UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
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Cytokines such as interleukin-1 (IL-1) and IL-6 stimulate the hypothalamic-pituitary-adrenal (HPA) axis. In addition, these proteins affect pituitary cell proliferation in vitro. Thymosin fraction 5 (TF5) is a partially purified preparation of the bovine thymus that enhances immune system functioning. Because TF5 similarly stimulates the HPA axis, we examined the effects of this preparation on neuroendocrine tumor cell proliferation. Cells of the PRL-secreting rat anterior pituitary adenoma, MMQ (5-50 x 10(3) cells/well), were exposed to vehicle (RPMI-1640 containing 2.5% FCS, 7.5% horse serum, and antibiotics) or TF5 (100-500 microg/ml) for up to 96 h and the proliferation of MMQ cells monitored using the MTT assay (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide). TF5-mediated inhibition of cell proliferation was dependent on both TF5 concentration and the initial MMQ cell number. Minimal reductions in optical densities resulted from exposure to 100 microg/ml TF5, whereas the highest concentration of this preparation (i.e. 500 microg/ml) completely blocked MMQ cell division. The concentration-dependent effects of TF5 were particularly striking at initial plating densities of 25 and 50 x 10(3) MMQ cells/well; in contrast, all concentrations of TF5 completely inhibited MMQ cell growth at 5 and 10 x 10(3) cells/well. The antiproliferative actions of TF5 on MMQ cells were demonstrable within 24 h and remained for up to 96 h as determined by the MTT assay and actual cell counts. Because the highest densities of MMQ cells were partially refractive to the antiproliferative effects of TF5, we examined the effects of PRL (1-1000 nM) and MMQ cell conditioned medium (50%) on TF5 inhibition of MMQ adenoma proliferation. The TF5 concentration-dependent inhibition of MMQ cell growth was largely reversed by the 50% conditioned medium, whereas PRL slightly potentiated the antiproliferative actions of TF5. The proliferation of the rat C6 glioma cell line (10-30 x 10(3) cells/well) demonstrated greater sensitivity to TF5: concentrations as low as 10 microg/ml TF5 inhibited C6 cell proliferation (P < 0.01), and near-maximal inhibition was noted at 200 microg/ml TF5. Significant reductions in MMQ and C6 cell viabilities accompanied decreases in cell number and morphological analysis indicated these cells were dying by apoptosis. The peptides thymosin alpha1 (T alpha1), thymosin beta4 (T beta4), MB35, and MB40 had no effect on either MMQ or C6 cell proliferation, indicating that these TF5 components are not the principle active peptides. Therefore, TF5 was further separated into 60 fractions by preparative reverse phase HPLC. HPLC fractions 17, 25, 26, and 27 significantly suppressed MMQ cell proliferation (P < 0.01) to the same extent as TF5; other HPLC fractions had no effect. These data demonstrate a new biological property of TF5: the inhibition of cell proliferation and the induction of apoptosis in neuroendocrine tumor cells. The proliferation effects were time and concentration dependent and could be partially reversed by an activity present in the MMQ cell conditioned medium. Thus, TF5 and cytokines have opposite effects on adenoma cells because IL-2 and IL-6 stimulate GH3 cell proliferation. We propose that circulating thymic peptides may act to prevent pituitary adenoma and glioma tumor formation, an action opposed by autocrine growth factors secreted by these tumors.
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PMID:Thymosin fraction 5 inhibits the proliferation of the rat neuroendocrine MMQ pituitary adenoma and C6 glioma cell lines in vitro. 952 5

Neurothelin/HT7, a transmembrane glycoprotein of the immunoglobulin superfamily, is a marker of blood-brain barrier (BBB)-forming endothelial cells. We have studied the expression of neurothelin in tumors grown on the chorioallantoic membrane (CAM) of chick embryos. We inoculated each 3-5 x 10(6) rat C6 glioma, rat 10AS pancreatic carcinoma, human A375 melanoma, and human mammary duct adenoma cells on the CAM of 10-day-old chick embryos. The tumors were harvested on day 17. All four tumor cell lines formed solid tumors which were supplied by vessels of CAM origin. Foci of bleeding were regularly observed within the tumors. All four tumors induced the expression of neurothelin/HT7 (but not of glucose transporter-1) in tumor endothelial cells, whereas expression in adjacent endothelial cells of normal CAM did not occur. Confocal laser scanning microscopy revealed that the pattern of neurothelin expression in tumor endothelial cells was different from that in normal central nervous system (CNS) endothelium, but the relative molecular weight of neurothelin, studied by western blot analysis, was the same in brain and in tumors. It has been shown that, with increasing malignancy, vessels of CNS tumors lose their morphological characteristics, and BBB markers such as the glucose transporter-1 are downregulated. Our results show that, in contrast, the BBB marker, neurothelin, is expressed de novo in tumor endothelial cells. Potential common functions of neurothelin in endothelial cells of the CNS and tumors are discussed.
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PMID:Induction of the blood-brain barrier marker neurothelin/HT7 in endothelial cells by a variety of tumors in chick embryos. 1076 63

Tumors of the cerebellopontine angle (CPA) are frequent; acoustic neuromas and meningiomas represent the great majority of such tumors. However, a large variety of unusual lesions can also be encountered in the CPA. The site of origin is the main factor in making a preoperative diagnosis for an unusual lesion of the CPA. In addition, it is essential to analyze attenuation at computed tomography (CT), signal intensity at magnetic resonance (MR) imaging, enhancement, shape and margins, extent, mass effect, and adjacent bone reaction. CPA masses can primarily arise from the cerebellopontine cistern and other CPA structures (arachnoid cyst, nonacoustic schwannoma, aneurysm, melanoma, miscellaneous meningeal lesions) or from embryologic remnants (epidermoid cyst, dermoid cyst, lipoma). Tumors can also invade the CPA by extension from the petrous bone or skull base (cholesterol granuloma, paraganglioma, chondromatous tumors, chordoma, endolymphatic sac tumor, pituitary adenoma, apex petrositis). Finally, CPA lesions can be secondary to an exophytic brainstem or ventricular tumor (glioma, choroid plexus papilloma, lymphoma, hemangioblastoma, ependymoma, medulloblastoma, dysembryoplastic neuroepithelial tumor). A close association between CT and MR imaging findings is very helpful in establishing the preoperative diagnosis for unusual lesions of the CPA.
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PMID:Unusual lesions of the cerebellopontine angle: a segmental approach. 1125 5

The aim of the study was to ascertain the occurrence of the sleep apnoea syndrome (SAS) in patients after pituitary afunctional adenoma operation or in patients with other affection in sella turcica region except acromegaly patients. Eighty-one patients were addressed. Sixteen patients (eight men, eight women) underwent the examination; the rest of them had no interest to be explored. Afunctional pituitary adenoma was diagnosed in twelve patients, afunctional pituitary adenoma and subsequently optic glioma in one patient, craniopharyngioma in one patient, prolactinoma in one patient and undifferentiated cystic pituitary tumour in one patient. Neurological examination was done in all patients (standardized sleep questionnaire was included). SAS was quantified using PolyMESAM. Severity of SAS were set up from the value of M index (M = ODI.delta saturation; ODI--oxygen desaturation index). Mild SAS: 40 < M < 100; middle SAS: 100 < M < 210; severe SAS: M > 210. SAS was diagnosed in 13 patients: mild SAS in three of them (average value of M index: 81.0 +/- 12.7), moderate SAS in seven patients (average value of M index: 129.0 +/- 18.7) and severe SAS in three patients (average value of M index: 790.0 +/- 563.0). Therapy by continuous positive airway pressure (CPAP) was recommended in six patients. Five of them continue in using of CPAP--four patients with good compliance. The occurrence of SAS was 16.05% in measured group, higher than in normal population.
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PMID:[The sleep apnea syndrome in hypophyseal disorders with the exception of acromegaly]. 1170 81

Isoprene, the monomeric unit of natural rubber and naturally occurring terpenes and steroids, is primarily obtained as a by-product of naphtha cracking for ethylene production. It is emitted from plants and trees, has been detected in tobacco smoke and automobile exhaust, and was identified as a major endogenous hydrocarbon in human breath. Isoprene was selected for toxicologic evaluation because of its structural similarity to 1,3-butadiene, a potent, multi-organ, rodent carcinogen, and the potential for human exposure due to its large annual production volume. A previous 26-week inhalation study followed by a 26-week recovery period provided clear evidence of carcinogenic activity of isoprene in male B6C3F1 mice. A similar study in male F344/N rats was inconclusive. Male and female F344/N rats were exposed to isoprene (99% pure) by whole body inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow and peripheral blood cells, and rat lung fibroblasts. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 220, 700, or 7,000 ppm isoprene by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights: Survival rates and mean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study. Urinary Vinyl Lactic Acid - Biomarker of Exposure: At 3, 6, 12, and 18 months, the concentrations of vinyl lactic acid normalized to creatinine in the urine increased with increasing exposure concentration in all exposed groups of male and female rats; however, these increases were not proportional to isoprene exposure concentrations, indicating nonlinear metabolism over this range of exposure concentrations. Pathology Findings: Exposure-related increases in the incidences of mam mary gland fibroadenoma were observed in male rats in all groups. The incidences of fibroadenoma in 7,000 ppm males and in all groups of exposed females were significantly greater than those in the chamber control groups. The incidences of fibroadenoma in all exposed groups of males and females and of multiple fibroadenoma in 7,000 ppm males and in all groups of exposed females exceeded the historical control ranges. In addition, the finding of mammary gland carcinoma in exposed male rats was noteworthy because this neoplasm rarely occurs in control male rats. The incidences of renal tubule adenoma in 700 and 7,000 ppm males and of renal tubule hyperplasia in 7,000 ppm males were significantly greater than those in the chamber controls. The severity of kidney nephropathy was slightly increased in 7,000 ppm males when compared to chamber controls. An exposure-related increase in the incidences of interstitial cell adenoma of the testis was observed in male rats. The incidences of bilateral interstitial cell adenoma and of unilateral and bilateral interstitial cell adenoma (combined) of the testis in 700 and 7,000 ppm males were significantly greater than those in the chamber controls. The incidences of interstitial cell adenoma in 700 and 7,000 ppm males exceeded the historical control range. Several rare neoplasms including benign astrocytoma, malignant glioma, malignant medulloblastoma be nign meningeal granular cell tumor, and meningeal sarcoma were observed in the brain of exposed female rats. These neoplasms have seldom or never occurred in historical chamber controls. The incidences of splenic fibrosis in 700 and 7,000 ppm males were significantly greater than that in the chamber control group. GENETIC TOXICOLOGY: Isoprene was not mutagenic in S. typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. The cell cycle duration of proliferating bone marrow cells of mice f mice exposed to 7,000 ppm isoprene was significantly lengthened. No increases in the frequency of chromosomal aberrations were observed in bone marrow cells of male mice after 12 days of exposure to isoprene, and lung fibroblasts of male and female rats exposed to isoprene for 4 weeks showed no increase in the frequency of micronuclei. CONCLUSIONS: Under the conditions of this 2-year inhalation study, there was clear evidence of carcinogenic activity of isoprene in male F344/N rats based on increased incidences of mammary gland fibroadenoma and carcinoma, renal tubule adenoma, and testicular interstitial cell adenoma. There was some evidence of carcinogenic activity of isoprene in female F344/N rats based on increased incidences and multiplicity of mammary gland fibroadenoma. A low incidence of rare brain neoplasms in exposed female rats may have been due to exposure to isoprene. Exposure to isoprene by inhalation for 2 years resulted in increased incidences of renal tubule hyperplasia and splenic fibrosis in male rats. Synonyms: Isopentadiene; b-methylbivinyl; 2-methyl-1,3-butadiene
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PMID:NTP Toxicology and Carcinogenesis Studies of Isoprene (CAS No. 78-79-5) in F344/N Rats (Inhalation Studies). 1257 89

Bromoethane is an alkylating agent used primarily as a chemical intermediate in various organic syntheses. In toxicology and carcinogenesis studies, groups of F344/N rats and B6C3F1 mice of each sex received whole-body exposure to bromoethane (greater than 98% pure) once for 4 hours or for 6 hours per day, 5 days per week, for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Single-Exposure, Fourteen-Day, and Fourteen-Week Studies: Single-exposure inhalation studies were conducted in rats and mice at target concentrations of 625, 1,250, 2,500, 5,000, or 10,000 ppm bromoethane. All rats exposed to 10,000 ppm bromoethane and 3/5 female rats exposed to 5,000 ppm died before the end of the single-exposure studies. All mice exposed to 5,000 or 10,000 ppm bromoethane and 2/5 female mice exposed to 1,250 ppm died before the end of the studies. Fourteen-day inhalation studies were conducted in rats and mice at target concentrations of 0, 250, 500, 1,000, 2,000, or 4,000 ppm bromoethane. All rats and mice exposed to 2,000 or 4,000 ppm died before the end of the 14-day studies. Final mean body weights of exposed and control rats were similar. Fourteen-week inhalation studies were conducted in rats and mice at target concentrations of 0, 100, 200, 400, 800, or 1,600 ppm bromoethane. Four of 10 male and 2/10 female rats exposed to 1,600 ppm died before the end of the 14-week studies. The final mean body weights of rats exposed to 1,600 ppm were lower than the initial mean body weights. Compound-related lesions observed in rats at 1,600 ppm, but not at lower concentrations, included minimal atrophy of the thigh muscle, minimal-to-moderate multifocal mineralization in the cerebellum of the brain, minimal-to-severe hemosiderosis of the spleen, marked atrophy of the testis, and minimal-to- mild atrophy of the uterus. The effects in the testis and uterus are probably due to chemical-related loss in body weight during the studies. In mice, compound-related deaths included 3/10 male and 1/10 female mice exposed to 1,600 ppm, 1/9 males exposed to 800 ppm, and 1/10 males exposed to 400 ppm. The final mean body weights of male and female mice exposed to 1,600 ppm were about 15% lower than those of controls. Compound-related effects included atrophy of the uterus and involution of the ovary in females exposed to 1,600 ppm bromoethane. Based on these results, 2-year studies were conducted by exposing groups of 49 or 50 rats or mice of each sex to bromoethane at 0, 100, 200, or 400 ppm, 6 hours per day, 5 days per week. Body Weight and Survival in the Two-Year Studies: Mean body weights of exposed and control rats were generally similar throughout the studies. No significant differences in survival were observed between any groups of male rats (control, 17/49; 100 ppm, 26/50; 200 ppm, 27/50; 400 ppm, 21/50); survival of the 100-ppm group of female rats was greater than that of controls (19/50; 29/50; 24/49; 23/50), and the number of control and 400-ppm male rats and control female rats surviving to the end of the studies was low. Mean body weights of the 400-ppm group of male mice were up to 9% lower than those of controls throughout the study. Mean body weights of the 400-ppm group of female mice were generally 6%-16% lower than those of controls after week 29. No differences in survival were observed between any group of male mice (35/50; 37/50; 30/50; 34/50). The survival of the 400-ppm group of female mice was lower than that of controls at the end of the study (36/50; 37/50; 37/49; 23/49). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidences of pheochromocytomas or malignant pheochromocytomas (combined) of the adrenal medulla were increased in exposed male rats (control, 8/40; 100 ppm, 23/45; 200 ppm, 18/46; 400 ppm, 21/46). Granular cell neoplasms of the brain were seen in exposed male rats but not in controls (0/49; 3/50; 1/50; 1/50). A glioma, an astrocytoma, or an oligodendroglioma was seen in 3/50 male rats exposed to 100 p in 3/50 male rats exposed to 100 ppm. Gliomas were not observed in control female rats, but they occurred in exposed female rats with a significant positive trend (0/50; 1/50; 1/48; 3/50). The historical incidence of granular cell tumors in male F344/N rat chamber controls at the study laboratory is 0/297. The incidences of gliomas in the exposed female groups were not significantly greater than that in the controls and were within the historical incidence range for glial cell neoplasms for untreated controls in NTP studies (mean: 23/1,969, 1&percnt;; range: 0/50-3/50), but they exceeded the historical incidence range for chamber controls at the study laboratory (mean: 1/297, 0.3&percnt;; range: 0/50-1/50). Alveolar epithelial hyperplasia was increased in rats exposed to 400 ppm bromoethane (male: 3/48; 7/49; 7/48; 18/48; female: 5/50; 4/48; 5/47; 10/49). Alveolar/bronchiolar adenomas or carcinomas (combined) were seen in four male rats exposed to 200 ppm and in one exposed to 400 ppm. Alveolar/bronchiolar adenomas were observed in 3/49 female rats at 400 ppm but not at lower concentrations or in controls. The incidences in exposed male and female rats were not significantly greater than those in controls; however, the historical incidence in rat chamber controls for alveolar/bronchiolar adenomas or carcinomas (combined) at the study laboratory is 6/299 (2&percnt;) for males and 4/297 (1.3&percnt;) for females. The incidences of epithelial hyperplasia and squamous metaplasia of the nasal cavity were increased in rats exposed to 400 ppm. The incidence of suppurative inflammation of the nasal cavity was increased in exposed male rats, and the incidences of suppurative inflammation of the larynx and metaplasia of the olfactory sensory epithelium were increased in exposed male and female rats. An adenoma of the nose was seen in one 400-ppm male rat and in one 400-ppm female mouse. Suppurative inflammation and dilatation of the salivary gland ducts were observed at increased incidences in the 200- and 400-ppm groups of female rats. Animals were found to be positive for rat coronavirus/sialodacryoadenitis virus antibodies. The incidence of mammary gland neoplasms was significantly lower in female rats at 400 ppm than in controls (18/50; 15/50; 10/48; 7/50). Adenomas (0/50; 1/50; 1/47; 6/48), adenocarcinomas (0/50; 2/50; 3/47; 19/48), and squamous cell carcinomas (0/50; 1/50; 1/47; 3/48) of the uterus occurred in exposed female mice and not in control mice. The incidence of alveolar/bronchiolar neoplasms was greater in male mice at 400 ppm than in controls (adenomas or carcinomas, combined: 7/50; 6/50; 12/50; 15/50). Acute/chronic inflammation of the lung was observed at increased incidences in female mice at 200 and 400 ppm. Genetic Toxicology: Bromoethane, tested in a closed environment of a desiccator, was mutagenic in S. typhimurium strain TA100 with and without exogenous metabolic activation; it was not mutagenic in strain TA98. In cultured CHO cells, bromoethane induced sister chromatid exchanges (SCEs) but not chromosomal aberrations in both the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of bromoethane for male F344/N rats, as indicated by increased incidences of pheochromocytomas of the adrenal gland; neoplasms of the brain and lung may also have been related to exposure to bromoethane. For female F344/N rats, there was equivocal evidence of carcinogenic activity, as indicated by marginally increased incidences of neoplasms of the brain and lung. For male B6C3F1 mice, there was equivocal evidence of carcinogenic activity, based on marginally increased incidences of neoplasms of the lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, as indicated by neoplasms of the uterus. Synonyms: monobromoethane; bromic ether; hydrobromic ether
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PMID:Toxicology and Carcinogenesis Studies of Bromoethane (Ethyl Bromide) (CAS No. 74-96-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1269 78

Diphenhydramine hydrochloride is a widely used antihistaminic drug in human and veterinary medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing USP-grade diphenhydramine hydrochloride (greater than 99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, dietary concentrations ranged from 620 to 10,000 ppm for rats and from 310 to 5,000 ppm for mice. All rats that received diets containing 10,000 ppm and 9/10 rats that received diets containing 5,000 ppm died before the end of the studies. The final mean body weights of rats receiving 1,250 or 2,500 ppm were 12%-13% or 30%-34% lower than those of controls. Feed consumption by rats at the three highest concentrations was more than 30% less than that by controls. All mice receiving 5,000 ppm, 4/5 males and 4/5 females receiving 2,500 ppm, and 4/5 males receiving 1,250 ppm died before the end of the studies. The final mean body weights of mice that received 1,250 or 2,500 ppm were lower than the initial weights. All dosed rats and mice were hyperactive and sensitive to sound and/or touch. In the 13-week studies, dietary concentrations of diphenhydramine hydrochloride ranged from 156 to 2,500 ppm for rats and from 78 to 1,250 ppm for mice. All rats lived to the end of the studies. The final mean body weights of rats receiving 1,250 or 2,500 ppm were about 15% or 35% lower than those of controls. The final mean body weight of female rats receiving 625 ppm was 9% lower than that of controls. Increased activity was observed for all male and female rats receiving 1,250 and 2,500 ppm. Cytoplasmic vacuolization of the liver, characteristic of fat accumulation, was observed in male and female rats receiving 313-2,500 ppm. The severity of this change increased with increased dose. For mice, 1/10 males receiving 313 ppm, 2/10 males receiving 625 ppm, and 8/10 males receiving 1,250 ppm died before the end of the studies. The final mean body weights of mice that received 625 or 1,250 ppm were about 9% or 16% lower than those of controls. No compound-related histopathological effects were observed in mice. Based on the mortality and body weight effects of diphenhydramine hydrochloride in the short-term studies, dietary concentrations selected for the 2-year studies were 0,313, and 635 ppm diphenhydramine hydrochloride for male rats and 0, 156, and 313 ppm for female rats and male and female mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and control rats were similar throughout the studies, and mean body weights of dosed mice were 3%-13% lower than those of controls throughout most of the studies. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: control, 29/50; low dose, 32/50; high dose, 24/50; female rats: 35/50; 32/50; 36/50; male mice: 29/50; 30/50; 24/48; female mice: 37/50; 39/50; 32/50). The estimated average daily feed consumption by dosed rats and dosed mice was similar to that by controls. The average amount of diphenhydramine hydrochloride consumed per day was approximately 13 or 27 mg/kg for low dose or high dose male rats, 7 or 15 mg/kg for low dose or high dose female rats, and 21 or 46-47 mg/kg for low dose or high dose male and female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: For three high dose male rats, astrocytomas were found in brain sections taken by routine sampling procedures. Gliomas, containing neoplastic astrocytes and oligodendrocytes, were found in one control and one additional high dose male rat. The incidence of glial cell tumors in high dose male rats (4/50) exceeded the highest incidence in historical controls in the Program (2/50). The historical incidence of glial cell tumors is less than 0.7% in approximately 2,000 untreated control male F344/N rats. Three addiless than 0.7&percnt; in approximately 2,000 untreated control male F344/N rats. Three additional sections of brain were prepared from the residual fixed tissues of each male and female rat. One additional astrocytoma in a high dose male rat and one astrocytoma in a high dose female rat were observed in these sections. Adenomas of the anterior pituitary gland in female rats occurred with a significant positive trend; the incidences in low dose male and high dose female rats were marginally greater than those in controls (male: control, 11/49; low dose, 21/50; high dose, 14/49; female: 23/50; 26/50; 35/50). The incidence of alveolar/bronchiolar adenomas in low dose male rats was slightly greater than that in controls (0/49; 5/50; 3/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in dosed male rats were not significantly different from that in controls (1/49; 6/50; 5/50) but exceeded the highest incidence in historicalcontrols (4/49). The historical incidence of alveolar/bronchiolar neoplasms in untreated control male F344/N rats is approximately 2.2&percnt;. Adenomatous hyperplasia of the lung was not increased in incidence in dosed male rats compared with controls. The incidences of granulomas of the liver were increased in dosed rats (male: 0/49; 3/50; 4/50; female: 8/50; 15/49; 18/50). At no site were the incidences of neoplastic lesions in dosed mice considered to be compound related. Cytoplasmic vacuolization (fatty metamorphosis) of the liver was observed at an increased incidence in high dose female mice (0/49; 1/49; 8/49). Genetic Toxicology: Diphenhydramine hydrochloride was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in either the presence or absence of exogenous metabolic activation. Exposure to this chemical did not induce trifluorothymidine (Tft) resistance in mouse L5178Y lymphoma cells with or without metabolic activation. In cytogenetic tests with cultured CHO cells, diphenhydramine hydrochloride induced chromosomal aberrations in the absence, but not the presence, of exogenous metabolic activation (S9); no induction of sister chromatid exchanges (SCEs) was observed in these cells with or without S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of diphenhydramine hydrochloride for male F344/N rats, based on marginally increased incidences of uncommon brain neoplasms (astrocytomas or gliomas) and of alveolar/bronchiolar neoplasms. There was equivocal evidence of carcinogenic activity for female F344/N rats, based on a marginal increase in the incidence of pituitary gland adenomas. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 156 or 313 ppm diphenhydramine hydrochloride. Synonyms: 2-diphenylmethoxy-N,N-dimethylethanamine hydrochloride; 2-(benzhydryloxy)-N,N-dimethylethylamine hydrochloride; b-dimethylaminoethyl benzhydryl ether hydrochloride; benzhydramine hydrochloride Trade Names: Alleran; Benadryl
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PMID:NTP Toxicology and Carcinogenesis Studies of Diphenhydramine Hydrochloride (CAS No. 147-24-0) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1270 39

Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the Bioassay Program is only 0.86%. The absence of this tumor in the high-dose female rat group reduces the likelihood that this tumor is related to propyl gallate administration. Increased incidences of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate were observed in dosed male rats. These findings were considered to be related to administration of propyl gallate. Tumors (mostly benign) of the preputial gland, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal gland were observed with significantly (P<0.05) higher incidences in the low- dose male rats, but there was little evidence of an effect in the high-dose group. The incidences of male rats with tumors of the preputial gland were 1/50 (2%) for controls, 8/50 (16%) for the low-dose, and 0/50 (0%) for the high-dose group. Islet-cell tumors of the pancreas occurred in 2/50 (4%) control males, 9/50 (18%) low-dose males, and 4/50 (8%) for high-dose males. Pheochromocytomas of the adrenal gland were observed in 4/50 (8%) control males, 13/48 (25%) low-dose males, and 8/50 (16%) high-dose males. Negative trends (P<0.05) were observed for leukemia in male rats (16/50, 7/50, 6/50) and for fibroadenomas of the mammary gland in female rats (11/50, 2/50, 5/50). In male mice, malignant lymphoma was observed with a significantly (P</=0.014) positive trend (control, 1/50, 2%; low-dose, 3/49, 6%; high-dose, 8/50, 16%), and the incidence in the high-dose group was significantly (P</=0.028) higher than that observed in the concurrent controls. However, the high-dose incidence was not statistically different from the historical rate (60/640, 9.4%) for the laboratory that conducted this bioassay. Adenomas of the liver in female mice occurred with a statistically significant (P</=0.022) positive trend, and the incidence in the high-dose group was significantly (P</=0.039) higher than that of the controls (0/50, 0%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative&percnt;; 2/50, 4&percnt;; 5/49, 10&percnt;). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6&percnt;; 3/50, 6&percnt;; 5/49, 10&percnt;). Negative trends (P<0.05) were obtained for fibromas of the skin or subcutaneous tissue in male mice (5/50, 1/49, 0/50). Under the conditions of this bioassay, propyl gallate was not considered carcinogenic for F344/N rats, although there was evidence of an increased proportion of low-dose male rats with preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low-dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the increased incidence of malignant lymphoma in male mice may have been related to the dietary administration of propyl gallate. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: 2,4,5 trihydroxybenzoic acid propyl ester; gallic acid propyl ester; Progallin P; Tennox PG
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PMID:NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study). 1275 Jul 52

DES carcinogenicity has been investigated in 2 mouse knockout models, the Xpa homozygous knockout, and the combined Xpa homozygous and p53 heterozygous knockout. Wild-type (WT) mice were also included. Xpa mice received diets containing DES at concentrations of 0, 100, 300, and 1500 ppb for 39 weeks; Xpa/p53 and WT mice received diets containing 0 or 1500 ppb. There were 15 of each sex per group. Both Xpa and WT mice had a similar incidence of tumors at the high dosage of 1500 ppb, including pituitary adenomas in 4 WT mice and 7 Xpa mice, and single incidences of osteosarcoma (Xpa), T-cell lymphoma (WT and Xpa), and testicular interstitial cell adenoma (WT and Xpa). The incidence of tumors was higher in the Xpa/p53 mice at 1500 ppb, mainly attributable to 5 osteosarcomas in males and 2 in females, but also 4 pituitary adenomas, testicular interstitial cell adenomas in 4 males, and single incidences of cerebral glioma, phaeochromocytoma, and cervical fibrosarcoma. The incidence of osteosarcomas was related to the severity of fibro-osseous lesions in the bone marrow. It was concluded that for carcinogenicity screening, Xpa mice were no more sensitive than wild-type mice for compounds like DES, but the Xpa/p53 model showed an increased sensitivity.
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PMID:Diethylstilbestrol (DES): carcinogenic potential in Xpa-/-, Xpa-/- / p53+/-, and wild-type mice during 9 months' dietary exposure. 1617 26

Mitochondrial membrane permeabilization (MMP) is a rate-limiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormone-dependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondrion-targeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization.
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PMID:Chemosensitization by knockdown of adenine nucleotide translocase-2. 1698 57

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