Chronic inflammation and oxidative stress in human carcinogenesis

A wide array of chronic inflammatory conditions predispose susceptible cells to neoplastic transformation. In general, the longer the inflammation persists, the higher the risk of cancer. A mutated cell is a sine qua non for carcinogenesis. Inflammatory processes may induce DNA mutations in cells via oxidative/nitrosative stress. This condition occurs when the generation of free radicals and active intermediates in a system exceeds the system's ability to neutralize and eliminate them. Inflammatory cells and cancer cells themselves produce free radicals and soluble mediators such as metabolites of arachidonic acid, cytokines and chemokines, which act by further producing reactive species. These, in turn, strongly recruit inflammatory cells in a vicious circle. Reactive intermediates of oxygen and nitrogen may directly oxidize DNA, or may interfere with mechanisms of DNA repair. These reactive substances may also rapidly react with proteins, carbohydrates and lipids, and the derivative products may induce a high perturbation in the intracellular and intercellular homeostasis, until DNA mutation. The main substances that link inflammation to cancer via oxidative/nitrosative stress are prostaglandins and cytokines. The effectors are represented by an imbalance between pro-oxidant and antioxidant enzyme activities (lipoxygenase, cyclooxygenase and phospholipid hydroperoxide glutathione-peroxidase), hydroperoxides and lipoperoxides, aldehydes and peroxinitrite. This review focalizes some of these intricate events by discussing the relationships occurring among oxidative/nitrosative/metabolic stress, inflammation and cancer.     

Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics

Mitomycin C (MC) is a naturally occurring anticancer agent which has been shown to be more cytotoxic to hypoxic tumor cells than to their aerobic counterparts. The mechanism of action of this agent is thought to involve biological reductive activation, to a species that alkylates DNA. A comparison of the cytotoxicity of MC to EMT6 tumor cells with that of the structural analogues porfiromycin (PM), N-(N',N'-dimethylaminomethylene)amine analogue of mitomycin C (BMY-25282), and N-(N',N'-dimethylaminomethylene)amine analogue of porfiromycin (BL-6783) has demonstrated that PM is considerably less cytotoxic to aerobic EMT6 cells than MC, whereas BMY-25282 and BL-6783 are significantly more toxic. The relative abilities of each of these compounds to generate oxygen free radicals following biological activation were measured. Tumor cell sonicates, reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase, xanthine oxidase, and mitochondria were used as the biological reducing systems. All four mitomycin antibiotics produced oxygen radicals following biological reduction, a process that may account for the aerobic cytotoxicity of agents of this class. The generation of relative amounts of superoxide and hydroxyl radical were also measured in EMT6 cell sonicates. BMY-25282 and BL-6783 produced significantly greater quantities of oxygen free radicals with the EMT6 cell sonicate, reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase, and mitochondria than did MC and PM. In contrast, BMY-25282 and BL-6783 did not generate detectable levels of free radicals in the presence of xanthine oxidase, whereas this enzyme was capable of generating free radicals with MC and PM as substrates. MC consistently produced greater amounts of free radicals than PM with all of the reducing systems. BMY-25282, BL-6783, and MC all generated hydroxyl radicals, while PM did not appear to form these radicals. The findings indicate that a correlation exists between the ability of the mitomycin antibiotics to generate oxygen radicals and their cytotoxicity to aerobic EMT6 tumor cells.     

The study of co-morbid conditions in children with allergic rhinitis, from Mumbai, Maharashtra, India

Allergic rhinitis (AR), an allergen-induced inflammation of the nasal mucosa, is frequently associated with co-morbid conditions. It is important to recognize the onset and existence of these co-morbid conditions, for adequate treatment and prevention of the development of new allergen sensitizations and air-way hypersensitivities. The aim of our study was to determine the prevalence of co-morbid conditions associated with AR, in Indian children. We selected 65 consecutive children below the age of 18 years, who attended the Allergy and Asthma Clinic of our hospital, between March 1, 2005 to November 30, 2006 and compared them with the available literature. The most common co-morbid condition with AR was asthma (75.4%), followed by urticaria (33.9%), conjunctivitis (29.2%) and sinusitis (23.1%) in that order. Two patients (3.1%) each, had adenoid hypertrophy and nasal polyps. Psoriasis was seen in 4/65 (6.2%). Four patients (6.2%) were free from any co-morbid conditions as opposed to 61/65 (93.8%), who suffered from one to three co-morbid conditions each. Co-morbid conditions are a rule rather than an exception, the most common association being asthma. Asthma often is asymptomatic and routine PFT testing is valuable. The association of psoriasis is interesting.     

Role of free radicals in the treatment of cancer

Free radicals including active oxygen species attack various cells by destroying lipids, proteins and enzymes, and often result in cell death. Recently, free radicals have been found to participate in the mechanism of anticancer therapy such as irradiation, chemotherapy, laser and immunotherapy. Since tumor cells contain fewer scavengers of radicals, it would be reasonable to look for a way to produce a large amount of free radicals in tumor tissues for future anticancer therapy. It should be noted that a variety of side effects induced by anticancer therapy are often related to the production of free radicals in normal organs.     

Allergic Rhinitis: an Overview

Allergic rhinitis is an inflammatory disorder of the nasal mucosa induced by allergen exposure triggering IgE-mediated inflammation. Clinically, it is characterized by four major symptoms–rhinorrhea, sneezing, nasal itching, and nasal congestion. It can also be associated with co-morbid conditions as Asthma, Atopic Dermatitis & Nasal polyps. Around 20–30 % of the Indian population suffers from allergic rhinitis and that 15 % develop asthma. The diagnosis & treatment of allergic rhinitis should follow ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines while of asthma should follow the GINA (Global Initiative for Asthma) guidelines. The treatment of allergic rhinitis should combine allergen avoidance (whenever possible), pharmacotherapy, and allergen immunotherapy. Intranasal corticosteroids are the most effective modality for treating allergic rhinitis and their sensory attributes are important in patient compliance.     

Nasal Polyposis: Current Trends

Nasal polyps (NP) are one of the most common inflammatory mass lesions of the nose, affecting up to 4% of the population. They present with nasal obstruction, anosmia, rhinorrhoea, post nasal drip, and less commonly facial pain. Their etiology remains unclear, but they are known to have associations with allergy, asthma, infection, fungus, cystic fibrosis, and aspirin sensitivity. However, the underlying mechanisms interlinking these pathologic conditions to NP formation remain unclear. Also strong genetic factors are implicated in the pathogenesis of NP, but genetic and molecular alterations required for its development and progression are still unclear. Management of NP involves a combination of medical therapy and surgery. There is good evidence for the use of corticosteroids (systemic and topical) both as primary treatment and as postoperative prophylaxis against recurrence, but the prolonged course of the disease and adverse effects of systemic steroids limits their use. Hence several new drugs are under trial. Surgical treatment has been refined significantly over the past 20 years with the advent of endoscopic sinus surgery and, in general, is reserved for cases refractory to medical treatment. Recurrence of the polyposis is common with severe disease recurring in up to 10% of patients. Over the last two decades, increasing insights in the pathophysiology of nasal polyposis opens perspective for new pharmacological treatment options, with eosinophilic inflammation, IgE, fungi and Staphylococcus aureus as potential targets. A better understanding of the pathophysiology underlying the persistent inflammatory state in NP is necessary to ultimately develop novel pharmacotherapeutic approaches. In this paper we present the newer treatment options available for better control and possibly cure of the disease.     

Formation of a mutagen, glyoxal, from DNA treated with oxygen free radicals

Oxygen free radicals cause extensive chemical changes in DNA,including base and sugar modifications and strand breaks. Inthe present study we found that a mutagen, glyoxal, is producedby exposure of DNA to an oxygen radical forming system (5 mMFeSO₄-EDTA, 37C, 60 min). It was produced with 17 times higherefficiency than 8-hydroxydeoxyguanosine. Thus it is possiblethat the formation of glyoxal is one of the major types of damagein DNA exposed to oxygen free radicals.     

Dextran sulfate enhances the level of an oxidative DNA damage biomarker, 8-oxo-7,8-dihydro-2'-deoxyguanosine, in rat colonic mucosa.

Dextran sodium sulfate (DSS) given in drinking water can induce colonic inflammation and produce colorectal tumors in rodents, although it is not directly genotoxic. The hypothesis that DSS can produce free radicals and induce oxidative DNA damage in colonic mucosa has been tested. In rats fed for 2 days with water containing 3% and 6% DSS, colonic inflammation manifestations were recorded and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), a major biomarker of oxidative DNA damage, was assayed in colonic mucosa. As compared with control rats given pure water, inflammatory manifestations were seen in rats given DSS. At the same time, 8-oxodGuo levels in colonic mucosa were doubled (P < 0.001). These results suggest that formation of oxidative DNA damage in colonic mucosa depends on inflammation and maybe on the production of reactive oxygen species. This study shows that DSS can induce oxidative DNA damage within only 2 days, which could explain in part its carcinogenic properties.     

Image cytometry characterization of ploidy level, proliferative activity and chromatin pattern in 50 nasal polyps

A computer-assisted microscope analysis of Feulgen-stained nuclei was carried out on a series of 50 nasal polyps in order to try to identify specific biological subgroups. The present series of 50 nasal polyps includes single polyps both associated (n=9) and unassociated (n=9) with allergy and diffuse polyposis both associated (n=7) and unassociated (n=9) with allergy, cystic fibrosis (n=9) and ASA (aspirin-sinusitis-asthma) related polyposis (n=7). The computer-assisted microscope analysis provides 36 quantitative variables which include 1 variable describing proliferative activity, 9 describing the nuclear desoxyribonucleic acid distribution (DNA ploidy level) and 26 describing nucleus morphology, i.e. its size and chromatin pattern. The results show that the methodology proposed here enabled four major groups of nasal polyps to be identified, i.e. diffuse polyposis associated with allergy, cystic fibrosis-related polyposis, single polyps both associated and unassociated either with allergy and a fourth group including diffuse polyposis not associated with allergy and ASA-related polyposis. These four groups of nasal polyps differed markedly in their morphonuclear characteristics, but not in the proliferative activity- and DNA ploidy-related variables.     

L-carnitine inhibits hepatocarcinogenesis via protection of mitochondria

Hepatocellular carcinoma is usually preceded by chronic inflammation. However, the molecular mechanism in hepatocarcinogenesis is not well known. Recently, we reported that mitochondrial dysfunction plays an important role in hepatocarcinogenesis via the production of free radicals. Furthermore, we proved that L-carnitine effectively protects mitochondrial function in vivo. Therefore, we investigated whether long-term administration of L-carnitine could prevent hepatitis and subsequent hepatocellular carcinoma in Long-Evans Cinnamon rats that are often analyzed as a model of hepatocarcinogenesis. The results indicated that oxidative stress elicited from abnormally accumulated copper increased the amount of free fatty acids, thereby inducing mitochondrial dysfunction, resulting in cell death and enhanced secondary generation of reactive oxygen species, which were significantly inhibited by carnitine treatment. Finally, the occurrence of placental glutathione S-transferase-positive foci as a marker for preneoplastic lesions and hepatocarcinogenesis were significantly inhibited by L-carnitine. These facts suggest that mitochondrial injury plays an essential role in the development of hepatocarcinogenesis and that the clinical use of carnitine has excellent therapeutic potential in individuals with chronic hepatitis.     

EXPERIMENTAL RESEARCH ON EFFECT OF ALLITRADI ON IMPROVING GJIC AND ANTI OXIDATION

本文从氧自由基、ＧＪＩＣ（细胞间缝隙连接通讯）及ＤＮＡ含量三个不同角度观察了大蒜素可显著减轻氧自由基对细胞的毒害，并能解除苯巴比妥对ＧＪＩＣ的抑制（Ｐ＜００１），提示大蒜素有明显的预防苯巴比妥的动物促癌作用及对抗氧自由基损害的功效。     

Mutagenic specificity of oxygen radicals produced by human leukemia cells.

An important source of endogenous oxygen radicals are phagocytic cells such as neutrophils and macrophages. The human leukemia cell line HL-60 can be induced to differentiate into a neutrophil-like cell population. Among the properties of these differentiated cells is the ability to produce reactive oxygen species when stimulated by tumor promoters. Mutagenesis induced by HL-60-generated free radicals was assessed using the M13mp2 forward mutation assay. Single-stranded M13mp2 DNA was coincubated with phorbol ester-stimulated HL-60 cells, after which mutations were scored by transfecting the DNA into SOS-induced Escherichia coli. The mutation frequency was increased 6-fold above background in DNA incubated with HL-60 cells. The majority of the mutations were single-base substitutions. However, approximately 6% of the mutations were tandem double substitutions that occurred in runs of adjacent cytidines. Overall, the mutations were clustered at apparent "hot spots," many of which were similar to sites seen using iron to generate oxygen radicals. These results suggest that human cells able to produce oxygen radicals in response to tumor promoters might play a significant role in the generation of tumors.     

Salivary analysis in oral cancer patients: DNA and protein oxidation, reactive nitrogen species, and antioxidant profile

BACKGROUND: Free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), which induce oxidative and nitrative stress, are main contributors to oral carcinogenesis. The RNS (nitrosamines: nitrates, NO(3), and nitrites, NO(2)) are also produced by the reaction of ROS and other free radicals with nitric oxide (NO) and are therefore in equilibrium with it. METHODS: Whole saliva was collected from a group of 25 consenting oral squamous cell carcinoma (OSCC) patients and from a control group of 25 healthy age- and gender-matched individuals. General and specific salivary antioxidant components, salivary nitrosamines, and oxidatively damaged salivary DNA and proteins were measured. RESULTS: The findings showed that oxidative and nitrative stress altered the salivary composition in OSCC patients. Analyzed salivary RNS were substantially higher (NO, 60%; NO(2), 190%; NO(3), 93%), whereas all salivary antioxidants were substantially reduced. The 8-hydroxy-deoxyguanosine (8-OHdG) marker (a widely used indicator of DNA oxidation) increased by 65% and the salivary carbonylation level was significantly higher. CONCLUSIONS: The increase in ROS and RNS may have been the event that led to the consumption and reduction of salivary antioxidant systems, thus explaining the oxidative damage to the DNA and proteins, and possibly the promotion of OSCC. The oxidized proteins and DNA found in the saliva of the cancer patients seems to be the first demonstration of a direct link between salivary free radicals, antioxidants, and OSCC. This may be important for better understanding the pathogenesis of the disease and may contribute to its diagnosis and treatment.     

Efficacy of superoxide dismutase mimetic M40403 in attenuating radiation-induced oral mucositis in hamsters

PURPOSE: M40403 is a small-molecule superoxide dismutase mimetic that has shown efficacy in animal model disease states in which superoxide anions are thought to play a key role. Radiation treatment and chemotherapy for cancer generate free oxygen radicals that are hypothesized to trigger unwanted side effects in healthy tissue. For some patients undergoing these antineoplastic treatments, one of the most prevalent side effects is oral mucositis, which is a painful, often dose-limiting condition. Preclinical and clinical studies of this condition have shown the positive effect of treatment with compounds that decrease free oxygen radicals. This study investigated the efficacy M40403 in a clinically relevant hamster model of acute, radiation-induced oral mucositis. Methods: Oral mucositis was induced in hamsters by irradiation of the cheek pouch. The ability of i.p. administered M40403 to decrease the duration and severity of oral mucositis was assessed after treatment at different doses and dosing schedules. Oral mucositis was scored using the WHO grading scale. RESULTS: Compared with placebo-treated animals, those irradiated on day 0 and treated twice daily with 30 mg/kg M40403 had significantly less severe and shorter duration mucositis over a range of treatment schedules, including from days -1 to 3, day 0 to 3, and day 0 alone. Similar efficacy was achieved at doses of 10 and 3 mg/kg twice daily on days -1 to 3. CONCLUSIONS: These results implicate free oxygen radicals in the onset of oral mucositis and also provide the basis for further development of M40403 in the prevention of this condition in at-risk cancer patients.     

The role of the mitochondria generating reactive oxygen species and nitric oxide in postischemic functional disturbance of the kidney

Experiments on 10 rats and 10 rabbits were made to investigate metabolic aftereffects of 40-minute heat ischemia and subsequent reperfusion. It was found that mitochondrial function deteriorated significantly in an early postischemic period. The disorder manifested with a relative prevalence of cell ATP consumption over its synthesis. This is accompanied with intensive production by mitochondria of nitric oxide and oxygen free radicals. Fluorescent probes and confocal microscopy of vital renal sections showed that mitochondria are responsible for excessive generation of nitric oxide and oxygen radicals in the kidney in an early reperfusion period. The discussion concerns the role of nitric oxide in reperfusion renal damage and participation of mitochondria in formation of its anti-ischemic resistance.     

Endoscopic Sinus Surgery in Chronic Rhinosinusitis and Nasal Polyposis: A Comparative Study

Nasal polyposis are common presentations in patients of chronic rhinosinusitis and are considered to be associated with more severe forms of disease with poor treatment outcome. The presentation and treatment outcome after endoscopic sinus surgery in patients of chronic rhinosinusitis and nasal polyposis have been analysed in this study. A prospective analysis of 90 patients of chronic rhinosinusitis who were classified into two groups depending on presence and absence of nasal polyps was performed in the study. The two groups were evaluated using subjective (patient complaints) and objective (computed tomography scan and endoscopy scores) criteria. Preoperative data were compared with data obtained 12 months post endoscopic sinus surgery. The study included 38 patients of chronic rhinosinusitis and 52 patients of nasal polyps. The patients of nasal polyp group presented with increased severity of symptoms of nasal blockage, nasal discharge and reduced sense of smell as compared to the chronic rhinosinusitis group who had significantly higher presentation of headache and facial pain. The preoperative CT scan revealed significantly higher bilateral disease with increased involvement of multiple sinuses in nasal polyp group. Post endoscopic sinus surgery both the groups showed significant improvement in their symptoms with the nasal polyp group demonstrating reduction in improvement on 1 year follow up. In our study we have found the patients with chronic rhinosinusitis and nasal polyp have varied severity of symptoms with the nasal polyp group having higher nasal symptoms and increased severity as compared to chronic rhinosinusitis group. Though the universal rationale of management by adequate drainage and ventilation of sinus is similar in both groups, there is a reduction in both objective and subjective scores during 1 year follow up in the nasal polyp group.     

Role of oxygen radicals in 12-O-tetradecanoylphorbol-13-acetate-induced squamous differentiation of cultured normal human bronchial epithelial cells

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits growth and induces terminal squamous differentiation of normal human bronchial cells when added to the culture media [J. C. Willey, A. J. Saladino, C. Ozanne, J. F. Lechner, and C. C. Harris, Carcinogenesis (lond.), 5: 209-215, 1984]. We have investigated the possibility of oxygen free radicals being involved as intermediates in this process. Electron paramagnetic resonance measurements using the spin-trapping agent 5,5-dimethyl-1-pyrroline-1-oxide failed to detect oxygen free radicals in bronchial epithelial cells exposed to TPA, although oxy radicals were detected in bronchial epithelial cells after a nontoxic exposure to menadione, and in human neutrophils after exposure to TPA. Addition to the culture media of free radical scavenger, i.e., reduced glutathione, N-acetylcysteine, D-alpha-tocopherol, copper (II) (3,5-diisopropylsalicyclic acid)2, or the combination of superoxide dismutase and catalase did not affect the dose-dependent growth inhibition of TPA on the bronchial epithelial cells. Moreover, exposure of the bronchial epithelial cells to TPA did not result in increased DNA single strand breaks measured by alkaline elution, as would be expected with a free radical mediated mechanism. Thus, our results argue against the importance of oxygen free radicals in the inhibition of growth and the induction of squamous differentiation by TPA in normal human bronchial epithelial cells.     

Radical causes of cancer

Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals--such as antioxidant scavengers and enzymes--and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.