Search

Objective: Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose.Methods: [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups.Results: No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt.Conclusions: In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial. [ABSTRACT FROM AUTHOR]

We have recently shown that immunodeficient (SCID) mice, which lack functional T and B cells, are highly susceptible to low dose site specific induction of colon aberrant crypt foci (ACF), surrogates for colon tumors, by 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ). To test whether long-term exposure to a high dose in the diet might prove carcinogenic to the SCID mouse colon, in contrast to other mice strains tested to date, the compound was administered at 300 p.p.m. in the diet to female 6–7-week-old SCID mice for 32 weeks. IQ induced high numbers of ACF, hyperplastic polyps, dysplasia, and colon adenomas, as well as hepatocellular altered foci and liver adenomas. Induction of colon tumors did not correlate with the main sites where ACF developed, the proximal colon, however, being seen mainly in the mid and distal colon. Induction of colon tumors correlated significantly with the incidence of dysplasia, crypt height, the mitotic index, cell proliferation and numbers of 8-hydroxydeoxyguanosine (8-OHdG)-positive cells in the colon crypt, particularly in mid and distal colon. Administration of 20% ωω-6 polyunsaturated fatty acids (corn oil), ωω-3 polyunsaturated fatty acids (perilla oil), or monounsaturated fatty acids (olive oil) simultaneously with IQ in the diet resulted in: (i) inhibition of colon and liver tumor induction by corn and perilla oil, whereas olive oil showed no effects; (ii) no reduction in total numbers of ACF by corn oil or perilla oil but significant suppression in the olive oil treated group; (iii) inhibition of tumor development particularly by ωω-3 polyunsaturated fatty acids in perilla oil, correlating significantly with decreased cell proliferation in both colon and liver and a marked decrease in crypt heights and mitotic indices. Selective reduction in the numbers of 8-OHdG-positive nuclei, mainly in the middle and distal colon crypts, was also found to correlate with tumor inhibition. Thus, the results indicate carcinogenicity of IQ in the colon of the SCID mouse and preventive effects of polyunsaturated fatty acids. [ABSTRACT FROM PUBLISHER]

1 An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y[sub 1] receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats. 2 Oral administration of the Yl antagonist (30 and 100 mg kg[sup -1], once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels. 3 Despite the fact that food intake was gradually returned to near the control level. the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment. 4 These results suggest that the Y[sub 1] receptor, at least in part, participate in pathophysiological feeding and or fat accumulation observed in Zucker fatty rats, Yl antagonists might be useful for the treatment of obesity. [ABSTRACT FROM AUTHOR]

To elucidate whether common genetic events in human urinary bladder carcinogenesis also occur in rodent models, we investigated the presence of 53, H- and K- mutations in 18 urinary bladder carcinomas induced by various concentrations of -butyl--(4-hydroxybutyl)nitrosamine (BBN) in male NON/Shi mice. Histopathologically, all were invasive, 11 being squamous cell carcinomas (SCCs) and the remaining seven being transitional cell carcinomas (TCCs). Using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis followed by DNA sequencing, 53, H- and K- mutations were observed in 14 (78%; exons 5–7), two (11%; one each on exons 1 and 2) and one (5.6%; exon 1) animals respectively. The frequencies of mutations in 53 exons 5, 6 and 7 were 7 (39%), 4 (22%), and 9 (50%) respectively, and no mutation was found in exon 8. All mutations involved one base-pair substitution with or without amino acid changes and the types of base-pair substitution were random. No evident association was observed between mutation sites and the histological phenotypes. In conclusion, 53 mutations are frequent in BBN-induced mouse invasive urinary bladder tumors, at similar levels to those observed for human high-grade invasive carcinomas, and this plus their distribution suggests their possible participation in this model of urinary bladder carcinogenesis. [ABSTRACT FROM PUBLISHER]

Elevation of urinary pH and Na ion concentration induced by feeding high doses of sodium salts plays a crucial role in promotion of urinary bladder carcinogenesis in male rats initially treated with -butyl--(4-hydroxybuty)nitrosamine (BBN). In the present study, urinary bladder carcinogenesis in male F344 rats was promoted by feeding the mono- and di-sodium salts of succinic acid, and the activity was enhanced by varying urinary sodium ion concentration under conditions of equally high pH. In Experiment 1, the rats were given 0.05% BBN in their drinking water for 4 weeks and then fed basal diet containing 5% succinic acid, 5% sodium succinate (Na-Suc) or 5% di-sodium succinate (2Na-Suc) for 32 weeks. The development of carcinomas in the urinary bladder was enhanced by treatment with Na-Suc and with 2Na-Suc. 2Na-Suc induced larger urinary bladder tumors than the Na-Suc. In Experiment 2, 5% Na-Suc and/or 5% 2Na-Suc were fed to the rats for 8 weeks without prior BBN treatment. Induction of simple hyperplasia as observed by light microscopy, was greater in rats fed 2Na-Suc than Na-Suc. Increased 5-bromo-2' -deoxyuridine labeling index and alterations of the urothelial surface observed by scanning electron microscopy of the urinary bladder were similarly greater in rats fed 2Na-Suc compared to Na-Suc. In addition, there was a tendency toward increased spermidine/spermine Nacetyltransferase activity in the urinary bladder epithelium of rats fed 5% 2Na-Suc. The results of Experiment 2 corresponded to differences in promoting activity for the different chemicals in Experiment 1. Thus, tumor growth was associated with sodium ion concentration level under conditions of equal increase of urinary pH. [ABSTRACT FROM PUBLISHER]

Describes the intracytoplasmic inclusions in dermal infiltrating cells of hyperkeratosis lenticularis perstans. Description and symptoms of the disease; Findings on the biopsy specimens with the use electron microscopy; Observations of the higher magification of the inclusions;

Investigates the contribution of inducible nitric oxide synthase (iNOS) to postischemic heart dysfunction of stroke-prone spontaneously hypertensive rats. Blood pressure and heart weight; Basal activity and messenger ribonucleic acid levels of iNOS; Amelioration of postischemic heart dysfunction by 2-amino-5,6-dihydro-6-methyl-4H-1,2 thiazin.

To clarify hepatocarcinogenesis by the heterocyclic amine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), we investigated the global expression of genes in rat liver. Rats were continuously fed MeIQx 100 ppm in their diet, and were sacrificed at weeks 4 and 16 for early time points, and week 104 for tumor sampling. Global expression analysis using oligonucleotide microarrays (Affimetrix Gene Chip, Rat Genome 230 2.0 Array) was carried out to detect altered genes in MeIQx-treated liver at 4 and 16 weeks (n=5, each), MeIQx-induced hepatocellular adenomas (HCA; n=3), and hepatocellular carcinomas (HCC; n=3), compared with age-matched normal livers (n=5). To investigate functional networks and gene ontology, two clusters were analyzed by Ingenuity Pathway Analysis. Clustering analysis of global genes demonstrated gene profiles of HCA and HCC to greatly differ from those of age-matched normal liver. However, after treatment with MeIQx for 4 or 16 weeks, no major differences were apparent. Ingenuity Pathway Analysis suggested pathways related to the cell cycle and glutathione metabolism may be involved in MeIQx-induced hepatocarcinogenesis. Real-time PCR analysis confirmed elevation of cyclin B1, cell division cycle 2, glutathione peroxidase 2 and glutathione S-transferase A2 in tumors, but not in early stage livers. In conclusion, molecular signatures of MeIQx-induced tumors clearly vary from that of age-matched normal liver, but no such shift is evident at early stages of hepatocarcinogenesis.