Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A lethal syndrome characterized clinically by growth retardation, progressive acrodermatitis, chronic pyoderma and paronychia, diarrhea, pneumonia, and abnormal behavior was observed in 17 related Bull Terrier pups. Median survival time was 7 months. Laboratory evaluation revealed non-degenerative neutrophilia, consistently low activities of serum alkaline phosphatase and alanine transaminase, and frequently, hypercholesterolemia. Lymphocyte blastogenic responses were decreased and there was dysgammaglobulinemia in pups in which quantitative studies of immunoglobulins were made. The mean of plasma zinc concentrations in 5 affected pups was significantly lower than the mean of age- and breed-matched controls. Pathologic findings included parakeratosis, hyperkeratosis, and superficial bacterial infections of the skin. There was severe reduction of lymphocytes in T-lymphocyte areas of lymphoid tissue. Bronchopneumonia and dilatation of the cerebral ventricles were found in most affected pups. Family studies indicated that the syndrome is inherited as an autosomal recessive trait. In spite of its similarities to lethal trait A46 in Black Pied Danish cattle and acrodermatitis enteropathica in man, oral or parenteral treatment with zinc failed to ameliorate the clinical signs of the syndrome.
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PMID:Lethal acrodermatitis in bull terriers. 371 Aug 72

A histoenzymological study was carried out on 41 tissue specimens removed at biopsy and for surgical operations of the following lesions: benign hyperkeratosis, lichen planus, severe epithelial dysplasia, carcinoma in situ, epidermoid carcinoma, radicular cyst, odontogenic keratocyst and ameloblastoma. The purpose of this study was to study some possibly significant variations in levels of activities of oxidative enzymes, diaphorases, acid phosphatases and Naphthol esterases in such lesions (normal oral mucosa and epidermis serving as controls). In the lesions of the oral mucosa, these histoenzymological variations were not sufficiently characteristic to contribute to histological diagnosis. In lichen planus, some vacuolated or necrotic basal cells lacked enzyme activities, whereas in the upper layers, enzyme activities were irregularly present. Benign hyperkeratosis showed enzymatic activities similar to those of the normal epidermis, namely high oxidative activities particularly prominent in basal cells and in granular layer, and esterase activity beneath the keratinized layer. In severe epithelial dysplasia, carcinoma in situ and epidermoid carcinoma, numerous variations of activities of oxidative enzymes, esterases and acid phosphatase were seen from one cell to the other. In cystic diseases of jaws, enzymatic activities were equally nonspecific in the epithelial lining of the radicular cyst and the odontogenic keratocyst (activities similar to those of normal oral epithelium and epidermis, respectively). But in common ameloblastoma, there was diffuse uniformly low oxidative enzymatic activities in the epithelium and high widespread activity of alkaline phosphatase in the stroma. The latter may be useful in differentiating the cystic acanthomatous variety of ameloblastoma from odontogenic keratocysts of the jaws.
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PMID:Histoenzymological features of epithelial cells in lesions of oral mucosa in cysts and ameloblastomas of jaws. 392 82

An histoenzymological study comprising oxidative enzymes, diaphorases, acid and alkaline phosphatases, naphtolesterases, referred to 60 biopsy and operation specimens. It showed interesting arguments for diagnosis and understanding of precancerous and cancerous lesions of the oral mucosa and also of ameloblastomas of jaws. The enzymatic activities of precancerous and cancerous oral lesions were compared with those of normal buccal mucosa and epidermis, benign hyperkeratosis (activities similar to those of the epidermis) and lichen planus. In severe dysplasia and epidermoid carcinoma, numerous variations of oxidative, esterase and acid phosphatase activities were seen from one cell to another. But this pattern was non conclusive for the diagnosis, a similar one being found in inflammatory lesions and especially in the lichen planus. In lobules of invasive carcinoma, the strong enzymological activities (particularly acid phosphatases, naphtolesterases) were correlated with a high degree of differentiation of the tumor and these enzymatic methods offered an interesting contribution for the fine evaluation of histoprognosis in malignant epithelial tumors. Among the lesions of jaws, radicular and dentigerous cysts had low enzymatic activities similar to those of normal buccal epithelium. The epidermoid cysts (keratocysts), because of their highly differentiated keratinization, like benign hyperkeratosis, had the same enzymatic activities as epidermis. Peculiar were the enzymatic activities of common ameloblastoma; they differed from those of other lesions of squamous tissues (low oxidative activities without decreasing gradient). Besides, round epithelial clumps, the stroma showed a high and widespread alkaline phosphatase activity. Thus, this peculiar stromal activity may be useful to differentiate ameloblastoma from the other epidermoid cysts of the jaws. In the other hand, such a constatation suggests a low degree of odontogenic induction.
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PMID:Histoenzymological features of epithelial cells in epidermoid carcinomas of oral mucosa and in ameloblastomas of jaws. 651 88

Two dogs with metabolic epidermal necrosis had hyperkeratosis of the footpads accompanied by erythematous, erosive and crusting lesions affecting the muzzle, external genitalia, perineum and periocular regions. Histopathological examination of skin biopsies revealed a superficial hydropic dermatitis with marked parakeratosis. Both dogs had high plasma activities of alkaline phosphatase and alanine aminotransferase and high concentrations of glucose, and also a marked hypoaminoacidaemia. Despite these similarities, the cutaneous eruptions were associated with different underlying diseases. One dog had a pancreatic carcinoma which had metastasised widely; the primary tumour and the metastases showed glucagon immunoreactivity on immunocytochemical staining, and the dog's plasma glucagon concentration was markedly greater than that of control dogs. The other dog had diffuse hepatic disease; its plasma glucagon concentration was similar to that of control samples and cirrhosis was identified post mortem. Metabolic epidermal necrosis in dogs is a distinct cutaneous reaction pattern which may be associated with different underlying systemic diseases; however, the pathogenesis of the skin lesions remains unclear.
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PMID:Metabolic epidermal necrosis in two dogs with different underlying diseases. 763 36

A total of 45 non-uremic dogs, with clinical signs indicating leishmaniosis, entered the study. Diagnosis was confirmed by indirect immunofluorescence assay (IFA) on serum and polymerase chain reaction (PCR) on bone marrow samples. The dogs were randomly allocated into Group A (n=37) that received allopurinol (10mg/kg B.W., per os, twice daily) for 4 consecutive months, and Group B (n=8) that were placebo-treated. Clinical signs were scored just before and at monthly intervals throughout the study period, in a blinded and independent fashion. Complete blood count, serum biochemistry profile, urinalysis, lymph node and bone marrow parasitology, IFA and enzyme-linked immunosorbent assay (ELISA) serology and bone marrow PCR were carried out at the beginning and at the end of the trial. A total of three Group A and one Group B dogs died of end stage kidney disease that developed during the trial. In Group A animals that endured the trial there was a significant improvement in the general body condition, conjunctivitis, peripheral lymphadenopathy, splenomegaly, masticatory muscle atrophy, ulcerative stomatitis, epistaxis, exfoliative dermatitis, cutaneous ulcerations, blepharitis and nasodigital hyperkeratosis. The same observation was made for anemia, lymphopenia, hyperproteinemia, hyperglobulinemia, hyperphosphatemia, increased alkaline phosphatase activity and the low albumin/globulin ratio. By contrast, no improvement of any kind was seen in Group B dogs. Lymph node and bone marrow parasite numbers were significantly decreased in Group A animals. In Group B, that occurred only in the lymph nodes. Apart from remission of clinical signs and restoration to normal of clinicopathological abnormalities, allopurinol did not eliminate Leishmania organisms, as the PCR result on bone marrow was still positive in all the dogs that finished the trial.
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PMID:A randomised, blinded, placebo-controlled clinical trial with allopurinol in canine leishmaniosis. 1142 83

beta-Bromo-beta-nitrostyrene is a wide-spectrum biocide most frequently used as a fungicide to combat the formation of slime in paper and pulp mill operations. Toxicity studies were conducted by administering beta-bromo-beta-nitrostyrene (99% pure, trans isomer) to groups of 10 male and 10 female F344/N rats and B6C3F1 mice by gavage, 5 days per week for 4 weeks. Doses of 0, 37, 75, 150, 300, or 600 mg/kg were administered in a corn oil vehicle. The parameters evaluated included hematology, clinical chemistry (rats only), and histopathology. The genetic toxicity of b-bromo-b- nitrostyrene was evaluated in Salmonella typhimurium and in peripheral blood erythrocytes of mice. In addition, the absorption, distribution, metabolism, and excretion of b-bromo-b- nitrostyrene were studied in male F344 rats following intravenous, dermal, or oral administration. In the 4-week study in rats, two males in the 150 mg/kg group, one male and one female in the 300 mg/kg groups, and all rats in the 600 mg/kg groups died or were killed moribund before the end of the study. The mean body weight gains and absolute and relative thymus weights of male and female rats in the 300 mg/kg groups were lower than those of the controls. Hematology evaluations in rats indicated the development of a mild anemia and monocytosis consistent with and likely related to inflammatory and ulcerative lesions that occurred in the gastrointestinal tract. Clinical chemistry evaluations indicated lower alkaline phosphatase activities and serum total protein and albumin concentrations in treated rats than in the controls. Treatment-related lesions in rats were observed in the forestomach, glandular stomach, cecum, nasal passages, and testis. Males were generally affected at lower doses than females. The most prominent lesions were in the forestomach and were characterized by inflammation, hemorrhage, and necrosis in rats dying early. In rats surviving to the end of the study, forestomach lesions included necrosis, ulceration, and regenerative epithelial hyperplasia and hyperkeratosis. Inflammation of the glandular stomach and cecum also occurred in rats dying early. Inflammation and degeneration of the nasal passage in treated rats were attributed to reflux of the irritant chemical in the gavage fluid. Testicular degeneration was seen in rats dying early and was characterized by necrotic germ cells and a decreased number of spermatozoa in the epididymal tubules and by multinucleated syncytial cells in the seminiferous tubules. In the 4-week study in mice, one male in the 300 mg/kg group and all mice in the 600 mg/kg groups died or were killed moribund before the end of the study. No significant changes in final mean body weights or mean body weight gains were observed in males or females. Hematologic changes consistent with inflammatory lesions occurred in male and female mice in the 300 mg/kg groups. Treatment-related lesions in mice occurred in the forestomach, gallbladder, and testis. Forestomach lesions were similar to those described in rats and were only present in male and female mice given doses of 300 mg/kg or greater. At these dose levels, inflammation and degeneration/necrosis of the gallbladder mucosa also occurred in male and female mice, but these lesions were absent in the bile ducts or liver. Testicular degeneration occurred in mice dying early and was similar to that observed in rats. In comparative disposition and metabolism studies in male F344 rats, clear differences were found between the fate of b-bromo- b-nitrostyrene following oral administration and the fate of radiolabeled beta-bromo-beta-nitrostyrene following intravenous or dermal administration. Oral exposure resulted in significant absorption of nonhydrolyzed beta-bromo-beta-nitrostyrene and the formation of parent compound metabolites, primarily 1-phenyl-2-nitroethyl-1-sulfonic acid (PNSA), a product of a sulfation reaction at the alpha carbon. Following dermal exposure, a limited amount of beta-bromo-beta-nitrostyrene entered the systemic circulation (approximately 10% per 24 hours from a 10 mg/cm2 dose) although lower doses were more completely absorbed. Once beta-bromo-beta-nitrostyrene entered the circulation, significant amounts of the dose were hydrolyzed or bound to macromolecules. PNSA was not a major metabolite in dermal or intravenous studies. Regardless of the route of administration, only low levels of radioactive label from beta-bromo-beta-nitrostyrene were retained in tissues following exposure, and most beta-bromo-beta-nitrostyrene metabolites were excreted in the urine and feces within 24 to 48 hours. beta-bromo-beta-nitrostyrene was mutagenic in S. typhimurium strains TA98 and TA100 in the absence of exogenous metabolic activation (S9). No mutagenic activity was observed with S9 in either of these strains, and no mutagenic activity was observed in strains TA97 or TA1535, with or without S9. The frequency of micronucleated normochromatic erythrocytes was significantly increased in the peripheral blood of male mice, but not female mice, following 4 weeks of exposure to beta-bromo-beta-nitrostyrene by corn oil gavage. In summary, under the conditions of these 4-week gavage studies, rats were more sensitive to the toxic and irritant effects of beta-bromo-beta-nitrostyrene than mice, and males were more affected by beta-bromo-beta-nitrostyrene than females. Although the specific cause of the early deaths could not be determined, significant inflammation and necrosis developed in the forestomach of rats and mice, in the glandular stomach and cecum of rats, and in the gallbladder of mice. Similar lesions in the nasal passages of rats were attributed to reflux of gavage materials. The no-observed- adverse-effect level (NOAEL) for histopathologic lesions was 37 mg/kg per day for rats and 150 mg/kg per day for mice.
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PMID:NTP Toxicity Studies of beta-Bromo-beta-Nitrostyrene (CAS No. 7166-19-0) Administered by Gavage to F344/N Rats and B6C3F1 Mice. 1196 39

We report the first diagnosed case of Papillon-Lefevre syndrome in Thailand. The patient is the youngest child of consanguinous parents, and she has had symmetrical hyperkeratotic plaques on both plantar surfaces since birth with a history of chronic gingivitis, periodontitis, and premature loss of primary dentition. The histologic study revealed compact hyperkeratosis with epidermal acanthosis. Radiologic studies of the skull were normal. The radiographic panoramic view of the oral cavity revealed generalized severe vertical and horizontal alveolar bone loss. The immunologic analysis of polymorphonuclear leukocyte phagocytic function by nitrobluetetrazolium test (NBT test) showed decreasing response to latex stimulation. Serum parathyroid hormone, calcium, phosphate, and alkaline phosphatase levels were within normal limits. The skin lesions were temporary relieved with topical keratolytic agents. The oral lesions were improved by the extraction of hopeless teeth and conventional periodontal treatments.
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PMID:Papillon-Lefevre syndrome: a case report. 1212 66

Turmeric oleoresin is the organic extract of turmeric, a ground powder from the root of the Curcuma plant, and is added to food items as a spice and coloring agent. Turmeric oleoresin, turmeric, and curcumin (the major component found in turmeric) were nominated by the National Cancer Institute and the Food and Drug Administration for study because these chemicals are used in food items and curry powders, and there was little information on their toxic or carcinogenic properties. Pure curcumin was not available in sufficient quantities for study, and a turmeric oleoresin with a high curcumin content (79% to 85%) was selected for evaluation. Toxicity and carcinogenicity studies were conducted by administering turmeric oleoresin in feed to groups of male and female F344/N rats and B6C3F1 mice for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 1,000, 5,000, 10,000, 25,000, or 50,000 ppm turmeric oleoresin. All rats survived until the end of the study. The final mean body weight of males receiving 50,000 ppm was 5% lower than that of the controls. Feed consumption by exposed male and female rats was similar to that by the controls. Dietary levels of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin were estimated to deliver average daily doses of 50, 250, 480, 1,300, or 2,600 mg/kg body weight to males and 60, 300, 550, 1,450, or 2,800 mg/kg to females. The absolute and relative liver weights of female rats and the relative liver weights of male rats receiving 5,000, 10,000, 25,000, and 50,000 ppm were significantly greater than those of the controls. There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters. Clinical findings included stained fur, and discolored feces and urine of exposed animals, presumably due to the parent compound or its metabolites. Hyperplasia of the mucosal epithelium was observed in the cecum and colon of male and female rats that received 50,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0,1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin. There were no deaths attributed to turmeric oleoresin and the final mean body weight gains and final mean body weights of all exposed groups of male and female mice were similar to those of the controls. Feed consumption by exposed male and female mice was similar to that by the controls. Dietary levels of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin were estimated to deliver average daily doses of 150, 750, 1,700, 3,850, or 7,700 mg/kg body weight to males and 200, 1,000, 1,800, 4,700 or 9,300 mg/kg to females. Absolute and relative liver weights of male mice that received 5,000 ppm and male and female mice that received 10,000, 25,000 and 50,000 ppm were significantly greater than those of the controls. Clinical findings in mice included stained fur, and discolored feces and urine. There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters, and there were no chemical related histopathologic lesions. 2-YEAR STUDY IN RATS: The exposure level selection for the 2-year study was based on the 13-week study, which showed that rats could tolerate diets containing up to 50,000 ppm. Groups of 60 male and 60 female F344/N rats were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 104 (males) or 103 (females) weeks, which were estimated to deliver average daily doses of 80, 460, or 2,000 mg/kg to males and 90, 440, or 2,400 mg/kg to females. Nine or 10 rats from each exposure group were evaluated after 15 months. Survival, Mean Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed male and female rats was similar to that of the controls (male: O ppm, 18/50; 2,000 ppm, 17/50; 10,000 ppm, 15/50; 50,000 ppm, 17/50; female: 33/50, 27/50, 28/50, 34/50). Th50, 28/50, 34/50). The final mean body weights of all exposed male rats and female rats receiving 2,000 and 10,000 ppm were similar to those of the controls. The final mean body weights of male and female rats that received 50,000 ppm were slightly lower (up to 10%) than those of the controls throughout much of the study. Feed consumption by exposed male and female rats was similar to that by controls throughout the study. The absolute and relative liver weights of female rats receiving 10,000 or 50,000 ppm were significantly greater than those of controls at the 15-month interim evaluation. There were no clinical findings related to toxicity. Hematology and Clinical Chemistry: In male and female rats receiving 50,000 ppm the hematocrit values, hemoglobin concentrations, and erythrocyte counts at the 15-month interim evaluation were significantly lower than those in the controls. In addition, platelet counts in male and female rats that received 50,000 ppm and reticulocyte counts in male rats that received 50,000 ppm were significantly higher than those in the controls. No biologically significant differences were observed in clinical chemistry parameters. Pathology Findings: Chemical-related nonneoplastic lesions occurred in the gastrointestinal tract of rats that received 50,000 ppm. Males receiving 50,000 ppm had increased incidences of ulcers, hyperplasia, and hyperkeratosis of the forestomach. Male and female rats that received 50,000 ppm had ulcers, chronic active inflammation, and hyperplasia of the cecum. Similar lesions also occurred in the colon of males receiving 50,000 ppm. Male and female rats that received 50,000 ppm and male rats that received 10,000 ppm had significantly increased incidences of sinus ectasia of the mesenteric Iymph node. The incidences of clitoral gland adenoma in all exposed groups of female rats were significantly increased. Clitoral gland carcinomas occurred in one control female and in four 2,000 ppm females, but not in females that received 10,000 or 50,000 ppm. The incidences of clitoral gland adenoma or carcinoma (combined) in all exposed groups of female rats were similar (6/50, 16/48, 15/47, 16/49) and did not increase with exposure level. The incidence of clitoral gland hyperplasia was similar among exposed and control groups of female rats (7/50, 5/48, 4/47, 7149). 2-YEAR STUDY IN MICE: The exposure level selection for the 2-year study was based on the 13-week study, which showed that mice could tolerate diets containing up to 50,000 ppm. Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 103 weeks, which were estimated to deliver average daily doses of 220, 520, or 6,000 mg/kg to males and 320,1,620, or 8,400 mg/kg to females. Nine or 10 mice from each exposure group were evaluated after 15 months. Survival, Mean Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed male and female mice was similar to that of the controls (male: O ppm, 43/50; 2,000 ppm, 43/50; 10,000 ppm, 37/50; 50,000 ppm 42/50; female: 39/50, 41/50, 34/50, 42/50). The mean body weight of female mice receiving 50,000 ppm was slightly lower (up to 12%) than that of the controls from about week 25. The final mean body weights of males that received 50,000 ppm and females that received 10,000 and 50,000 ppm were significantly lower than those of controls. The final mean body weights of other exposed groups of male and female mice were similar to those of the controls. Feed consumption by exposed male and female mice was similar to that by the controls throughout the study. The absolute and relative liver weights of male and female mice receiving 10,000 and 50,000 ppm were significantly greater than those of the controls at the l5-month interim evaluation. There were no clinical findings related to toxicity. Hematology and Clinical Chemistry: No biologically significant differences were observed in hematologic parameters. The alkaline phosphatase values of male and female mice that received 10,000 and 50,000 ppm were significantly higher than those of controls at the 15-month interim evaluation. Pathology Findings: The incidences of hepatocellular adenoma in male and female mice receiving 10,000 ppm, but not those in mice receiving 2,000 or 50,000 ppm, were significantly increased (male: 25/50, 28/50, 35/50, 30/50; female: 7/50, 8/50, 19/51, 14/50). The number of male and female mice in the 10,000 and 50,000 ppm groups with multiple hepatocellular neoplasms was significantly greater than that in the controls. The incidences of hepatocellular carcinoma were similar among exposed and control groups. In contrast to rats, there were no chemical-related nonneoplastic lesions of the gastrointestinal tract in mice. Three males that received 2,000 ppm and three males that received 10,000 ppm had carcinomas of the small intestine; neoplasms of the small intestine were not observed in control males or in males that received 50,000 ppm. Female mice receiving 50,000 ppm had a significantly increased incidence of thyroid gland follicular cell hyperplasia. GENETIC TOXICOLOGY: Turmeric oleoresin was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9). It induced small but significant increases in sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. The positive response in the sister chromatid exchange test occurred in the presence of S9, whereas the aberrations response occurred without S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of turmeric oleoresin in male F344/N rats administered 2,000, 10,000, or 50,000 ppm. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female F344/N rats based on increased incidences of clitoral gland adenomas in the exposed groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in male B6C3F1 mice based on a marginally increased incidence of hepatocellular adenoma at the 10,000 ppm level, and the occurrence of carcinomas of the small intestine in the 2,000 and 10,000 ppm groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female B6C3F1 mice based on an increased incidence of hepatocellular adenomas in the 10,000 ppm group. Turmeric oleoresin ingestion was also associated with increased incidences of ulcers, hyperplasia, and inflammation of the forestomach, cecum, and colon in male rats and of the cecum in female rats. In female mice, ingestion of diets containing turmeric oleoresin was also associated with an increased incidence of thyroid gland follicular cell hyperplasia. Synonyms for Turmeric Oleoresin: curcuma oil; oil of turmeric; turmeric oil; curcuma longa oils; curcuma long oil; Curcumin Synonyms for Curcumin: 1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione; C.I. Natural Yellow 3; C.I. 75300; Curcuma; diferuloylmethane; E 100; Haidr; Halad; Haldar; Halud; HSDB 4334; Indian Saffron; kacha haldi; Kurkumin; merita earth; Souchet; Turmeric Yellow; yellow ginger; yellow root; Yo-kin; Zlut Prirodni 3; NCI-C613253
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PMID:NTP Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (CAS No. 8024-37-1) (Major Component 79%-85% Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 4

Tamoxifen (TAM) is a nonsteroidal antiestrogen that prevents estrogen receptor-positive breast cancer in rodents and humans. Bexarotene (BEX), a selective agonist for retinoid X receptors, inhibits mammary carcinogenesis in rodents. The present study was conducted to support the preclinical development of TAM (tamoxifen citrate) + BEX for use in breast cancer chemoprevention, and to investigate the influence of these agents on hepatic gene expression. Female CD rats (20 per group) received daily oral (gavage) exposure to TAM (0 or 60 microg/kg/day) and/or BEX (0, 5, 15, or 45 mg/kg/day) for a minimum of 90 days. BEX induced mild, dose-related anemia and dose-related increases in serum alkaline phosphatase, cholesterol, triglycerides, and calcium levels, and increased platelet counts. TAM had no biologically significant effect on any clinical pathology parameter and did not alter the effects of BEX on these endpoints. Microscopic alterations induced by BEX included epidermal hyperplasia, hyperkeratosis (stomach), and cytoplasmic clearing (liver). Microscopic changes in TAM-treated rats were limited to mucous cell hypertrophy in the cervix and vagina. The toxicity of administration of the combination of TAM + BEX can generally be predicted on the basis of the toxicity of each drug as a single agent. BEX induced dose-related alterations in the expression of several genes involved in steroid, drug, and/or fatty acid metabolism; TAM did not alter these effects of BEX. Differential expression of genes involved in drug and lipid metabolism may underlie the observed effects of BEX on cholesterol and triglyceride levels and its effects on liver histology.
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PMID:Subchronic toxicity and toxicogenomic evaluation of tamoxifen citrate + bexarotene in female rats. 1763 Apr 14

A 55-year-old man presented with multiple gradually progressing asymptomatic swellings on his body for the preceding 6 months. He had no personal or family history of any skin disease. There was no systemic symptom apart from occasional constipation. Examination revealed multiple discrete, firm, nontender, skin-colored nodules of varying sizes, fixed to the skin but free from the underlying structures on his chest, abdomen, and back. The overlying skin of the nodules was erythematous at places (Figure 1). A solitary depigmented, nonanesthetic patch (measuring 3 cm x 3 cm) was noted around a central gray macule (4 mm x 4 mm) on his left shin (Figure 2). The surface of this lesion was otherwise normal. Wood's lamp examination of this area showed attenuation of pigmentation in the central area and total depigmentation surrounding it. No dyspigmented area was noted on Wood's lamp examination of the other areas. There was no abnormality of the orogenital mucosae. General examination revealed mild pallor and multiple discrete, nontender, firm lymph nodes, measuring 3 cm x 3 cm, attached to the skin in the left inguinal region. The overlying skin was normal. Ocular examination (including direct and indirect ophthalmoscopy) and otolaryngologic evaluation were normal. Proctoscopic examination revealed a reddish-black indurated mass at the right lateral wall of the lower third of the rectum. Examination of the other system was noncontributory. Complete hemogram showed mild anemia (hemoglobin % = 10 gm%) and raised ESR, (80 mm in the first hour; Westergren's method). Biochemistry panel was normal apart from raised levels of aspertate transaminase (78 U/L), alanine transaminase (68 U/L), alkaline phosphatase (386 U/L), and lactate dehydrogenase (692 U/L). Chest x-ray showed a rounded opacity in the left apical area suggestive of cannon-ball metastasis (Figure 3). Ultrasonography and computed tomography of the abdomen revealed multiple liver nodules suggestive of hepatic metastasis. Findings from omputed tomography of the brain and upper gastrointestinal endoscopy were normal. Colonoscopic examination did not reveal any colonic lesion. Fine needle aspiration cytology of the enlarged inguinal lymph node was suggestive of malignant melanoma (MM). Histopathologic examination of the excision biopsy specimen of a skin nodule showed a tumor mass in the dermis composed of nests of oval to polygonal cells with vesicular nuclei and large prominent nucleoli (Figure 4). Extensive areas of necrosis were also seen. The tumor cells contained brownish pigment that stained positively with Masson Fontana stain. Pearl's stain was negative. Excision biopsy of the depigmented patch on the left shin showed mild hyperkeratosis, proliferation of capillary-sized blood vessels in the dermis, and thick-walled blood vessels in the subcutaneous tissue (Figure 5). No cellular atypia or any other evidence of malignancy was noted in this specimen. Biopsy from the rectal growth was suggestive of MM. Tumor cells were positive for S100 and human melanin black 45. Based on the clinical presentation, histopathology, and laboratory investigations, a diagnosis of metastatic MM (stage IV: T(x)N(3)M(1c)) with unknown primary site was made. Treatment was started with injection dacarbazine 250 mg/m2 intravenous infusion daily for 5 days intended to be given every 3 weeks for palliation. The patient died 2 week after the first treatment with chemotherapy.
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PMID:Metastatic melanoma from an unknown primary site presenting as skin-colored nodules and multiple visceral involvement. 2334 71


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