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Biomedical subjects

R E Stoll

Publications and source records attributed to R E Stoll.

At least 19 recordsLinked to original sources
PubMed2005

Phenolphthalein and bisacodyl: assessment of genotoxic and carcinogenic responses in heterozygous p53 (+/-) mice and syrian hamster embryo (SHE) assay.

Phenolphthalein (800 and 2400 mg/kg/day by gavage and 2400 mg/kg/day by diet) and bisacodyl (800-500, 4000-2000, and 8000 mg/kg/day by gavage) were administered to 15 male and 15 female and 20 male and 20 female p53(+/-) mice respectively for 26 weeks to investigate the potential carcinogenicity of each compound. Toxicokinetic analyses confirmed systemic exposure. p-Cresidine was administered by gavage (400 mg/kg/day) and served as the positive control agent in each study. Dietary phenolphthalein reduced survival in both sexes and early deaths were attributed to thymic lymphoma. No bisacodyl-related neoplasms were observed. Regardless of route of administration to p53(+/-) mice, phenolphthalein but not bisacodyl was unequivocally genotoxic, causing increased micronuclei in polychromatic erythrocytes. In the Syrian hamster embryo (SHE) cell transformation assay, phenolphthalein caused increases in morphologically transformed colonies, thereby corroborating NTP's earlier reports, showing phenolophthalein has potential carcinogenic activity. Bisacodyl was negative in the SHE assay. Results of these experiments confirm an earlier demonstration that dietary phenolphthalein causes thymic lymphoma in p53(+/-) mice and show that (1) phenolphthalein causes qualitatively identical results in this transgenic model regardless of route of oral administration, (2) phenolphthalein shows evidence of micronucleus induction in p53(+/-) mice for up to 26 weeks, (3) phenolphthalein induced transformations in the in vitro SHE assay, and (4) bisacodyl in p53(+/-) mice induces neither drug-related neoplasm, nor micronuclei in polychromatic erythrocytes, and did not induce transformations in the in vitro SHE assay.

Animals↗
PubMed2001

Loss of critical palindromic transgene promoter sequence in chemically induced Tg.AC mouse skin papillomas expressing transgene-derived mRNA.

The Tg.AC transgenic mouse carries a v-Ha-ras transgene. Skin papillomas develop in Tg.AC mice upon repeated dermal application of tumor promoters and carcinogens. The transgene is inserted at a single site on chromosome 11 in a multiple-copy array. Although most of the >or= 40 copies are arranged in a direct-repeat orientation, two copies of the transgene are inserted in a palindromic, inverted-repeat orientation. Deletion of the palindromic transgene promoter sequence is associated strongly with and diagnostic of loss of phenotypic responsiveness to Tg.AC papillomagens, such as 12-O-tetradecanoylphorbol-13-acetate (TPA). Unexpectedly, a loss of palindromic transgene sequence, in the absence of an observable reduction in copy number of the direct-repeat-oriented transgene sequence, is seen in DNA from papillomas when compared to genomic DNA from tail clips or skin samples away from the application site. Transgene-derived transcripts were detectable in all Tg.AC papillomas sampled. The transgene locus was hypomethylated in papillomas but not in samples from tail clips from the same animal or from skin samples away from the application site in responder Tg.AC mice, as shown by loss of resistance to digestion by HpaII. A cell line derived from a Tg.AC squamous cell carcinoma showed complete loss of the palindromic transgene sequence, hypomethylation of the transgene locus, and strong expression of v-Ha-ras mRNA. These data indicate that the palindromic transgene sequence, which appears to be necessary for initial responsiveness to tumorigens, may be susceptible to deletion during rapid cellular proliferation and is not required for transgene expression in later phases of papilloma growth.

Animals↗
PubMed2001

Tg.AC genetically altered mouse: assay working group overview of available data.

In a Government/Industry/Academic partnership to evaluate alternative approaches to carcinogenicity testing, 21 pharmaceutical agents representing a variety of chemical and pharmacological classes and possessing known human and or rodent carcinogenic potential were selected for study in several rodent models. The studies from this partnership project, coordinated by the International Life Sciences Institute, provide additional data to better understand the models' limitations and sensitivity in identifying carcinogens. The results of these alternative model studies were reviewed by members of Assay Working Groups (AWG) composed of scientists from government and industry with expertise in toxicology, genetics, statistics, and pathology. The Tg.AC genetically manipulated mouse was one of the models selected for this project based on previous studies indicating that Tg.AC mice seem to respond to topical application of either mutagenic or nonmutagenic carcinogens with papilloma formation at the site of application. This communication describes the results and AWG interpretations of studies conducted on 14 chemicals administered by the topical and oral (gavage and/or diet) routes to Tg.AC genetically manipulated mice. Cyclosporin A, an immunosuppresant human carcinogen, ethinyl estradiol and diethylstilbestrol (human hormone carcinogens) and clofibrate, an hepatocarcinogenic peroxisome proliferator in rodents, were considered clearly positive in the topical studies. In the oral studies, ethinyl estradiol and diethylstilbestrol were negative, cyclosporin was considered equivocal, and results were not available for the clofibrate study. Of the 3 genotoxic human carcinogens (phenacetin, melphalan, and cyclophosphamide), phenacetin was negative by both the topical and oral routes. Melphalan and cyclophosphamide are, respectively, direct and indirect DNA alkylating agents and topical administration of both caused equivocal responses. With the exception of clofibrate, Tg.AC mice did not exhibit tumor responses to the rodent carcinogens that were putative human noncarcinogens, (di(2-ethylhexyl) phthalate, methapyraline HCl, phenobarbital Na, reserpine, sulfamethoxazole or WY-14643, or the nongenotoxic, noncarcinogen, sulfisoxazole) regardless of route of administration. Based on the observed responses in these studies, it was concluded by the AWG that the Tg.AC model was not overly sensitive and possesses utility as an adjunct to the battery of toxicity studies used to establish human carcinogenic risk.

Animal Testing Alternatives↗
PubMed2001

Assessment of cisplatin-induced nephrotoxicity by microarray technology.

Microarrays are a new technology used to study global gene expression and to decipher biological pathways. In the current study, microarrays were used to examine gene expression patterns associated with cisplatin-mediated nephrotoxicity. Sprague-Dawley rats received either single or seven daily ip doses of cisplatin (0.5 or 1 mg/kg/day) or the inactive isomer transplatin (1 or 3 mg/kg/day). Histopathological evaluation revealed renal proximal tubular necrosis in animals that received cisplatin for 7 days, but no hepatotoxic findings. Microarray analyses were performed using rat specific arrays containing 250 toxicity-related genes. Prominent gene expression changes were observed only in the kidneys of rats that received cisplatin for 7 days. Mechanistically, the gene expression pattern elicited by cisplatin (e.g., Bax upward arrow and SMP-30 downward arrow) suggested the occurrence of apoptosis and the perturbation of intracellular calcium homeostasis. The induction of multidrug resistance genes (MDR1 upward arrow, P-gp upward arrow) and tissue remodeling proteins (clusterin upward arrow, IGFBP-1 upward arrow, and TIMP-1 upward arrow) indicated the development of cisplatin resistance and tissue regeneration. Select gene expression changes were further confirmed by TaqMan analyses. Gene expression changes were not observed in the liver following cisplatin administration. In contrast to these in vivo findings, studies using NRK-52E kidney epithelial cells and clone-9 liver cells suggested that liver cells were more sensitive to cisplatin treatment. The discrepancies between the in vivo and in vitro results suggest that caution should be taken when extrapolating data from in vivo to in vitro systems. Nonetheless, the current study elucidates the biochemical pathways involved in cisplatin toxicity and demonstrates the utility of microarrays in toxicological studies.

Animals↗
PubMed2001

Loss of palindromic symmetry in Tg.AC mice with a nonresponder phenotype.

The Tg.AC transgenic mouse carries the v-Ha-ras oncogene under the control of the zeta-globin promoter and is currently being used in a short-term carcinogenesis assay for safety testing of pharmaceuticals. A subset of hemizygous Tg.AC mice was found to be nonresponsive to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, which characteristically induces skin papillomas in these mice with repeated dermal applications. We previously showed that responder and nonresponder hemizygous Tg.AC mice carry about 40 copies of transgene but that the nonresponders had lost a 2-kb BamHI fragment containing the zeta-globin promoter sequence. The present restriction enzyme and S1 nuclease digestion experiments strongly suggested that the 2-kb BamHI fragment resulted from the orientation of two transgenes in an inverted repeat formation. Two subsets of nonresponder Tg.AC mice were identified. Restriction enzyme and S1 nuclease digestion experiments suggested that one nonresponder genotype was produced by a large deletion of one or more near complete copies of transgene sequence and the other genotype was produced by a small deletion near the apex of the "head-to-head" juncture of the inverted repeat. Polymerase chain reaction amplification, cloning, and sequencing results confirmed the palindromic orientation of transgene in Tg.AC mice. Our results indicated that, despite the presence of multiple copies of transgene in a direct repeat orientation, loss of symmetry in the palindromic array of transgene sequence results in the loss of the responder phenotype in Tg.AC mice. Mol. Carcinog. 30:99-110, 2001. Published 2001 Wiley-Liss, Inc.

Animals↗
PubMed2000

Hemodynamic and electrophysiologic effects of ontazolast in dogs.

OBJECTIVE: To determine whether QT interval is prolonged or sudden death is caused by ventricular fibrillation resulting from torsades de pointes and to identify hemodynamic effects of ontazolast. ANIMALS: 28 Beagles. PROCEDURE: Physiologic variables were measured for 2 hours in conscious dogs given ontazolast (0, 1, or 3 mg/kg of body weight, IV) and for 1 hour in anesthetized dogs given cumulative doses of ontazolast (0, 1, 3, 6, or 8 mg/kg, IV). RESULTS: Ontazolast prolonged QT interval and QT interval corrected for heart rate (QTc) at doses of 6 mg/kg in anesthetized dogs. At 8 mg/kg, both variables remained prolonged but tended to decrease. In conscious dogs, ontazolast increased QT interval and QTc 15 minutes after administration, but both variables returned to reference ranges by 60 minutes. In conscious dogs, ontazolast increased maximum rate of increase of left ventricular pressure and maximal velocity of fiber shortening, indicators of inotropy, and increased tau, indicating a decreased rate of relaxation. One conscious dog receiving 3 mg/kg developed nonfatal torsades de pointes, but another conscious dog developed ventricular fibrillation. Two anesthetized dogs receiving 6 mg/kg developed early afterdepolarizations, and all dogs developed secondary components in theirT waves. CONCLUSION AND CLINICAL RELEVANCE: Ontazolast possesses potent class-III antiarrhythmic properties and induces prolongation of QTc in a dose-dependent fashion. Because there was a clear dose-dependent prolongation of QT interval in all instances, ontazolast may serve as a positive-control compound for studying other compounds that are believed to prolong the QT interval.

Action Potentials↗
PubMed1994

Analysis of radiolabeled CHO cell-derived rHuGM-CSF pharmacokinetics and biodistribution in rhesus monkeys following intravenous and subcutaneous injection.

The purpose of these studies was to examine the biodistribution and pharmacokinetics of radiolabeled human CHO cell-derived rHuGM-CSF in normal Rhesus monkeys (Macaca mulatta) following intravenous (i.v.) and subcutaneous (s.c.) injection. A dual radioisotope tracer technique was utilized to monitor the behavior of rHuGM-CSF in vivo. Recombinant HuGM-CSF was radiolabeled with I-123 (a 13.2 h half-life, 140 KeV pure gamma emitting radionuclide detected using gamma scintigraphic imaging) using a mild chloramine T reaction. A separate preparation of rHuGM-CSF radiolabeled with S-35 methionine by bioincorporation in tissue culture was mixed with the I-123-labeled protein, permitting comparison of data obtained from the two radiolabels. Two dose levels of rHuGM-CSF were used for i.v. bolus (15 and 300 micrograms/kg) and s.c. (10 and 100 micrograms/kg) studies. The results of these studies demonstrated that the co-administered I-123 rHuGM-CSF and S-35 rHuGM-CSF followed similar blood elimination kinetics after i.v. or s.c. injection. Following i.v. bolus injection, rHuGM-CSF was found to rapidly distribute to all central body cavity high blood flow organs, followed by rapid uptake in the kidneys and elimination in the urine. There were no differences in the pharmacokinetic values obtained for I-123- and S-35-labeled rHuGM-CSF nor for the two dose levels examined. Following, s.c. injection, I-123- and S-35-labeled rHuGM-CSF were found to reach maximal plasma levels after approximately 16 h. The primary route of elimination was the urine. Monkeys previously exposed to rHuGM-CSF were found to have circulating antibodies to rHuGM-CSF. Studies in these animals revealed a significantly altered distribution and clearance of radiolabeled rHuGM-CSF, with the majority of the injected activity being cleared by the liver.

Animals↗
PubMed1992

Studies of an improved rhesus hematopoietic progenitor cell assay.

We have improved Rhesus monkey marrow cell growth in semisolid media by means of substituting supplemented calf serum for fetal bovine serum. The cloning efficiency of light-density marrow cells separated on 60% Percoll was 126 (+/- 54)/10(5) (n = 12, +/- SD), and for light-density peripheral blood cells 60 (+/- 46)/10(6) (n = 11). Thirty-five percent of the colonies were multilineage, whereas the remainder were unilineage colonies composed of erythrocytes, megakaryocytes, and neutrophilic or monocytic granulocytes. Unilineage megakaryocyte colonies comprised 12% of the total marrow progenitor cells. The [3H]TdR suicide index of marrow progenitor cells was 47% +/- 9% (n = 12). This progenitor cell assay should prove useful in preclinical studies of the effect of recombinant hematopoietic growth factors on the number and cycling status of Rhesus hematopoietic progenitor cells.

Animals↗
PubMed1990

Post-mortem biochemistry of beagle dog lenses after treatment with Fluvastatin (Sandoz) for 2 years at different dose levels.

Post-mortem biochemical analyses of dog lenses and of aqueous humour of a 2 year oral toxicity study in the dog with Fluvastatin (control, 1, 8 and 16 mg/kg/day) did not show any relationship to the observed lens opacities (3 animals out of 8 at 16 mg/kg/day). With respect to lens transparency, a daily dosage of 8 mg/kg/day Fluvastatin to dogs over a period of 2 years is non-cataractogenic. Mean data on lenticular enzyme activities (GPX, G6PH, GAPDH, ALD, AR, LDH, PFK and SDH) as well as measurements of GSH/GSSG, ATP, ADP, AMP, Gluc, Fruc, Sorb, G6P and F6P do not indicate changes which may directly lead to lens opacifications. Conformational changes of lens proteins (heat lability of PFK-activity), a shift in the albumin/IgG ratio of aqueous humour and equatorial lens protein composition changes (after isoelectrofocusing) were observed. The biological significance of these changes is unknown as the non-cataractogenic dose for lens opacities in beagle dogs is 8 mg/kg/day.

Animals↗
PubMed1988

Noninvasive measurement of systemic arterial blood pressure in the conscious beagle dog.

The objectives of this study were to evaluate a technique for routine, noninvasive measurement of systemic arterial blood pressure and heart rate (HR) in conscious Beagle dogs for toxicologic research. HR, systolic, diastolic, and mean arterial (MAP) pressures were measured with a DINAMAP research monitor (Model 1255, Critikon, Inc.) as follows: Dogs were restrained in a Harvard dog sling, a neonatal cuff was wrapped around the base of the tail, and blood pressure and HR were determined once a minute. Initially, normal values were obtained, 5-10 trials/session, one to three sessions/day for 15 days in six dogs. The day to day, session to session, and trial variabilities were determined and found to be minimal. The day to day diastolic pressure ranged from 74 +/- 18 to 91 +/- 13 mm Hg, systolic pressure from 125 +/- 25 to 156 +/- 22 mm Hg, MAP from 94 +/- 20 to 113 +/- 15 mm Hg, and HR from 111 +/- 21 to 126 +/- 24 beats/minute (bpm). The effects of various drugs on these parameters were determined. Norepinephrine increased diastolic, systolic, and MAP by 75 to 110 mm Hg and decreased HR by half. Epinephrine increased HR by 20 bpm. Phentolamine decreased diastolic, systolic, and MAP by up to 25 mm Hg. Isoproterenol increased HR by up to 130 bpm and decreased diastolic, systolic, and MAP by 20 mm Hg. In addition, the effect of a classic drug interaction on these parameters was determined. When dogs pretreated with the monoamine oxidase inhibitor tranylcypromine were challenged with tyramine, diastolic, systolic, and MAP pressures were increased, whereas HR was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Five-month oral (diet) toxicity/infectivity study of Bacillus thuringiensis insecticides in sheep.

Bacillus thuringiensis insecticides (Bt) [Dipel (test substance D or Thuricide-HP (test substance T)] were administered in the diet for 5 months to castrated mixed rambouillet/merino sheep (24-34 kg at the beginning of the study) at a dose of 500 mg/kg/day (approximately 10(12) spores per day). No treatment-related effect was seen on weight gain or clinical chemistry parameters nor were significant gross clinical changes observed. Several blood and tissue samples taken just prior to the time the animals were killed or at necropsy were found to be positive for Bt when cultured. Detailed gross and microscopic pathologic examination of the sheep revealed several incidental lesions. However, the only lesion that may have been associated with the treatment was lymphocytic hyperplasia in Peyer's patches seen in the cecum of three sheep and it was not considered to be clinically significant.

Administration, Oral↗
PubMed1984

Chronic toxicity/carcinogenesis study of temazepam in mice and rats.

The benzodiazepine temazepam was given to Charles River CD rats for 2 years in the diet at dosages of 10, 40, and 160 mg/kg day. An 18-month study was performed in Charles River CD-1 mice via dietary admixture at dosages of 10, 80, and 160 mg/kg/day. Mean body weights were significantly decreased for high dose rats of both sexes from Treatment Week 39 until termination. All drug treated male groups had a higher rate of mortality when compared to the male control groups, primarily due to deaths occurring between 19 to 24 months. Compound-related hepatic lipidosis accompanied by an increase in liver weights was observed at the high dose level in the 6- and 12-month and terminal sacrifices, as well as the middle dose level at the 12-month interim sacrifice. No evidence was found of compound induced carcinogenicity at any time period. Mortality for male mice was significantly higher in the two higher dose groups; this resulted from bite wounds associated with a drug-related increase in fighting behavior. An isolated finding of borderline statistical significance (p = 0.0556) was noted for hepatocellular adenomas in high dose female mice (4/100) at the 18-month terminal sacrifice. This incidence is well within the reported historical control range (0-14%). Minimal hepatoproliferative (hyperplastic nodules) and vascular effects (telangiectasis) were seen in the high dose male and female mice at the 18-month terminal sacrifice. Thus, these results were similar to those previously reported for oxazepam although meaningful effects on neoplasia did not occur with temazepam. Unlike in man, temazepam is primarily metabolized to oxazepam in the mouse and thus these results are not adverse with regard to human safety evaluation.

Animals↗
PubMed1976

Barbital alteration of central nervous system sensitivity to hexobarbital in the rat.

Alteration in central nervous system (CNS) sensitivity to the hypnotic effect of the hexobarbital was assessed by analytical, electroencephalographic, and pharmacokinetic techniques in barbital-treated rats. Each of these conceptually diverse experimental methodologies yielded similar conclusions concerning the alteration of CNS sensitivity by barbital treatment.

Animals↗