UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of potential synergistic interactions, we added 25 mg/m2 i.v. cisplatin (P) 25 given on days 1-5 to the combination of 45 mg/m2 i.v. doxorubicin (A) given on day 1, 800 mg/m2 i.v. cyclophosphamide (C) given on day 1, and 50 mg/m2 i.v. etoposide (E) given on days 1-5. The resulting PACE regimen was given every 21 days for the first three courses and then every 28 days for the next five courses. PACE was used in two trials: the first, for both limited and extensive disease, was conducted at the University of Maryland Cancer Center and North Shore University Hospital; and the second, for extensive disease, was carried out as a Cancer and Leukemia Group B pilot study. Chest irradiation was not used. Prophylactic cranial irradiation at a dose of 3,000 cGy was given to all patients achieving a complete response (CR). A total of 33 subjects were entered in the first study; 8 of the 15 (53%) presenting with limited disease and 7 of the 18 (39%) exhibiting extensive disease achieved a CR. A partial response (PR) was obtained in 27% and 33% of cases, respectively. Of the 34 patients entered in the second study, 25 were eligible; 8 (32%) achieved a CR and 6 (24%) showed a PR. Toxicity was severe in both studies, including greater than 90% severe or life-threatening leukopenia and thrombocytopenia. Serial creatinine-clearance evaluations in the first study indicated progressive deterioration, which required discontinuation of the cisplatin before the planned completion of treatment in most cases. Since the response rate was no higher than the historic data reported for the three-drug ACE combination and because the toxicity was severe, the studies were stopped and patients were followed for survival. After a follow-up period of greater than 6 years, the median survival was 24 months for limited disease, with 33% and 27% of the patients being alive at 3 and 6.5 years, respectively. The median survival for extensive disease was 15 and 11 months in the first and second studies, respectively. These pilot studies suggest that the addition of cisplatin may augment the activity of the ACE regimen, but at the cost of severe toxicity. Further studies seem warranted if the myelotoxicity can be better controlled.
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PMID:Cisplatin, doxorubicin, cyclophosphamide, and etoposide combination chemotherapy for small-cell lung cancer. 131 12

To investigate the mechanisms of membrane protein localization to the Golgi complex, we have examined the intracellular trafficking of epitope-tagged forms of the mammalian endopeptidase, furin, in stably transformed rat basophilic leukemia cells. Our studies show that furin is predominantly localized to the trans-Golgi network (TGN) at steady state, with smaller amounts present in intracellular vesicles. Biochemical and morphological analyses reveal that furin is progressively delivered to a lysosomal compartment, where it is degraded. Analyses of furin deletion mutants and chimeric proteins show that the cytoplasmic domain is both necessary and sufficient for localization to the TGN in various cell types. Interestingly, deletion of most of the cytoplasmic domain of furin results in a molecule that is predominantly localized to intracellular vesicles, some of which display characteristics of lysosomes. To a lesser extent, the cytoplasmically deleted molecule is also localized to the plasma membrane. These observations suggest the existence of an additional determinant for targeting to the endosomal/lysosomal system within the lumenal and/or transmembrane domains of furin. Thus, the overall pattern of trafficking and steady state localization of furin are determined by targeting information contained within more than one region of the molecule.
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PMID:The cytoplasmic domain mediates localization of furin to the trans-Golgi network en route to the endosomal/lysosomal system. 791 93

We describe the clinical, cytological and cytogenetic features of 49 cases of myelodysplastic syndromes (MDS) in childhood. Three children had received prior cytotoxic treatment (group 1); all of these had cytogenetic abnormalities and died shortly after diagnosis. 22 children had constitutional anomalies (group 2). The remaining 24 MDS were considered as 'primary' (group 3). Hypoplastic marrow was found in nine cases, and only 53% of the MDS fitted the adult FAB classification. Transformation to AML occurred in 11 cases, development of aplastic anaemia in three cases, and spontaneous remission in one case each of RA and RAEB. Differences were observed between groups 2 and 3 in terms of mean age at diagnosis (11.1 months v 5 years), rate of cytogenetic anomalies (15% v 38%) and rate of progression towards acute leukaemia (13% v 29%). In group 2, all the fur girls studied exhibited a polyclonal pattern of X-inactivation, which suggests that MDS may be only the haematological expression of an embryological defect with different target tissues. This study suggests that some MDS in childhood can exhibit particular features such as congenital anomalies associated with MDS, bone marrow hypoplasia, polyclonality, and spontaneous remission. It emphasizes that the FAB classification is not adequate for children and addresses the question of whether these MDS are always malignant diseases.
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PMID:Myelodysplastic syndromes in childhood: report of 49 patients from a French multicentre study. French Society of Paediatric Haematology and Immunology. 885 63

Phage display libraries are widely used for selection and optimization of polypeptide ligands or protease substrates. Because they are expressed and amplified in bacterial hosts, phage are not ideal for displaying eukaryotic polypeptides or for probing mammalian cells. As retroviruses do not suffer from these limitations we constructed plasmids encoding replication-competent murine leukemia viruses displaying a virally encoded epidermal growth factor (EGF) domain at the N-terminus of the envelope glycoprotein. The EGF-displaying viruses replicated freely on EGF receptor-poor cells without deleting the displayed EGF domain but did not propagate on EGF receptor-rich cells because they were sequestered by the EGF receptors. A retrovirus display library was then generated by diversifying the seven-residue linker between the envelope glycoprotein and the displayed EGF domain. Selective pressure for loss of EGF receptor-binding activity was applied to the library by serial passage on EGF receptor-rich HT1080 cells. The selected viruses propagated on these cells with wild-type efficiencies, a phenotype that was conferred by intracellular cleavage of their displayed linker sequences. The selected linker sequences invariably presented arginine-rich motifs matching the consensus cleavage signal for furin-like proteases. Retrovirus display libraries can be used for the selection of polypeptides interacting with components of living mammalian cells.
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PMID:In vivo selection of protease cleavage sites from retrovirus display libraries. 978 52

Proteolytic processing is required for the activation of numerous viral glycoproteins. Here we show that the envelope glycoprotein from the Zaire strain of Ebola virus (Ebo-GP) is proteolytically processed into two subunits, GP1 and GP2, that are likely covalently associated through a disulfide linkage. Murine leukemia virions pseudotyped with Ebo-GP contain almost exclusively processed glycoprotein, indicating that this is the mature form of Ebo-GP. Mutational analysis identified a dibasic motif, reminiscent of furin-like protease processing sites, as the Ebo-GP cleavage site. However, analysis of Ebo-GP processing in LoVo cells that lack the proprotein convertase furin demonstrated that furin is not required for processing of Ebo-GP. In sharp contrast to other viral systems, we found that an uncleaved mutant of Ebo-GP was able to mediate infection of various cell lines as efficiently as the wild-type, proteolytically cleaved glycoprotein, indicating that cleavage is not required for the activation of Ebo-GP despite the conservation of a dibasic cleavage site in all filoviral envelope glycoproteins.
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PMID:Endoproteolytic processing of the ebola virus envelope glycoprotein: cleavage is not required for function. 988 47

Induction of an optimal immune response will likely be a prerequisite for successful immunotherapy of human leukemias and other malignancies. Dendritic cells are highly effective at inducing an immune response to antigens to which the host is unresponsive, while transgenic expression of the costimulator molecule CD40 ligand (gp39/CD154) and the T cell growth factor interleukin 2 (IL2) are also able to augment immune responsiveness. We therefore investigated whether a combination of these two distinctive approaches to immunostimulation could safely increase the anti-tumor immune response compared to each stimulus alone. We injected BALB/CBYJ mice with syngeneic dendritic cells (DC) exposed to A20 lymphoblastic leukemia cell-derived peptides and proteins which had been acid-eluted from the cell surface. In additional mice, the pulsed DC were mixed with genetically modified syngeneic fibroblasts that were expressing CD40 ligand or secreting interleukin 2 (IL2). Three days after their third, weekly, vaccination, they were challenged with parental A20 cells. Tumor growth was suppressed by responses to pulsed DC alone (P < 0.02). This suppression was further enhanced when pulsed DC were coinjected with fibroblasts expressing CD40 ligand and IL2 (P < 0.0005 compared to DC alone) even though CD40 ligand and IL2-expressing fibroblasts alone offered no significant protection in this model. Mice receiving the full complement of immunostimulants either failed to develop visible tumors or developed small tumors which quickly necrosed and regressed, allowing the mice to become long term tumor-free survivors. Antibody mediated depletion of either CD4+ or CD8+ T-cell subset significantly reduced the level of protection afforded by the vaccination. However, it became evident that this intensive stimulation of the immune system lead not only to tumor eradication but also to destruction of cells bearing normal self antigens. Hence, 60 days after challenge with A20 cells all mice in the DC/IL2/CD40 ligand group developed a severe, systemic autoimmune disorder that resembled graft versus host disease and manifest itself by significant peripheral blood cytotoxicity against autologous fibroblasts, blood dyscrasias, gross hepatosplenomegaly, cachexia and fur loss. This phenomenon depended on CD8+ cytotoxic T lymphocytes. Our results therefore suggest that the most effective strategies of immunotherapy against leukemia may also exceed the threshold of anergic cells, leading to a loss of self tolerance to normal self-antigens and the induction of an CD8+ anti-self effector response.
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PMID:Autoimmune disease induced by dendritic cell immunization against leukemia. 1037 48

We have previously shown that the myeloid progenitor cell line 32Dc13 transduced with mIL-12 cDNAs (32DIL-12 cells) induces IFN-gamma and NK-cell-mediated cytotoxicity in vivo. Since systemic therapy with recombinant IL-12 protein has been shown to produce moderate to severe toxic side effects we examined whether IL-12 gene therapy with hematopoietic progenitor cells also induces systemic toxicities that are commonly associated with the administration of rIL-12 protein. Injection of large doses of IL-12 secreting 32DIL-12 cells (5 to 6 x 10(7) cells) significantly reduced mortality in mice injected with a lethal dose of 32Dp210 myeloid leukemia cells. More importantly, injection of similar doses of transduced cells failed to reduce body weight significantly or produce other visible signs of toxicity, i.e., fur ruffling or lethargy. There was no evidence of hematologic or hematopoietic toxicity resulting from the injection of transduced cells. In addition, microscopic examination of liver, kidney, lung, and intestine of mice injected with transduced cells revealed the absence of tissue necrosis or inflammatory response in any of these organs. Finally, 32DIL-12 cells were not found to interfere with the engraftment of syngeneic bone marrow transplant or the hematopoietic reconstitution of irradiated mice. These results demonstrate that IL-12 gene therapy with hematopoietic progenitor cells is nontoxic and provide a rationale for exploring the feasibility of treating minimal residual leukemia with IL-12 gene therapy.
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PMID:IL-12 gene therapy of leukemia with hematopoietic progenitor cells without the toxicity of systemic IL-12 treatment. 1116 74

Salicylazosulfapyridine is widely used for the treatment of ulcerative colitis and Crohn's disease. It has been beneficial in the treatment of psoriasis and rheumatoid arthritis, and it has been used in veterinary medicine for the treatment of granulomatous colitis. Salicylazosulfapyridine was nominated for toxicity and carcinogenicity testing by the National Cancer Institute on the basis of its widespread use in humans and because it is a representative chemical from a class of aryl sulfonamides. Salicylazosulfapyridine is a suspect carcinogen because reductive cleavage of the azo linkage yields a p-amino aryl sulfonamide (sulfapyridine), and a related p-amino aryl sulfonamide (sulfamethoxazole) has been shown to produce thyroid neoplasms in rats. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F1 mice. Rats and mice were administered salicylazosulfapyridine (96% to 98% pure) in corn oil by gavage for 16 days, 13 weeks, or 2 years. The gavage route of administration was selected for these studies because it approximates the typical route of human exposure to the chemical. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow and mouse peripheral blood cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. All rats survived to the end of the study. With the exception of the 675 mg/kg male group, the final mean body weights of all dosed groups of males and females were significantly lower than those of controls. Mean body weight gains of all dosed groups were less than those of controls. Clinical findings included ruffled fur and distended abdomens in male and female rats receiving 2,700 mg/kg. Hypothyroidism, evidenced by decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentrations, occurred in 2,700 mg/kg male and female rats. The absolute and relative thymus weights of male rats receiving,350 or 2,700 mg/kg and female rats receiving 2,700 mg/kg were significantly lower than those of controls. At necropsy, all dosed rats had enlarged cecae/large intestines. Male rats receiving 1,350 mg/kg and male and female rats receiving 2,700 mg/kg had red, enlarged thyroid glands. Chemical-related microscopic lesions were present in the forestomach, thymus, thyroid gland, and pituitary gland. Minimal to mild hyperplasia of the forestomach mucosa was present in the 1,350 and 2,700 mg/kg male and female groups. Lymphoid depletion was observed in the thymus of three male and three female rats in the 2,700 mg/kg groups. Male and female rats receiving 1,350 and 2,700 mg/kg had thyroid gland follicular cell hyperplasia and an increase in thyroid-stimulating hormone producing cells in the pars distalis of the pituitary gland. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. There were no chemical-related deaths, and final mean body weights of dosed mice were similar to those of controls. No chemical-related clinical findings were noted for male or female mice. There were no differences in triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice. There were no biologically significant differences in absolute or relative organ weights between dosed and control male and female mice. At necropsy, male mice receiving 2,700 mg/kg had enlarged cecae/large intestines. There were no biologically significant histopathologic lesions attributed to salicylazosulfapyridine administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 84, 168.8, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All rats survived to the end of the study. The finaludy. The final mean body weights of dosed male rats were similar to those of controls; the final mean body weights and body weight gains of dosed females were significantly lower than those of controls. No chemical-related clinical findings were noted in dosed male or female rats during the 13-week study. No significant differences in hematology or urinalysis parameters between control and dosed rats were observed. The absolute and relative right kidney weights of 337.5 mg/kg females were significantly greater than those of controls. At necropsy, some 337.5 mg/kg male rats had red, enlarged thyroid glands. Histopathologic changes were noted primarily in the thyroid gland and pituitary gland of males and females in the 337.5 mg/kg groups. The thyroid gland lesions observed were similar to those present in the 16-day study. Nine male rats receiving 168.8 mg/kg and ten male and seven female rats receiving.5 mg/kg had minimal but consistent changes in thyroid gland follicular cells. In the pituitary gland of 337.5 mg/kg males and females, the thyroid-stimulating hormone producing cells were enlarged and contained pale-staining cytoplasm and prominent Golgi complexes. Decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentration, similar to differences observed in the 16-day study, occurred in 337.5 mg/kg male rats; thyroid hormone concentrations were not affected in female rats. Sperm motility of all dosed groups of males was significantly lower than that of controls. Vaginal cytology parameters of dosed groups of females were similar to those of controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All mice survived to the end of the study. The final mean body weights of dosed male and female mice were similar to those of controls. The mean body weight gains of 1,350 and 2,700 mg/kg male mice were less than that of controls. No chemical-related clinical findings were noted in dosed male or female mice during the 13-week study. There was minimal evidence of a responsive anemia in mice in the 13-week study. The anemia was probably related to a methemoglobinemia. There were minimal decreases in thyroxine concentration in all dosed groups of male and female mice in the -week study. There were, however, no differences in triiodothyronine and thyroid-stimulating hormone concentrations between dosed and control animals. Absolute and relative liver weights of all groups of dosed male and female mice were significantly greater than those of controls. There were no chemical-related gross lesions. Microscopic evaluation of the liver revealed centrilobular hypertrophy in five 1,350 mg/kg and all 2,700 mg/kg male mice. The right cauda weight of the 1,350 mg/kg group and the right epididymis weights of all dose groups were significantly lower than those of controls. There was no evidence of chemical-related alteration in the vaginal cytology parameters of female mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered 84, 168, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 105 weeks. Groups of 70 male and 60 female rats were administered the corn oil vehicle by gavage for up to 105 weeks. A stop-exposure group of 70 male rats was administered 337.5 mg/kg salicylazosulfapyridine in corn oil by gavage for 6 months, after which animals received the corn oil vehicle by gavage for the remainder of the 2-year study. Ten animals from the vehicle control male group and 10 animals from the 337.5 mg/kg stop-exposure group were evaluated at 6 months; animals from each core-study group were evaluated at 15 months. Survival, Body Weights, and Clinical Chemistry: Survival of 337.5 mg/kg male core-study rats was significantly lower than that of controls; survival of 84 and 168 mg/kg core-study males, all groups of dosed females, and the stop-exposure male group was similar to controls. Mean body weights of core-study males and stop-exposure males were similar to controls throughout the study. From week 45 to the end of the study, females in the 337.5 mg/kg group had mean body weights that were lower than those of controls. The serum thyroxine concentration in 337.5 mg/kg core-study males at study termination was minimally lower than that of controls; the serum thyroid-stimulating hormone, triiodothyronine, and reverse triiodothyronine concentrations of dosed males and females were similar to those of controls. Pathology Findings: Administration of salicylazosulfapyridine for 2 years was associated with transitional epithelial papilloma in the urinary bladder of male rats and may have been associated with transitional epithelial papilloma of the kidney and of the urinary bladder of female rats. Nonneoplastic effects in the urinary bladder and kidney of male and female rats and in the spleen of male rats were also observed. Dosed male and female rats had increased incidences of grossly and microscopically observed urinary bladder concretions (diagnosed grossly as calculi at necropsy); male and female rats that developed transitional epithelial papillomas of the urinary bladder had grossly observed concretions (calculi) in the urinary bladder at necropsy. The microscopic neoplastic and nonneoplastic urinary bladder and kidney effects observed in dosed male rats during the 2-year continuous study did not occur in dosed rats during the 2-year stop-exposure study, nor were there gross observations of concretions (calculi) at necropsy. The incidences of mononuclear cell leukemia in male and female rats were decreased. The thyroid gland hyperplasia seen in the -week study was not observed in the 2-year study, and there was no evidence of chemical-related thyroid gland follicular cell adenomas or carcinomas. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 104 weeks. Ten animals from each group were evaluated at 15 months. Survival, Body Weights,and Clinical Chemistry: Survival of all the dosed groups of male and female mice was similar to that of controls. Mean body weights of 675 and 1,350 mg/kg male and female mice were similar to controls throughout the study. From week 12 to the end of the study, 2,700 mg/kg male mice had mean body weights that were lower than those of controls. From week 14 to the end of the study, the 2,700 mg/kg female mice had mean body weights that were lower than those of controls. There were no chemical-related differences in triiodothyronine, reverse triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice at the 15-month evaluation. Pathology Findings: Exposure of mice to salicylazosulfapyridine in corn oil by gavage for 2 years was associated with increased incidences of hepatocellular neoplasms in males and females. Nonneoplastic effects in the liver and spleen were also observed in male and female mice. The incidences of forestomach squamous cell papilloma in females and forestomach hyperplasia in males and females were decreased. GENETIC TOXICOLOGY: Salicylazosulfapyridine was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro assays were performed with and without S9 metabolic activation enzymes. Results from in vivo mouse bone marrow chromo somal aberration tests were uniformly negative, while results of micronucleus assays performed on male or female mice exposed to salicylazosulfapyridine for periods ranging from 3 days to weeks were positive. Micronucleus tests in male mice for shorter exposure times (1 to 2 days) yielded negative or very weakly positive results. A three-treatment (72-hour exposure time) micronucleus test performed in male rats yielded equivocal results. Overall, results of these in vivo assays indicate that salicylazosulfa pyridine is capable of inducing chromosomal damage, possibly in the form of aneuploidy, in mouse bone marrow cells after multiple administrations. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of salicylazosulfapyridine in male and female F344/N rats based on increased incidences of neoplasms in the urinary tract. There was an increased incidence of transitional epithelial papilloma of the urinary bladder in males and a low incidence of rare transitional epithelial papillomas of the kidney and of the urinary bladder in females. There was clear evidence of carcinogenic activity of salicylazosulfapyridine in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Increased incidences of nonneoplastic lesions of the urinary bladder and kidney in male and female rats and of the spleen in male rats were observed. Increased incidences of nonneoplastic lesions of the liver and spleen in male and female mice were observed. Decreased incidences of mononuclear cell leukemia in male and female rats were related to salicylazosulfapyridine administration. Decreased incidences of forestomach squamous cell papilloma in female mice and forestomach hyperplasia in male and female mice were related to salicylazosulfapyridine administration. Synonyms: 2-Hydroxy-5-[[4-[2-(pyridinylamino)sulfonyl]phenyl]azo]benzoic acid; 5-[p- (2-pyridylsulfamoyl)phenylazo]salicylic acid; sulfasalazine; salazosulfapyridine; 5-[4-(2-pyridylsulfamoyl)phenylazo]-2-hydroxybenzoic acid; 4-(pyridyl-2-amidosulfonyl)-3'-carboxy-4'-hydroxyazobenzene; sulphasalazine Trade names: Azopyrin, Azulfidine, Benzosulfa, Colo-Pleon, Reupirin, Salazopyrin
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PMID:NTP Toxicology and Carcinogenesis Studies of Salicylazosulfapyridine (CAS No. 599-79-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1258 19

Isobutyl nitrite is used to a limited extent as an intermediate in the syntheses of aliphatic nitrites. It is also an ingredient of various incenses or room odorizers and is used as a euphoric. The chemical has also been used as a jet propellant and in the preparation of fuels. Isobutyl nitrite was nominated by the Consumer Product Safety Commission to the NTP for toxicology and carcinogenicity studies because of its possible contribution to the high incidence of Kaposi's sarcoma among male homosexual acquired immune deficiency syndrome patients and because of the lack of available data on the potential carcinogenicity of isobutyl nitrite. Male and female F344/N rats and B6C3F1 mice were exposed to isobutyl nitrite (purity of 93% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All males and females exposed to 600 or 800 ppm and one 400 ppm female died on the first day of the study. Final mean body weights and mean body weight gains of 400 ppm males and females were significantly lower than those of the controls. Clinical findings observed in 400 ppm males and females included ocular discharge, lethargy, hunched posture, and rough coats. Absolute and relative lung weights of all exposed groups of males and of 200 and 400 ppm females were less than those of the controls. Chemical-related hyperplasia of the bronchial epithelium was observed in 200 and 400 ppm males and females and hyperplasia of the nasal turbinate epithelium was observed in rats exposed to 400 ppm or less. Hemosiderin pigmentation was observed in the spleen of 200 and 400 ppm males and females and bone marrow hematopoietic hyperplasia was observed in rats exposed to 400 ppm or less. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. Three males and four females exposed to 800 ppm died before the end of the study. Final mean body weights and mean body weight gains of 600 and 800 ppm males and females were significantly lower than those of the controls. Mice exposed to 400 ppm or greater were lethargic and exhibited hunched posture and rough coats. Absolute and relative lung weights of 600 and 800 ppm males and the relative lung weight of 600 ppm females were significantly greater than those of the controls. Chemical-related hyperplasia of the bronchiolar epithelium was observed in all exposed groups of males and females. Lymphocytic atrophy of the spleen and thymus was observed in males and females exposed to 400 ppm or greater. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. All rats survived to the end of the study. Final mean body weights and mean body weight gains of 300 ppm males and females were significantly lower than those of the controls, as was the mean body weight gain of 150 ppm females. Clinical findings observed during the study included ruffled fur in 300 ppm males and females, hypoactivity in 300 ppm males, and hyperactivity in 150 and 300 ppm females. A very mild chemical-related methemoglobinemia and anemia occurred in male and female rats in the 75, 150, and 300 ppm groups. Hematopoietic hyperplasia occurred in the bone marrow of all exposed groups of males and females and was considered to be a secondary response to the anemia and methed methemoglobinemia. There was minimal hemosiderin pigment accumulation in the spleens of males and females exposed to 75 ppm or greater, mild to moderate epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males and females, and minimal hyperplasia occurred in 150 ppm males and females. Hyperplasia of the bronchial epithelium was observed in 300 ppm males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. There were no chemical-related deaths. Final mean body weights and mean body weight gains of 150 and 300 ppm females were significantly less than those of the controls. Final mean body weights and mean body weight gains of exposed groups of males were similar to those of the controls. There were no chemical-related clinical findings. A very mild chemical-related methemoglobinemia occurred in male and female mice in the 150 and 300 ppm groups. A very mild anemia occurred in the 300 ppm groups. In the lung, increased incidences of mild to moderate hyperplasia of the bronchiolar epithelium occurred in males and females exposed to 300 ppm. Minimal hyperplasia occurred in males exposed to 75 ppm or greater and in females exposed to 150 ppm. Minimal epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males. Increased hematopoiesis of the spleen, secondary to the hematotoxicity, occurred in males exposed to 75 ppm or greater and in females exposed to 150 or 300 ppm. Increased hemosiderosis of the spleen occurred in males exposed to 300 ppm and in females exposed to 75 ppm or greater. 2-YEAR STUDY IN RATS: Based on the low final mean body weights, anemia, and the mild to moderate nasal mucosal lesions and the hyperplastic bronchial lesions observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in rats were 37.5, 75, and 150 ppm. Groups of 56 male and 56 female rats were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. Ten male and 10 female rats from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, Hematology, and Clinical Chemistry: Survival rates of exposed groups of rats were greater than those of the controls, and the survival rates of 75 and 150 ppm males were significantly greater than that of the control. Mean body weights of 150 ppm males and females were 3&percnt; to 11&percnt; lower than those of the controls throughout the course of the study. There were no clinical findings considered to be related to isobutyl nitrite exposure. A very mild methemoglobinemia and anemia occurred in male and female rats exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms in 75 ppm males and in 150 ppm males and females were significantly greater than those in the controls. The incidence of alveolar/bronchiolar carcinoma was significantly greater in 150 ppm male rats than that in the controls. The incidences of alveolar epithelial hyperplasia were also increased in 75 and 150 ppm males and in all exposed groups of females. The incidences of mononuclear cell leukemia in exposed groups of males and females were significantly less than those in the controls. 2-YEAR STUDY IN MICE: Based on the low final mean body weight of 300 ppm females and the mild to moderate bronchiolar hyperplasia observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in mice were 37.5, 75, and 150 ppm. Groups of 60 male and 60 female mice were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. As many as 10 male and 10 female mice from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, and Hematology and Clinical Chemistry: Survival rates of exposed groups of males were similar to those of the controls. Survival rates of exposed groups of females were greater than those of the controls, and the survival rate in 37.5 ppm females was significantly greater than that of the controls. Mean body weights of exposed groups of males and of 37.5 and 75 ppm females were similar to those of the controls throughout the study. Mean body weights of 150 ppm females were lower than those of the controls from week 20 until the end of the study. There were no biologically significant clinical findings noted in the 2-year study in mice. A very mild methemoglobinemia and anemia occurred in male and female mice exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms were significantly greater than those in the controls in 75 ppm males and in 150 ppm males and females. Incidences of alveolar epithelial hyperplasia were significantly increased in 75 and 150 ppm male and female mice. Thyroid gland follicular cell adenoma occurred with a significant positive trend in male mice; the incidences of thyroid gland follicular cell hyperplasia were increased in all exposed groups of males, and the incidences in males exposed to 37.5 or 150 ppm were significantly greater than those in the controls. Incidences of serous exudate and olfactory epithelium atrophy in the nose of 150 ppm females were significantly greater than those in the controls. Incidences of minimal to mild hemosiderin pigment in the spleen of 75 and 150 ppm male mice were significantly greater than those in the controls. GENETIC TOXICOLOGY: Isobutyl nitrite was found to be mutagenic in vitro and in vivo. It induced base-pair substitution mutations in Salmonella typhimurim strains TA100 and TA1535 and sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. Positive responses in the S. typhimurium tests required S9 activation, but isobutyl nitrite induced chromosomal effects in cultured Chinese hamster ovary cells with and without S9. In vivo, no induction of sex-linked recessive lethal mutations was noted in the germ cells of male Drosophila melanogaster exposed to isobutyl nitrite via feeding or injection. However, significant increases in micronucleated normochromatic erythrocytes were observed in the peripheral blood of male and female mice treated with isobutyl nitrite for 90 days by inhalation. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of isobutyl nitrite in male and female F344/N rats based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of isobutyl nitrite in male and female B6C3F1 mice based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) in males and females. The increased incidence of thyroid gland follicular cell adenoma in male mice may have been related to isobutyl nitrite exposure. Exposure of rats and mice to isobutyl nitrite by inhalation for 2 years resulted in increased incidences of alveolar epithelial hyperplasia (male and female rats and mice), thyroid gland follicular cell hyperplasia and splenic hemosiderin pigmentation (male mice), and serous exudate and atrophy of the olfactory epithelium of the nose (female mice). Exposure of rats to isobutyl nitrite by inhalation for 2 years resulted in decreased incidences of mononuclear cell leukemia in males and females.
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PMID:NTP Toxicology and Carcinogenesis Studies of Isobutyl Nitrite (CAS No. 542-56-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies). 1259 27

C.I. Acid Red 114 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. C.I. Acid Red 114 was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering desalted, industrial grade C.I. Acid Red 114 in drinking water to groups of F344/N rats of each sex for 13 days, 13 weeks, 9 or 15 months, or 2 years. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila melanogaster. 13-Day Studies: Rats were exposed to C.I. Acid Red 114 in drinking water at doses of 0, 10,000, 20,000, or 30,000 ppm. All control and dosed rats survived except one male rat in the 20,000 ppm dose group. Final mean body weights in the three dosed groups were 94%, 83%, or 77% of controls for males and 92%, 88%, or 80% of controls for females. Water consumption declined with increased dose. Clinical findings included red stained fur, ears, and tail in all test animals. On gross necropsy, organs and tissues were also stained red. 13-Week Studies: C.I. Acid Red 114 was administered in drinking water at doses of 0, 600, 1,200, 2,500, 5,000, or 10,000 ppm. All control and dosed animals survived until the end of the study. Final mean body weights in the five dosed groups were 97%, 89%, 87%, 87%, or 85% of controls for males and 97%, 94%, 94%, 92%, or 89% of controls for females. Water consumption was decreased in dosed animals. As was seen in the 13-day studies, major organs and tissues from treated animals were stained red. Kidney toxicity characterized by regeneration and karyomegaly of tubule epithelial cells with chronic inflammation was observed in female rats at doses of 1,200 ppm or above. Treatment-related increases in relative liver weights and elevated liver enzyme levels were seen in males and females, centrilobular pallor in the liver was seen in all male dose groups. Because of these body weight differences, decreases in water consumption, and organ toxicity, the doses chosen for the 2-year studies were 70,150, and 300 ppm for males and 150, 300, and 600 for females. 2-Year Studies: Male rats received doses of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150, 300, or 600 ppm. Seventy animals were in the control and high-dose groups, 45 in the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated from the control and high-dose groups at 9 months, and ten animals from all dose groups were evaluated at 15 months. The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Survival and Body Weights: Survival at 105 weeks for male rats receiving 0, 70, 150, or 300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300 ppm, survival was 36/50, 13/35, and 6/64. All female rats receiving 600 ppm died by week 89. The decreased survival in treated groups was due primarily to the development of chemical-related neoplasms. Of the surviving animals, the final mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight differences began in the second year of the studies and were attributed in part to the development of neoplasms in the dosed groups. Histopathologic Effects in the 2-Year Studies: At 9 and 15 months, a few neoplasms were seen in the liver, lung, clitoral gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as the studies progressed. At 2 years, there was a clear carcinogenic response in the skin, Zymbal's gland, and liver of male and female rats, and in the clitoral gland, oral cavity epithelium, small and large intestine, and lung in female rats. Treatment-related increases were also seen in the incidence in neoplasms of the oral cavity epithelium, adrenal gland, and lung of male rats, and in mononuclear cell leukemia and in neoplasms of the mammary gland and adrenal gland in female rats. The incidence of these neoplasms was generally lower, but was significant and considered to be marginally related to chemical treatment. The same neoplastic effects have been previously observed in some or all of the NTP studies with dimethoxybenzidine, dimethylbenzidine, or C.I. Direct Blue 15. Genetic Toxicology: In a standard preincubation protocol, C.I. Acid Red 114 was mutagenic in Salmonella typhimurium strain TA98 in the presence of induced hamster liver S9, and an equivocal response was noted in strain TA100 with hamster liver S9. However, no significant mutagenic activity was noted in strains TA1535 or TA1537 with or without S9 activation. In a modified S. typhimurium gene mutation test which employed reductive metabolism followed by oxidative metabolism with S9 liver enzymes, C.I. Acid Red 114 was strongly mutagenic in strain TA1538. C.I. Acid Red 114 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. No increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster administered C.I. Acid Red 114 by feeding or injection. Conclusions: Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. Synonyms: 1,3-Naphthalenedisulfonic acid, 8-((3,3'-dimethyl-4'-((4-(((4-methylphenyl)sulfonyl)oxy)phenyl)azo)(1,1'-bipheny)-4-yl)azo)-7-hydroxy, disodium salt, Acid Leather Red BG, Acid Red 114, Amacid Milling Red PRS, Benzyl Fast Red BG, Benzyl Red BR, Cerven Kysela, C.I. 23635, Erionyl Red RS, Folan Red B, Kayanol Milling Red RS, Leather Fast Red B, Levanol Red GG, Midlon Red PRS, Milling Red B, Milling Red BB, Milling Red SWB, NCI C61096, Polar Red RS, Sandolan Red N-RS, Sella Fast Red RS, Sulphonol Fast Red R, Supranol Fast Red GG, Supranol Red PBX-CF, Supranol Red R, Telon Fast Red GG, Tertracid Milling Red B, Vondamol Fast Red RS
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PMID:Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 (CAS No. 6459-94-5) in F344/N Rats (Drinking Water Studies). 1262 13

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