Local carcinogenicity, rates of absorption, extent and persistence of macromolecular binding, and acute histopathological effects of N-hydroxy-1-naphthylamine and N-hydroxy-2-naphthylamine.
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The N-hydroxy derivatives of 1- and 2-naphthylamine (NA) are directly carcinogenic at sites of application. In this study, the carcinogenicity of these two compounds at s.c. injection sites was compared with their relative rates of absorption, with the extent and persistence of their binding to protein, RNA, and DNA in the skin-subcutis, and with acute histopathological changes observed after local application. Male Sprague-Dawley rats were given injections of the N-hydroxy derivatives in the right rear leg at 16 mumol/dose. When administered twice weekly for 12 weeks, N-hydroxy-1-NA caused a 100% incidence (30 of 30) of poorly differentiated sarcomas at the injection site. N-Hydroxy-2-NA administered in a similar manner resulted in a low yield of tumors (7%; 2 of 30). Injection of N-hydroxy-1-NA once weekly for 12 weeks or twice weekly for 6 weeks also induced a high incidence of sarcomas (93 to 97%), but the time to tumor formation was significantly longer (p less than 0.0001) than in animals treated twice weekly for 12 weeks. The tumors were classified as malignant fibrous histiocytomas. Possible antagonistic or synergistic effects between the two compounds were also investigated. A sequential 6-week treatment with each of the N-hydroxy derivatives did not alter the expected tumor yields. However, alternating injections over 12 weeks caused a significant lengthening in the time to tumor formation (p less than 0.05). N-Hydroxy-1-NA bound covalently to protein, RNA, and DNA to a much greater extent than did N-hydroxy-2-NA. Protein binding with both derivatives decreased by 80 to 90% by 7 days after treatment. RNA binding in N-hydroxy-1-NA-treated rats markedly decreased, while N-hydroxy-2-NA-bound residues diminished only slightly. During this period, the extent of DNA binding with both derivatives remained fairly constant. When N-hydroxy-2-NA was injected 3 days after N-hydroxy-1-NA, there was a marked reduction in the apparent levels of N-hydroxy-1-NA bound to RNA and DNA. The greater tumorigenicity of N-hydroxy-1-NA versus N-hydroxy-2-NA correlated with its greater extent of macromolecular binding. Examination of acute histopathological changes occurring after single injections of N-hydroxy-1-NA and/or N-hydroxy-2-NA indicated that both compounds caused extensive necrosis in tissues at the injection site.(ABSTRACT TRUNCATED AT 400 WORDS) (+info)
Interaction of an acute phase reactant, alpha 1-acid glycoprotein (orosomucoid), with the lymphoid cell surface: a model for non-specific immune suppression.
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alpha 1-Acid glycoprotein (AG), a serum component elevated during acute inflammation, has been implicated in the suppression of various immunological responses. Pretreatment of lymphoid cells with AG at a concentration commonly found in patients with acute inflammation results in the inhibition of mitogen induced lymphoproliferation as well as capping of concanavalin A (Con A) receptors and surface immunoglobulin (sIg) on the lymphoid cell surface. In order to determine a potential interaction of AG with the lipid bilayer we examined the effects of purified AG on synthetic phosphatidyl choline vesicles. AG displaces 1-anilino-8-naphthalene sulphonate (ANS), an anionic surface probe from these vesicles yet is unable to perturb the binding of N-phenyl-1-naphthalamine (NPN), a hydrophobic probe of the membrane interior. The non-immunosuppressive asialo-derivative of AG is incapable of displacing ANS from the vesicles. The interaction of AG with the membrane may partially involve electrostatic forces mediated by sialic acid and/or steric hindrance of receptor mobility. The results suggest that AG has the capacity to perturb the lymphoid cell surface and interfere with events required for lymphocyte proliferation. (+info)
Dansyl chloride labeling of Pseudomonas aeruginosa treated with pyocin R1: change in permeability of the cell envelope.
(67/96)
Pyocin R1, a bacteriocin of Pseudomonas aeruginosa, caused an increase in binding of fluorescent label, 1-dimethylaminonaphthalene-5-sulfonyl chloride (dansyl chloride), to sensitive cells. In pyocin R1-treated cells, cytoplasmic soluble proteins and crude ribosomes as well as cell envelopes were labeled by dansyl chloride. The amount of bound dye was proportional to the multiplicity of pyocin R1 and reached a maximal level at high multiplicity. In addition, pyocin R1 rapidly caused an increase in fluorescence intensity of the hydrophobic probes N-phenyl-1-naphthylamine, pyrene, and perylene, which were mixed with cells. These results show that pyocin R1 damages locally a cell envelope barrier to hydrophobic solutes and allows dyes to penetrate into the intracellular space across the barrier. (+info)
Studies on the degranulation test for carcinogens.
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The radiometric assay of degranulation of the hepatic endoplasmic reticulum by chemical carcinogens has been re-examined. Both 1,2,3,4,- and 1,25,6-dibenzanthracenes caused degranulation of rough membranes in vitro; with acetamidofluorenes and naphthylamines the carcinogenic analogues caused moderately greater degranulation. Degranulation by 1,2,3,4-dibenzantracene was rapid and was maximal after 5 min incubation. Pretreatment of animals with phenobarbital or methylcholanthrene increased the fraction of rough membranes, but these were not fully granulated. The assay is limited in specificity and sensitivity because the 1.35 M sucrose gradient does not effectively separate rough and smooth membranes, and sedimented membranes are contaminated with aggregates of free ribosomes. (+info)
Ionic changes in the mitotic apparatus at the metaphase/anaphase transition.
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We have employed a series of permeant, nontoxic, fluorescent probes to detect changes in ionic conditions within the mitotic apparatus of living endosperm cells of Haemanthus during the transition from metaphase to anaphase. Fluorescence emission intensity measurements from the spindle for chlorotetracycline (CTC) decline before the onset of anaphase, indicating a reduction in the amount of membrane-associated Ca2+ and suggesting an efflux of Ca2+ from membrane compartments into the spindle. Subsequent to the onset of anaphase, we observe increases in fluorescence with both 8-anilino-1-naphthalene sulfonate (ANS) and 3,3'-dipentyl 2,2'-dioxacarbocyanine (diO-C5(3)), sensitive to cationic and anionic charges at membrane surfaces, respectively. The increases with ANS and diO-C5(3) suggest that redistributions of ions within the spindle accompany anaphase motion. During the metaphase/anaphase transition, spindle membrane content remains constant, as evidenced by unchanging fluorescence with the hydrophobic probe, N-phenyl-1-naphthylamine (NPN). Shifts in emission intensity from the nonspindle cytoplasm or from the spindle poles do not accompany the changes in fluorescence we observe in the spindle, suggesting that any ionic fluxes responsible for the changes in fluorescence are restricted to the spindle domain. (+info)
Thymus-dependent and thymus-independent antibody responses: contrasting patterns of immunosuppression.
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The effects of mitoclomine, an anti-tumour agent, and of cortisone acetate on the antibody response of mice to thymus-dependent and thymus-independent antigens were compared. Both agents yielded patterns of immunosuppression which differed from that seen after X-rays, an agent which is likely to be active equally against T and B cells. Mitoclomine, at low doses, depressed thymus-independent responses the most; this effect can be explained if the drug is more active against B than T cells. Cortisone acetate at low doses, while depressing thymus-dependent responses, increased thymus-independent responses; this can be explained if the drug is more active against T than B cells. Thus three different patterns of immunosuppression (for X-rays, mitoclomine and cortisone acetate) can be interpreted in terms of effects simply on T or B cells. (+info)
Increased therapeutic efficiency of a lipid-soluble alkylating agent incorporated in liposomes.
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A highly hydrophobic alkylating agent, 1-N,N-bis(beta-bromoethyl) amino-3-methylnaphthalene, given as the free drug in oil, cured a substantial proportion of mice bearing the PC6 myeloma in the dose range 2-7 mg/kg. However, these doses were toxic, and the LD50 was 6-7 mg/kg. When incorporated in liposomes, similar curative effects were obtained at doses of 10-41 mg/kg without material toxicity, even at the highest dose. Liposome entrapment therefore greatly increases the therapeutic efficiency of this agent. (+info)
Lifetime carcinogenicity study of 1- and 2-naphthylamine in dogs.
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Groups of male and female beagle dogs were given daily doses of 400 mg of various mixtures of naphthylamines for up to 109 months. Survivors were killed at 128 months. A variety of pathological conditions was diagnosed, but the only effect related to treatment was the induction of bladder neoplasms. All dogs which received pure 2-naphthylamine developed transitional-cell carcinomas of the bladder within 34 months. Two of 8 dogs receiving 6% 2-naphthylamine in 1-naphthylamine developed early carcinoma and 2/8 dogs receiving 0.5% 2-naphthylamine in 1-naphthylamine developed haemangioma of the bladder. Some of the dogs receiving 1-naphthylamine (total dose 950 g) and the controls had focal cystitis or hyperplasia, but no neoplasia of the bladder. These results confirm the carcinogenicity of 2-naphthylamine to dogs. No carcinogenic effect of 1-naphthylamine was observed, indicating that it is at least 200 times less potent as a carcinogen than 2-naphthylamine. The incidence of bladder cancer in dogs fed mixtures of both naphthylamines explains why previous experimental and epidemiological studies of impure 1-naphthylamine have revealed carcinogenicity. (+info)