sodium-nitrite and Neoplasms

Over the past several years, investigators studying nitric oxide (NO) biology and metabolism have come to learn that the one-electron oxidation product of NO, nitrite anion, serves as a unique player in modulating tissue NO bioavailability. Numerous studies have examined how this oxidized metabolite of NO can act as a salvage pathway for maintaining NO equivalents through multiple reduction mechanisms in permissive tissue environments. Moreover, it is now clear that nitrite anion production and distribution throughout the body can act in an endocrine manner to augment NO bioavailability, which is important for physiological and pathological processes. These discoveries have led to renewed hope and efforts for an effective NO-based therapeutic agent through the unique action of sodium nitrite as an NO prodrug. More recent studies also indicate that sodium nitrate may also increase plasma nitrite levels via the enterosalivary circulatory system resulting in nitrate reduction to nitrite by microorganisms found within the oral cavity. In this review, we discuss the importance of nitrite anion in several disease models along with an appraisal of sodium nitrite therapy in the clinic, potential caveats of such clinical uses, and future possibilities for nitrite-based therapies.

Topics: Animals; Autoimmune Diseases; Bacteria; Humans; Inflammation; Inorganic Chemicals; Ischemia; Mouth; Neoplasms; Nitric Oxide; Oxidation-Reduction; Sodium Nitrite

Nitric oxide concentrations in tumors do not reach apoptosis inducing levels when their excess NO is rapidly depleted. The out-flux of NO from a tumor to air or blood scales with the contacting area and with the concentration gradient; the gradient scales with the tumor-air or tumor-blood concentration difference and scales inversely with the thickness of the boundary layer, i.e. the fluid's flow rate. Air-contacting skin and lung cancers account for approximately 60% of all cancers in part because out-diffusion of NO from nascent tumors to air increases the likelihood of their survival. Out-diffusion of NO also explains their initially 2-D spreading at the air interface. Blood is an NO sink because its proteins are rapidly S-nitrosated; depletion of NO by the blood explains the dormancy of tumors until their vascularization and their virulence after vascularization. Erythrocytes store NO(2)- and their carbonic anhydrase converts it to NO and NO(3)(-). Thus, NaNO(2), a common additive in cured meats, may reduce NO out-diffusion by raising the blood NO concentration.

Topics: Animals; Eating; Electrochemistry; Humans; Neoplasms; Neovascularization, Pathologic; Nitric Oxide; Sodium Nitrite

A number of papers relating N-nitroso compounds as carcinogens for experimental animals and man was reviewed. These summerized in (1) early works, (2) amines and sodium nitrite, (3) disease models, (4) species susceptible to nitrosamines, (5) target organs, (6) strain specificity, (7) individual specificity and (8) minimum carcinogenic dose. Through these literature references and the results of animal experiments in the author's own laboratory on various acylated N-nitroso compounds, the possibility that various preformed nitrosamines in the environment, as well as those which are formed in our body, can cause tumors of various organs in human body is highly suggested.

Topics: Amines; Animals; Carcinogens; Cricetinae; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Male; Maternal-Fetal Exchange; Neoplasms; Neoplasms, Experimental; Nitroso Compounds; Organ Specificity; Pregnancy; Rats; Sodium Nitrite; Species Specificity

Hypoxia is an important mechanism of resistance to radiation therapy in many human malignancies including prostate cancer. It has been recently shown that ultrasound targeted microbubble cavitation (UTMC) can increase blood perfusion in skeletal muscle by triggering nitric oxide signaling. Interestingly, this effect was amplified with a sodium nitrite coinjection. Since sodium nitrite has been shown to synergize with radiotherapy (RT), we hypothesized that UTMC with a sodium nitrite coinjection could further radiosensitize solid tumors by increasing blood perfusion and thus reduce tumor hypoxia. We evaluated (1) the ability of UTMC with and without nitrite to increase perfusion in muscle (mouse hindlimbs) and human prostate tumors using different pulse lengths and pressure; (2) the efficacy of this approach as a provascular therapy given directly before RT in the human prostate subcutaneous xenografts PC3 tumor model. Using long pulses with various pressures, in muscle, the provascular response following UTMC was strong (6.61 ± 4.41-fold increase in perfusion post-treatment). In tumors, long pulses caused an increase in perfusion (2.42 ± 1.38-fold) at lower mechanical index (MI = 0.25) but not at higher MI (0.375, 0.5, and 0.750) when compared to control (no UTMC). However, when combined with RT, UTMC with long pulses (MI = 0.25) did not improve tumor growth inhibition. With short pulses, in muscle, the provascular response following UTMC (SONOS) + nitrite was strong (13.74 ± 8.60-fold increase in perfusion post-treatment). In tumors, UTMC (SONOS) + nitrite also caused a provascular response (1.94 ± 1.20-fold increase in perfusion post-treatment) that lasted for at least 10 min, but not with nitrite alone. Interestingly, the blunted provascular response observed for long pulses at higher MI without nitrite was reversed with the addition of nitrite. UTMC (SONOS) with and without nitrite caused an increase in perfusion in tumors. The provascular response observed for UTMC (SONOS) + nitrite was confirmed by histology. Finally, there was an improved growth inhibition for the 8 Gy RT dose + nitrite + UTMC group vs 8 Gy RT + nitrite alone. This effect was not significant with mice treated by UTMC + nitrite and receiving doses of 0 or 2 Gy RT. In conclusion, UTMC + nitrite increased blood flow leading to an increased efficacy of higher doses of RT in our tumor model, warranting further study of this strategy.

Topics: Animals; Humans; Male; Mice; Microbubbles; Muscle, Skeletal; Neoplasms; Sodium Nitrite; Ultrasonography

Iron oxide magnetic nanoparticles have been proposed for an increasing number of biomedical applications, such as drug delivery. To this end, toxicological studies of their potent effects in biological media must be better evaluated. The aim of this study was to synthesize, characterize, and examine the potential in vitro cytotoxicity and genotoxicity of thiolated (SH) and S-nitrosated (S-NO) iron oxide superparamagnetic nanoparticles toward healthy and cancer cell lines. Fe3O4 nanoparticles were synthesized by coprecipitation techniques and coated with small thiol-containing molecules, such as mercaptosuccinic acid (MSA) or meso-2,3-dimercaptosuccinic acid (DMSA). The physical-chemical, morphological, and magnetic properties of thiol-coating Fe3O4 nanoparticles were characterized by different techniques. The thiol groups on the surface of the nanoparticles were nitrosated, leading to the formation of S-nitroso-MSA- or S-nitroso-DMSA-Fe3O4 nanoparticles. The cytotoxicity and genotoxicity of thiolated and S-nitrosated nanoparticles were more deeply evaluated in healthy (3T3, human lymphocytes cells, and chinese hamster ovary cells) and cancer cell lines (MCF-7). The results demonstrated that thiol-coating iron oxide magnetic nanoparticles have few toxic effects in cells, whereas S-nitrosated-coated particles did cause toxic effects. Moreover, due to the superaramagnetic behavior of S-nitroso-Fe3O4 nanoparticles, those particles can be guided to the target site upon the application of an external magnetic field, leading to local toxic effects in the tumor cells. Taken together, the results suggest the promise of S-nitroso-magnetic nanoparticles in cancer treatment.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Apoptosis; Cell Survival; Cells, Cultured; CHO Cells; Comet Assay; Cricetinae; Cricetulus; Humans; Lymphocytes; Magnetic Phenomena; Magnetite Nanoparticles; MCF-7 Cells; Mice; Neoplasms; Nitrosation; Sodium Nitrite; Succimer; Thiomalates

Sodium nitrite is used as a color fixative and preservative in meats and fish. It is also used in manufacturing diazo dyes, nitroso compounds, and other organic compounds; in dyeing and printing textile fabrics and bleaching fibers; in photography; as a laboratory reagent and a corrosion inhibitor; in metal coatings for phosphatizing and detinning; and in the manufacture of rubber chemicals. Sodium nitrite also has been used in human and veterinary medicine as a vasodilator, a bronchial dilator, an intestinal relaxant, and an antidote for cyanide poisoning. Sodium nitrite was nominated by the FDA for toxicity and carcinogenesis studies based on its widespread use in foods. Male and female F344/N rats and B6C3F1 mice were exposed to sodium nitrite (99% pure) in drinking water for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 375, 750, 1500, 3,000, or 5000 ppm sodium nitrite (equivalent to average daily doses of approximately 30, 55, 115, 200, or 310 mg sodium nitrite/kg body weight to males and 40, 80, 130, 225, or 345 mg/kg to females) in drinking water for 14 weeks. Clinical pathology study groups of 15 male and 15 female rats were exposed to the same concentrations for 70 or 71 days. One female exposed to 3000 ppm died before the end of the study. Body weights of males exposed to 3000 or 5000 ppm and females exposed to 5000 ppm were significantly less than those of the controls. Water consumption by 5000 ppm males and 3000 and 5000 ppm females was less than that by the controls at weeks 2 and 14. Clinical findings related to sodium nitrite exposure included brown discoloration in the eyes and cyanosis of the mouth, tongue, ears, and feet of males exposed to 3000 or 5000 ppm and of females exposed to 1500 ppm or greater. Reticulocyte counts were increased in males and females exposed to 3000 or 5000 ppm. The erythron was decreased on day 19 but increased by week 14 in males and females exposed to 5000 ppm. Methemoglobin concentrations were elevated in almost all exposed groups throughout the 14 week study; a no-observed-adverse-effect level was not achieved. The relative kidney and spleen weights of males and females exposed to 3000 or 5000 ppm were significantly greater than those of the controls. Sperm motility in 1500 and 5000 ppm males was significantly decreased. Increased e. Sodium nitrite was mutagenic in Salmonella typhimurium strain TA100, with and without Aroclor 1254-induced hamster and rat liver S9 enzymes; no mutagenicity was observed in strain TA98. Results of acute bone marrow micronucleus tests with sodium nitrite in male rats and mice by intraperitoneal injection were negative. In addition, a peripheral blood micronucleus assay conducted with mice from the 14-week study gave negative results.. Under the conditions of this 2-year drinking water study, there was no evidence of carcinogenic activity of sodium nitrite in male or female F344/N rats exposed to 750, 1500, or 3000 ppm. There was no evidence of carcinogenic activity of sodium nitrite in male B6C3F1 mice exposed to 750, 1500, or 3000 ppm. There was equivocal evidence of carcinogenic activity of sodium nitrite in female B6C3F1 mice based on the positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the forestomach. Exposure to sodium nitrite in drinking water resulted in increased incidences of epithelial hyperplasia in the forestomach of male and female rats and in the glandular stomach of male mice. Decreased incidences of mononuclear cell leukemia occurred in male and female rats.

Topics: Analysis of Variance; Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Cricetinae; Female; Male; Methemoglobin; Mice; Mice, Inbred Strains; Mutagenicity Tests; Mutagens; Neoplasms; Pregnancy; Quality Control; Rats; Rats, Inbred F344; Sodium Nitrite; Survival Analysis; Time Factors; Tissue Distribution; Water Pollutants, Chemical; Water Supply

The carcinogenicity of sodium and of sodium nitrate was examined in F-344 rats. Sodium nitrite was administered in the drinking-water for 2 yr at levels of 0.125 or 0.25%. Sodium nitrate was given in the diet at levels 2.5 or 5%. A variety of tumours occurred in all groups including the controls. The only significant difference between treated and control groups in the total number of tumours detected in either of the studies was a significant decrease in tumour incidence in the high-dose females given nitrite compared with controls. There was no positive dose-response relationship either in the incidence or in the induction time of tumours in either of the studies. The only significant result was a reduction in the incidence of mononuclear cell leukaemias in the experimental groups in both studies. It is concluded that sodium nitrite and sodium nitrate did not exert a carcinogenic effect that could be detected under the conditions of this study in which the animals showed a high incidence of spontaneous tumours.

Topics: Animals; Female; Leukemia; Liver Neoplasms; Male; Mammary Neoplasms, Experimental; Neoplasms; Nitrates; Nitrites; Nitroso Compounds; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach

An epidemiologic study in an engineering company was prompted by the observation of three cases of cancer; it revealed several more cancers among women who wrapped bearing rings covered with antirust oil, i.e., 12 cases vs 3.9 expected. The 12 tumors were situated in different organs, including the uterus, ovaries, breast, thyroid, brain, colon, and bladder. No known carcinogenic substance was found that could explain the increased incidence of cancer. If the increased incidence is not a random phenomenon, N-phenyl-1-naphthylamine or its nitroso derivative is likely to be the causative agent.

Topics: 1-Naphthylamine; Adult; Aged; Aged, 80 and over; Carcinogens; Cohort Studies; Female; Humans; Industrial Oils; Male; Middle Aged; Neoplasms; Nitrosamines; Occupational Exposure; Sodium Nitrite; Sweden

Hamster embryos in utero on the 11th or 12th day of gestation were treated simultaneously with aminopyrine (Ap) and sodium nitrite (NaNO2) by oral administration of the compounds to the mothers by stomach tube. For measurement of induction of 8 AG-resistant mutations, the embryonic cells from treated and control mothers were cultured in MEM plus 10% FBS for 72 h and then selected in medium containing 10 or 20 microgram/ml of 8 AG. The number of 8 AG-resistant colonies was markedly increased after co-administration of Ap and NaNO2, and slight induction of mutations was also observed in cells from mothers given NaNO2 alone. This treatment also caused morphological or malignant transformation of cultured cells. About 5- to 6-fold increase in the number of transformed colonies was observed in cells from mothers given Ap plus NaNO2. Cells from the transformed colonies produced tumors when implanted into the cheek pouches of young golden hamsters. These tumors were diagnosed as pleomorphic fibrosarcomas. Similar results were obtained with cells from embryos treated transplacentally with NDMA as positive controls. A single transplacental oral application of Ap at 200 mg/kg or of NaNO2 had only slight biological actions to the cultured embryonic cells. NDMA was produced in the stomach of animals treated simultaneously with Ap and NaNO2. A small amount of NDMA was also detected in the stomach after a single dose of NaNO2.

Topics: Abnormalities, Drug-Induced; Aminopyrine; Animals; Azaguanine; Cells, Cultured; Cricetinae; Dimethylnitrosamine; Female; In Vitro Techniques; Maternal-Fetal Exchange; Mutation; Neoplasms; Nitrites; Pregnancy; Sodium Nitrite

Topics: Carcinogens; Cobalt; Epidermis; Methylcholanthrene; Mice; Neoplasms; Neoplasms, Experimental; Nitrites; Pharmacology; Propiophenones; Research; Skin Neoplasms; Sodium Nitrite; Toxicology