (p<0.05) were higher at day 68 than in infants without these diseases. CuZn-SOD and GSH-Px at 3 days and CuZn-SOD at 68 days correlated positively (p<0.05) with the duration of oxygen treatment. In conclusion, in ELBW infants, trace element concentrations decreased over the first 10 weeks of life. Lower trace element concentrations, did not affect the activities of CuZn-SOD, GSH-Px, and CAT. Typical diseases of prematurity were not associated with decreased antioxidant enzyme activities.     

Clinical significance of serum gastrin levels in patients with colorectal cancer

AIMS: An association between elevated serum gastrin levels and the presence of human colorectal cancer has been reported, and gastrin has been shown to stimulate the growth of experimentally induced colon neoplasia. The aim of this study was to determine the preoperative and postoperative concentrations of serum gastrin in 53 patients with colorectal cancer and to assess the correlation between gastrin levels and tumor characteristics and prognosis. MATERIALS AND METHODS: A prospective study was performed over a six-year period during which 53 patients received potentially curative surgery for colorectal cancer. The prognostic variables used for the analysis included age, sex, tumor site, stage and degree of differentiation, preoperative and postoperative serum values of carcinoembryonic antigen (CEA) and gastrin, cancer-related mortality, and survival. CEA and gastrin serum values were determined using radioimmunological methods. Follow-up was carried out with clinical and radiological tests. RESULTS: The mean preoperative gastrin concentration was 51.2+/-27.4 pg/mL (range 12-146). Significantly increased serum gastrin concentrations, which returned to normal after surgery, were detected only in patients with well-differentiated cancer (74.2+/-28.3 pg/mL; moderately differentiated, 52.1+/-23.8; poorly differentiated, 29.9+/-12.3, p=0.02). The prognosis was unrelated to serum gastrin level; instead, tumor stage, preoperative CEA value, and degree of differentiation affected patient survival. CONCLUSIONS: This study showed that the serum gastrin concentration is not an appropriate clinical oncogenic factor. Although occurring only in well-differentiated tumors, serum gastrin is unrelated to the prognosis of patients with colorectal cancer.     

Differentiation of serum levels of trace elements in normal and malignant breast patients

The objective of this study was to determine which elements in serum best differentiated breast cancer in a case-control study. Concentrations of 13 elements in serum of 68 breast tumor patients (25 malignant and 43 benign) and 26 healthy controls were measured. Logistic regression with different variable-selection procedures was used to determine a possible configuration of elements. Sensitivity and specificity of the model were calculated to obtain the optimal cutoff point for discriminating malignant breast cancers vs other individuals (including benign breast disease and normal ones). A combination of Cd, Mn, and Fe was found to have a specificity and sensitivity of 100% using forward-type logistic regression, when the cutoff value of the combination score was 52.71. Using stepwise-type logistic regression, a combination of Cr and Mn had a sensitivity of 100% and a specificity of 97.1% when the combination score of 17.4 was chosen as the cutoff. Similar analysis could be implemented to compare the malignant and control groups. Specificity and sensitivity were 100% for Mn (forward and stepwise type) with a cutoff point of 6.40. For the backward regression, specificity was 84.6% and sensitivity was 100% for Zn, with a cutoff point of 869.1. In conclusion, there was a significant difference in concentrations of all 13 elements in serum between breast cancer patients and controls. A combination among Cd, Mn, Fe, Cr, and Zn might be important to determine a differentiating reference for breast cancers if a long-term followed-up study is to be conducted.     

Trace element levels in serum and gastric mucosa in patients with Helicobacter pylori positive and negative gastritis

BackgroundMost trace elements are inhibited by Helicobacter pylori-infection, and variations in specific element levels are linked to the development of stomach cancer. This is the first study to show the relationship between serum and tissue concentrations of twenty-five trace elements and H. pylori infection status. This study purposed to define serum and tissue trace element levels of 25 healthy individuals with Helicobacter pylori-positive gastritis and Helicobacter pylori-negative gastritis and to reveal their relationship with the disease.MethodsStudy groups consisted of sixty-two patients with Helicobacter pylori-positive, thirty-seven patients with Helicobacter pylori-negative, and thirty healthy individuals. Serum and tissue concentrations of twenty-five elements (aluminum, boron, arsenic, barium, calcium, beryllium, copper, cadmium, iron, chromium, mercury, lithium, potassium, magnesium, sodium, manganese, nickel, phosphorus, lead, scandium, strontium, selenium, tellurium, titanium, zinc) were defined by inductively coupled plasma optical emission spectrometry.ResultsExcept for copper, lithium, and strontium elements in serum samples, other trace elements differed significantly between the groups (p < 0.05). The serum chromium (p = 0.002), mercury (p = 0.001), boron (p < 0.001), and cadmium (p < 0.001) levels of H. pylori-negative gastritis and H. pylori-positive gastritis participants were significantly different, and their serum concentrations were less than 0.5 µ/l. Boron, barium, beryllium, chromium, lithium, phosphorus and strontium elements in tissue samples did not differ significantly between the groups (p > 0.05). Manganese, nickel, tellurium and titanium elements were not detected in tissue and serum samples. The mean concentrations of calcium, beryllium, chromium, iron, potassium, lithium, magnesium, scandium, and selenium were higher in the tissues of patients with H. pylori gastritis compared to healthy control tissues. Also, cadmium could not be detected in tissue samples. There was a significant difference between H. pylori-infected tissue and serum chromium levels (p = 0.001), with lower levels detected in tissue samples.ConclusionThis is the first study that we are knowledgeable of that reports the concentrations of twenty five elements in both serum and tissue samples, as well as the relationship between trace elements and Helicobacter pylori-infection status. Dietary adjustment is indicated as an adjunct to medical therapy to stabilize trace elements because Helicobacter pylori bacteria cause inflammation and impair element absorption in gastritis patients. We also think that this study will shed light on studies on the relationship between Helicobacter pylori-trace elements and serum-tissue/healthy serum-tissue trace element levels of patients with Helicobacter pylori gastritis.     

Investigation of the relationship between GSTM1 gene variations and serum trace elements,plasma malondialdehyde levels in patients with colorectal cancer

Background

The aim of this study is to investigate of the relationship between GSTM1 gene variations and serum trace elements, plasma malondialdehyde levels in patient with colorectal cancer.

Mateials and Methods.

Genotype distributions of GSTM1 gene variations were determined using real-time polymerase chain reaction method. Serum trace element levels were determined using atomic absorption spectrophotometer method and plasma MDA levels were measurement by spectrophotometric method.

Results

Serum Cu levels, plasma MDA levels and Cu/Zn ratio were determined significantly higher in the group of CRC patient carrying the GA heterozygous genotype of the GSTM1 (rs 112,778,559) gene variation compared to healthy controls (p?<?0.05). Serum Cu, Zn levels, plasma MDA levels and Cu/Zn ratio were determined significantly higher in patients carrying GG homozygous genotype of the GSTM1 (rs 112778559) gene variation compared to healthy controls carrying same genotype (p?<?0.05). Serum Cu, Zn levels, plasma MDA levels and Cu/Zn ratio were determined significantly higher in the group of CRC patient carrying the GG homozygous genotype of the GSTM1 (rs 12068997) gene variation compared to healthy controls (p?<?0.05). On the other hand, serum Se levels were detected significantly lower in CRC patients carrying GA heterozygous and GG homozygous genotypes for GSTM1 (rs 112,778,559) and (rs 12,068,997) gene variations compared to healthy controls (p?<?0.05).

Conclusion

In our study, the evaluation of serum Cu, Zn and Se trace element levels and plasma MDA levels according to GSTM1 gene variations genotype distributions were enabled to obtain important biomarkers in terms of CRC development and progression.

     

Preoperative and longitudinal serum levels of CA 125 and CA 15.3 in patients with breast cancer

Serum levels of ovarian carcinoma antigen (CA 125) and breast carcinoma antigen (CA 15.3) were determined in 237 patients with breast carcinoma, 121 before any therapy and 116 after initial treatment, during uneventful follow-up or at the time of relapse. The aim was to assess how often the CA 125 test failed, i.e., was false-negative in patients in whom the CA 15.3 test was true-positive and, more important, whether it gave diagnostic information in patients in whom the CA 15.3 test failed. Before surgery or other initial therapy, serum CA 125 and CA 15.3 gave similar information in 85.1 percent of the patients: true-positive in 4.1 percent and false negative in 81.0 percent: CA 125 gave less information in 13.2 percent; and more information in only 1.7 percent. During follow-up, serum CA 125 and CA 15.3 gave similar information in 73.3 percent of the patients: true-positive (i.e., rising persistently from a nadir or elevated above 65 U/ml) in 23.3 percent, true-negative in 36.2 percent, and false-negative in 13.8 percent; CA 125 gave less information in 25.0 percent: false negative in 22.4 percent and false-positive in 2.6 percent; and more information in only 1.7 percent. Therefore, the CA 125 test appears useless for staging and is redundant when the CA 15.3 test is employed, for management of patients with breast cancer.     

Plasma lipid peroxidation and antioxidant levels in patients with rheumatoid arthritis

In recent years, a great number of studies have investigated the possible role of reactive oxygen species in the aetiology and pathogenesis of rheumatoid arthritis (RA). The aim of this study was to investigate plasma concentrations of vitamin E, beta-carotene, activities of glutathione peroxidase (GSH-Px) and catalase, levels of lipid peroxidation (MDA) and reduced glutathione (GSH) in 36 patients with rheumatoid arthritis (RA) and 22 healthy age-matched controls. The plasma activity of GSH-Px and catalase (p < 0.001), levels of GSH (p < 0.01), concentration of beta-carotene (p < 0.05) and vitamin E (p < 0.001), haemoglobin and hematocrit (p < 0.05) were significantly lower in patients with RA than in controls. The MDA levels (p < 0.01), C reactive protein, rheumatoid factor, anti-streptolysin-o values (p < 0.001), platelet count (p < 0.05) and erythrocyte sedimentation rate (p < 0.001) were higher in the patient group than in the control group. These results provide some evidence for a potential role of increased lipid peroxidation and decreased enzymic and non-enzymic antioxidants in RA by its inflammatory character. These results suggested that oxidant stress plays a very important role in the pathogenesis of RA.     

Elevated serum endothelin-1 levels in patients with colorectal cancer; relevance for prognosis

BACKGROUND: It has been demonstrated that the Doppler Perfusion Index (DPI) is increased in patients who are at risk of developing liver metastases from colorectal cancer. It has been postulated that a circulating hormonal factor is involved in the relative vasoconstriction throughout the splanchnic bed. Endothelin-1 (ET-1), a potent vasoconstrictor which has been associated with tumor growth and is produced by colorectal tumors, may play an important role in this phenomenon. In this paper the prognostic value of serum ET-1 in colorectal cancer is discussed. METHODS: Preoperative serum levels of ET-1 were assessed in three groups of patients: group A underwent resection of the colorectal tumor and remained free of recurrence (n=20); group B developed metachronous liver metastases at least six months after colorectal resection (n=14); and group C presented with colorectal cancer and synchronous liver metastases (n=22). RESULTS: The mean (SD) serum ET-1 levels in groups A, B and C were 1.59 (0.41) pmol/L, 1.70 (0.32) pmol/L and 1.85 (0.47) pmol/L, respectively. These values were significantly different from those of healthy controls (1.22 (0.31), p<0.05). Kaplan-Meier analyses revealed no prognostic value of preoperative serum ET-1 levels. CONCLUSIONS: These preliminary results demonstrate that serum ET-1 levels are raised in patients with colorectal cancer. Serum ET-1 levels do not seem to be of prognostic value for survival.     

Trace elements and lipid peroxidation in uremic patients on hemodialysis

Trace elements and lipid peroxidation in 26 patients with chronic renal failure treated with hemodialysis and 25 healthy subjects were observed. Both plasma and erythrocyte trace elements and plasma malon dialdehyde (MDA) were examined immediately before and after hemodialysis. Increased levels of plasma Cu, MDA, and erythrocyte Pb, Mn, Zn, and a significantly decreased plasma Se, Zn and erythrocyte Se were found in patients before hemodialysis. After a single hemodialysis, erythrocyte Mn, Cu, Zn, and plasma Cu, Al, and MDA were significantly increased whereas both plasma and erythrocyte Se were lower in patients than in healthy subjects. The level of MDA was not significantly changed during the single hemodialysis. Both plasma and erythrocyte Zn levels and plasma Cu and Al were significantly higher after hemodialysis than before hemodialysis. In conclusion, levels of trace elements are altered by hemodialysis, which may increase patient susceptibility to lipid peroxidation in uremia.     

Trace elements removal ability and antioxidant activity of Phragmites australis (from Algeria)

Abstract

In this study, roots, stems and leaves of the worldwide distributed macrophyte Phragmites australis (common reed) were tested as potential removal and biomonitors of trace elements contamination in sediment. In particular, the concentrations (100, 200, and 500?mg/kg) of the following elements were analyzed: Zn, Cu, Pb, and Fe. Results showed that the amount of concentrations in plant tissues is significantly (p?≤?0.01) dependent on the kind of organ and element. Trace element concentrations decreased according to the pattern of Fe^a (Roots^a > Stems^b > Leaves^b) > Zn^b (Root^a > Leaves^b > Stems^c) > Cu^c (Roots^a > Leaves^b > Stems^c) > Pb^c (Roots^a > Stems^b > Leaves^c), as well as the roots acted as the main centers of bioaccumulation for all elements studied, and stems as the transit organs for translocation from roots to leaves. The major mechanisms employed by the plant were probably phytostabilization on the basis of the calculated Biological Concentration Factor (BCF – metal concentration ratio of plant root to soil); and Translocation Factor (TF – metal concentration ratio of plants roots to above ground part). Finally, due to the low scavenger effect of the radical DPPH, we excluded the hypothesis of the use of antioxidant mechanism in the tolerance of metals.     

Identification of gastric cancer patients by serum protein profiling

Using surface-enhanced laser desorption ionization mass spectrometry (SELDI/TOF-MS) and ProteinChip technology, coupled with a pattern-matching algorithm and serum samples, we screened for protein patterns to differentiate gastric cancer patients from noncancer patients. A classifier ensemble, consisting of 50 decision trees, correctly classified all gastric cancers and all controls of a training set (100% sensitivity and 100% specificity). Eight of 9 stage I gastric cancers (88.9% sensitivity for stage I) were correctly classified. In addition, 28 sera from gastric cancer patients taken in different hospitals were correctly classified (100% sensitivity). Furthermore, all 11 control sera obtained from patients without gastric cancer (100% specificity) were classified correctly and 29 of 30 healthy blood-donors were classified as noncancerous. ProteinChip technology in conjunction with bioinformatics allows the highly sensitive and specific recognition of gastric cancer patients.     

幽门螺杆菌相关性胃癌患者血清白介素-4和干扰素-γ变化

目的观察幽门螺杆菌(Helicobacter pylori,H.pylori)相关性胃癌患者血清白介素-4(IL-4)和干扰素-γ(IFN-γ)含量的变化,以探讨H.pylori感染时宿主TH1/TH2细胞的免疫应答变化。方法采用酶联免疫吸附测定法测定7例H.pylori阴性胃癌患者和13例H.pylori阳性胃癌患者血清IL-4及IFN-γ的含量。结果 2组患者血清IL-4及IFN-γ含量差异均无统计学意义(P=0.897)。结论 H.pylori感染对胃癌患者TH1/TH2细胞的免疫应答无明显影响。     

Concentrations of some major and minor elements in larynx tissues with and without cancer

In this study, concentrations of some major and minor elements were determined in the larynx tissues with and without cancer, and results obtained were statistically compared. No meaningful differences were found between sodium, potassium, calcium and copper concentrations in cancer tissues, corresponding cancer-free adjacent tissues and in control larynx tissues. Phosphate concentrations of the cancer tissues were higher compared with cancer-free adjacent tissues and control tissues. Iron, zinc and magnesium concentrations were found increased in both cancer and corresponding cancer-free adjacent tissues relative to control values. Intra- and inter-element correlations established within and between groups indicated that relations between elements were also disordered in the cancer tissues. We suggest that the changed element status of cancerous larynx tissues may arise from increased requirements of cancer tissues for some elements such as iron, zinc, magnesium and phosphate.     

Trace element profiles in cancer patients

It has become evident over the last two decades that there is an intimate relationship between the trace elements and cancer. Some trace elements have been shown to be carcinogens, others appear to provide protection against cancer. Profound changes in trace element concentrations and distribution occur in patients with cancer, but most changes remain undefined. A review of a number of studies of trace element changes in patients with cancer demonstrates that simple correlations of trace element levels in disease are of only limited use. Such reports underscore the need for large-scale studies that consider the many variables of malignancies and of trace element chemistry. The variables that must be considered for cancer include tissue of origin; histologic, pathologic and clinical staging; nutritional status as reflected by serum levels of calcium, iron, magnesium, phosphorus, the electrolytes, pH, albumen, and globulin; endocrine balance, effects of previous and concurrent therapies such as surgery, chemotherapy, hormonal manipulation, immunotherapy, and radiotherapy; history of exposure to toxic agents; and the presence of other disease. Similarly, trace element studies entail variables that must be considered and controlled prospectively, including timing and techniques of sampling, storage, and analysis, and simultaneous measurement of at least the majority of possibly interrelated elements rather than studying one element at a time. The various national cooperative oncology groups such as ECOG, SWOG, and SEOG now offer unusually well-studied groups of cancer patients who are managed according to carefully and prospectively defined protocols in participating institutions. With present knowledge, it is now time to approach these groups with a proposal to incorporate trace element studies in their protocols. A potential protocol will be discussed.