Role of hydroxyl radical in DNA damage.
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Asbestos↗
Biomedical subjects
S A Weitzman
Publications and source records attributed to S A Weitzman.
Effects of hydrogen peroxide on oral carcinogenesis in hamsters.
The effects of twice weekly topical applications of hydrogen peroxide on the buccal epithelium of Syrian hamsters were studied. Animals were treated either with hydrogen peroxide alone, with hydrogen peroxide and the carcinogen 9, 10-dimethyl-1,2-benzanthracene (DMBA), or with DMBA alone. In animals treated with 30% H2O2 alone, histopathologic examination after 22 weeks revealed hyperkeratosis and hyperplasia in all animals with hyperchromatic cells and mild dysplasia in four of nine: no tumors were seen. In animals treated with DMBA alone, three of seven (43%) developed epidermoid carcinoma, while six of 11 (55%) of animals treated with DMBA plus 3% hydrogen peroxide and five of five (100%) of animals treated with DMBA plus 30% hydrogen peroxide (P = 0.054) developed carcinoma. Thus, hydrogen peroxide can, by itself, induce pathologic changes frequently associated with preneoplastic lesions; it may also augment carcinogenesis associated with DMBA.
9,10-Dimethyl-1,2-benzanthracene↗
Augmentation of 1,2-dimethylhydrazine-induced colon cancer by experimental colitis in mice: role of dietary vitamin E.
Because ulcerative colitis predisposes to colonic cancer, for determination of the effect of colitis on experimental colon carcinogenesis, rectal instillations of peptides that attract and activate neutrophils were used to induce colitis in CD-1 (ICR) BR mice receiving 20 weekly injections of the carcinogen 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]. From week 4 through week 15 of DMH injections, twice-weekly enemas of formyl-norleucyl-leucyl-phenylalanine were given to DMH-treated mice. The effect of the antioxidant vitamin E in the diet (1,750 IU/kg diet) was studied in another group of mice treated with DMH and having colitis. Four weeks after DMH was discontinued, cancer occurred in 9 of 28 (32%) animals with DMH plus control enemas, in 22 of 29 (76%) animals with DMH plus colitis (P = .001), and in 16 of 28 (57%) animals with DMH plus colitis plus supplemental vitamin E (P = .11 compared with the group with DMH and colitis). Colitis enhances DMH-induced colonic carcinogenesis.
1,2-Dimethylhydrazine↗
Phagocytes as carcinogens: malignant transformation produced by human neutrophils.
In a study of the relation between chronic inflammation and carcinogenesis, C3H mouse fibroblasts of the 10T 1/2 clone 8 line (10T 1/2 cells) were exposed to human neutrophils stimulated to synthesize reactive oxygen intermediates or to a cell-free enzymatic system generating superoxide (xanthine oxidase plus hypoxanthine). After exposure, the 10T 1/2 cells were either placed in tissue culture or immediately injected into athymic nude mice. Both malignant and benign tumors developed in the mice injected with treated cells, but not in those injected with control cells; in one instance cells grown from one of the benign tumors subsequently developed a malignant phenotype. Malignant transformation was also observed in treated cells in the experiments in vitro.
Animals↗
Asbestos-catalysed lipid peroxidation and its inhibition by desferroxamine.
In an effort to understand the properties of asbestos fibres that might contribute to their being toxic, we incubated three different varieties of asbestos with phospholipid emulsions and looked for evidence of lipid peroxidation. Although all three types of asbestos were able to catalyse lipid peroxidation in the native state, this catalytic activity was inhibited by pre-washing of the asbestos with the iron chelator desferroxamine. This suggests that: lipid peroxidation may be one of the mechanisms by which asbestos produces tissue injury, and treatment with iron chelators might diminish the potential to produce this injury.
Adenosine Diphosphate↗
The effect of vitamin C on oxygen radical-induced sister-chromatid exchanges.
We studied the effects of vitamin C (sodium ascorbate) on the genotoxicity of oxygen radicals to tissue culture cells. Chinese hamster ovary cells (CHO cells), when exposed to an enzymatic oxygen radical generating system (xanthine oxidase plus hypoxanthine), develop increased numbers of sister-chromatid exchanges (SCEs). Inclusion of ascorbate in these incubations resulted in significant, but variable effects. In some cases, ascorbate (less than 0.1 mM) was protective and fewer SCEs were produced. In others, significant augmentation of oxygen radical-induced SCEs occurred. These experiments illustrate the complexity of the interactions of ascorbate in biologic systems and the difficulty of predicting a desirable or harmful effect.
Animals↗
The insidious development of symptomatic secondary hormone syndromes in patients with malignant endocrine tumors.
Endocrine tumors may produce secondary or "ectopic" hormones that cause paraneoplastic syndromes. Such syndromes may be confused with more common complications related to a patient's tumor, and thus escape detection and appropriate treatment. The secondary hormone secretion responsible for these syndromes often occurs late in the course of such diseases and presents in an insidious manner. Two patients are presented that illustrate these points. The first, a woman with medullary carcinoma of the thyroid (MCT), developed a syndrome secondary to ACTH secretion that was confused initially with the changes caused by the massive diarrhea that accompanies MCT. The second, a man with malignant glucagonoma, is the first with this disease to have developed symptomatic hyperinsulinemia as a late complication. We stress the clinical courses of these patients and note that treatment of these syndromes may improve the quality of patients' lives.
ACTH Syndrome, Ectopic↗
Implantable device for drug delivery and blood sampling in the rat.
An implantable drug-delivery and venous sampling device is described that is constructed from a polyvinyl chloride catheter and a rubber intravenous catheter plug coated with Silastic. The implant was used for repeated venous sampling and for both administration of parenteral solutions and injections into the right colon of the rat for periods to 1 mo.
Animals↗
Antineutrophil autoantibodies in Graves' disease. Implications of thyrotropin binding to neutrophils.
The hyperthyroidism of Graves' disease may be caused by autoantibodies to thyrotropin (TSH) receptors. We have found that patients with this disease have autoantibodies to neutrophils as well, which can be displaced by TSH. Using a radiochemical opsonic assay, we found serum antibodies against homologous neutrophils in 6 of 11 Graves' patients. With a staphylococcal protein A-binding assay, we detected circulating antibodies to homologous neutrophils in 10 of 20 patients, while finding cell-bound antibody on autologous neutrophils in 7 of 8 (including 2 with negative serum tests). Use of human 125I-TSH in a radioligand binding assay revealed that TSH bound to neutrophils rapidly (maximum binding within 10 min at 22 degrees C, pH 7.4), specifically (less than 20% nonspecific binding), and reversibly. Adding TSH to the radiochemical assay resulted in a dose-dependent inhibition of opsonic antibody activity in serum from patients with Graves' disease. In contrast, TSH did not inhibit antibody activity of serum from patients with immune neutropenia not associated with thyroid disease. Our findings suggest a basis for the association of Graves' disease with neutropenia. Furthermore, the discovery of such antineutrophil antibodies in Graves' disease permits detection of cell-bound antibody when free antibody is not present.
Adult↗
Effects of antioxidants on oxidant-induced sister chromatid exchange formation.
Stimulated human phagocytes produce sister chromatid exchanges in cultured mammalian cells by a mechanism involving oxygen metabolites. Experiments were designed to determine whether antioxidants inhibit this process. Superoxide dismutase, catalase, and hydroxyl radical scavengers (benzoate, mannitol) protected target Chinese hamster ovary cells from phagocyte-induced sister chromatid exchanges, implicating the involvement of hydroxyl radicals in this chromosomal damage. N-acetylcysteine and beta-carotene were also protective. alpha-Tocopherol (greater than 5 microM) protected target cells exposed to phagocytes but not to enzymatically generated oxidants when the vitamin was added just before the source of oxygen radicals, suggesting, as reported by others, that the principal action of tocopherol in this setting was to inhibit the release of oxidants from phagocytes. On the other hand, cultivation of target cells with supplemental tocopherol protected them from the toxic effects of the enzymatic oxidant-producing system, indicating a role for membrane-associated free radicals in the mechanism of sister chromatid exchange induction. Low concentrations of sodium selenite (0.1-1.0 microM) protected the target cells. However, higher concentrations (10 microM) of selenite had no effect on oxidant-induced sister chromatid exchange formation, and 0.1 mM selenite increased the number of exchanges. Sodium selenite concentrations of 0.1 mM also decreased the intracellular glutathione concentration of target cells during an oxidant stress, and reducing target cell glutathione concentrations with buthionine sulfoximine increased their sensitivity to oxygen-related chromosomal damage. Therefore, the potentiation of oxygen radical-induced chromosomal damage observed with high concentrations of selenite may result from a decrease in the thiol antioxidant defense systems within the cell. The findings suggest that the hydroxyl radical has an important role in the production of phagocyte-induced cytogenetic injury, membrane-derived intermediates may be involved, depletion of intracellular glutathione renders cells more susceptible to this injury, and supplementation of target cells with antioxidants can protect them from oxygen radical-generated chromosomal injury.
Acetylcysteine↗
Treatment of squamous-cell carcinoma of the head and neck with cisplatin and 5-fluorouracil.
Seventy patients with squamous-cell carcinoma of the head and neck were treated with a 24-hour infusion of cisplatin, followed by a 5-day continuous infusion of 5-fluorouracil (5-FU). Among 31 patients without prior treatment, stage III (six patients) and IV (25 patients), there were seven complete responses (CRs) and 19 partial responses (PRs) for an overall response rate of 84%. In the group of 30 patients with recurrent disease after surgery and/or radiotherapy, there were five CRs and ten PRs (total response rate of 50%). Among nine patients who failed prior chemotherapy, there were two CRs and one PR. Performance status and stage had minor effects on response frequency. The projected survival in the no prior treatment group was 59% at 22 months while the median survival of the recurrent cancer group was nine months. Compared to our previous study using cisplatin-vincristine-bleomycin (COB) chemotherapy, our present regimen has a higher CR rate (P less than .008). Durations of response and survival in the present study appear to be longer in the unresectable group and the recurrent cancer group. Toxicity was generally mild. The use of dexamethasone, diphenhydramine, droperidol, and perphenazine as antiemetics prophylactically resulted in 28% of treatment cycles associated with vomiting. This compares favorably with our previous 79% incidence of vomiting. This regimen appears to be more effective than our previous regimen and can be given with less toxicity.
Adult↗
Immunogenicity of hepatitis B vaccine in oncology patients receiving chemotherapy.
We evaluated the immunogenicity and safety of three 40 micrograms doses of hepatitis B vaccine in oncology patients receiving chemotherapy. Of 76 patients screened for entry into the study, 13 (17%) already had been exposed to hepatitis B and were ineligible; 26 chose to join the study. The cumulative life-table response rate during the 12-month observation period was 70.8%; adequate immune response was linked to survival, 73% in survivors completing the study and 9% in nonsurvivors. Adverse effects were minor. We conclude that hepatitis B vaccine is safe and usually effective in inducing immunity in oncology patients younger than 60 years of age who are receiving chemotherapy.
Adult↗
Acute colitis produced by chemotactic peptides in rats and mice.
Colonic inflammation was produced in rats and mice by peptides chemotactic for polymorphonuclear leukocytes. Instillation of formylmethionyl-leucyl-phenylalanine (FMLP) and formylnorleucyl-leucyl-phenylalanine (FNLP) into isolated segments of rat colon caused marked mucosal edema and polymorphonuclear leukocyte infiltration within 2 hours. Higher concentrations of FNLP caused ulceration and necrosis as well. Formylmethionine (FMet), a compound with less chemotactic activity, caused much less inflammation. In mice, rectal instillation of FNLP caused dose-dependent acute mucosal inflammation which persisted for longer than 12 hours. Twice-weekly rectal instillation of FNLP provided a model of colitis based on neutrophil chemotaxis.
Acute Disease↗
Asbestos catalyzes hydroxyl and superoxide radical generation from hydrogen peroxide.
To understand chemical characteristics of the asbestos minerals which might contribute to tissue damage, the catalytic properties of three different varieties were studied. Using spin trapping techniques it was determined that crocidolite, chrysotile, and amosite asbestos were all able to catalyze the generation of toxic hydroxyl radicals from a normal byproduct of tissue metabolism, hydrogen peroxide. The iron chelator desferroxamine inhibits this reaction, indicating a major role for iron in the catalytic process, and suggesting a possible mechanism by which asbestos toxicity might be reduced.
Asbestos↗
Phagocyte-induced mutation in Chinese hamster ovary cells.
Human phagocytic cells elaborate toxic oxygen metabolites which can cause mutations in bacteria and sister chromatid exchanges in cultured mammalian cells. In the present study we demonstrate that human phagocytes can induce mutations in Chinese hamster ovary cells.
Animals↗
The severity of immune neutropenia correlates with the maturational specificity of antineutrophil antibodies.
Sera from 15 patients with antineutrophil antibodies against peripheral blood neutrophils were incubated with normal bone marrow, and the reaction with marrow precursors was determined. Serum from controls did not deposit IgG on either peripheral blood or marrow myeloid cells. Serum from patients with moderate immune neutropenia with myeloid hyperplasia deposited IgG on neutrophils, bands and metamyelocytes, but not on earlier precursors. Serum from one patient with severe neutropenia and myeloid hypoplasia deposited IgG on myelocytes and promyelocytes as well as more mature cells. Serum from a patient with antineutrophil antibodies which impaired chemotaxis but who did not have neutropenia deposited IgG only on neutrophils and occasional bands. Immune neutropenia may become increasingly severe as antibodies become directed against earlier precursors.
Agranulocytosis↗
Chronic treatment with hydrogen peroxide. Is it safe?
The regular application of hydrogen peroxide to gingival tissues is becoming widely used as part of dental hygiene. Since hydrogen peroxide can be toxic under certain experimental conditions, proof of both safety and efficacy of its chronic administration should be available before prescription to the general public.
Animals↗
Stimulated human phagocytes produce cytogenetic changes in cultured mammalian cells.
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Animals↗