We histopathologically examined rat kidneys which were obtained 1 hour, 1 day, and 3 days after a single administration of cisplatin (CDDP). Pretreatment with KW-3902 (0.1 mg/kg) reduced an increase in TUNEL-positive tubular cells on day 1 and day 3. On day 1 and thereafter, in the CDDP-treated groups, ultrastructural examination revealed findings characteristic of apoptosis such as nuclear chromatin condensation of the proximal tubular epithelia. Moreover, we determined the effect of KW-3902 on the CDDP content of urine, blood, and kidney in rats. Pretreatment with KW-3902 (0.1 mg/kg) did not affect plasma CDDP concentration or cumulative urinary excretion of CDDP, until 40 min after a bolus injection of CDDP, but induced diuresis, resulting in decreased urinary concentration of CDDP and reduced accumulation of CDDP in the kidney. These results suggest that the protective effect of KW-3902 against CDDP-induced acute renal failure is at least partly attributable to reduced apoptosis of the proximal tubular epithelium, possibly resulting from the reduction of CDDP accumulation in the same place.

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In oder to evaluete the chronic toxicity of iron lactate, a food additive, rats consisting of ten male and ten female per group, were fed a powdered commercial diet containing 0%, 0.625%, 1.25%, 2.50% or 5.00% of iron lactate for 3 months. Main histopathologic changes were an accumulation of excess iron in the hepatocytes, renal tubular epithelial cells, macrophages in the reticuloendothelial system of liver, spleen, bone marrow, and lymph nodes. Hemosiderin-laden macrophages aggregated in the mucosal lamina propria of the stomach and the whole length of the intestinal tract, and formed small nodules without any degenerative changes in other mucosal tissue. The number of hemosiderin-laden macrophages also increased in the interstitial tissue of the testes, epididymis, and thyroid glands, but no degenerative changes were detected in cell components of these organs. A slight elevation of AST, ALT, creatinine, and blood urea nitrogen (BUN) levels in the higher dosage group suggested the toxic effect of iron overload on the function of liver and kidneys which accumulated iron deposits in their parenchymal cells. However, apparent histopathologic changes suggesting tissue damage were not clear even in the liver and kidneys, as well as in many organs infiltrated with hemosiderin-laden macrophages in the interstitium. From these results, of damage is not dependent on the amount of iron deposition.

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To examine whether febantel has a tumor promoting activity, a total of 50 male F344 rats, divided into five groups each consisting of 10 rats, were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN). Starting 1 week later, Groups 1, 2, and 3 were fed diet containing 2,500,500, and 0 ppm febantel, respectively, for 7 weeks. D-galactosamine (DGA) of 300 mg/kg was administered intraperitoneally at Weeks 1 and 6 of febantel treatment. The remaining two groups (Groups 4 and 5) were fed diet containing 2,000 or 0 ppm febantel without DGA treatment for 7 weeks. Animals in the DEN/DGA + 2,500 ppm group showed a significant depression of body weight gain, as compared to the DEN/DGA + 0 ppm group. Significant increases in the absolute and relative liver weights were observed in the DEN/DGA + 2,500 ppm and DEN +2,000 ppm groups in comparison with the corresponding controls. Similar increases in the relative liver weights were also seen in the DEN/DGA + 500 ppm group. Histologically, centrilobular hepatocellular hypertrophy was observed in the DEN/DGA + 2,500 ppm and DEN +2,000 ppm groups. Significant induction of CYP1A1/2, 2B1/2 and 4A1/3 was observed in the DEN/DGA + 2,500 ppm and DEN +2,000 ppm groups, as compared to the corresponding control groups. Similar induction of CYP1A2 and 2B1 was observed in the DEN/DGA + 500 ppm group. Significant increases in GST-P positive cells and/or mini-foci in the liver were observed in the DEN/DGA + 2,500 ppm group. These results suggest that febantel exerts liver tumor promotion potential. Since no increases in GST-P positive cells and/or foci in the liver were observed at the dose level of DEN/DGA + 500 ppm febantel, this dose is considered to be a no effect level for this promotion effect.

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Mini rats, a Wistar-derived transgenic rat strain harboring a rat growth hormone (GH) antisense gene, show lower plasma GH levels than Wistar rats. In our previous study, Mini rats showed a smaller femur size with lower mineral density and a reduction of the metaphyseal and diaphyseal bone mass at 8 and 22 weeks of age. In the present study, we examined the femur and tibia from Mini rats and Wistar rats at 10 to 60 weeks of age, and we performed cancellous and cortical bone histomorphometry on the tibia to examine the status of bone turnover. We found that the bone size, mineral content, and mineral density of the femur and tibia were significantly lower in Mini rats and tended to increase in both strains until 38 or 60 weeks of age. The longitudinal growth rate was significantly higher in Wistar rats until 26 weeks of age, and at 38 weeks of age that in Wistar rats is comparable to that in Mini rats. The periosteal bone formation rate tended to be higher in Wistar rats until 60 weeks of age. The longitudinal growth rate in both strains and the periosteal bone formation rate in Wistar rats tended to decrease with age. In contrast, bone turnover in the secondary spongiosa of the proximal tibial metaphysis showed no apparent difference between the two strains and seemed to remain unchanged until 60 weeks of age. Therefore, it is suggested that the reductions of bone mass in the metaphysis and diaphysis in Mini rats may be attributable to the lower longitudinal growth rate and periosteal bone formation rate, and that GH may influence bone modeling but not bone remodeling.

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Growth hormone (GH) plays an important role in longitudinal bone growth, and hypophysectomized rats have generally been used as a model for GH deficiency in humans. Recently, researchers have bred Mini rats, a Wistar-derived transgenic rat strain harboring a rat GH antisense gene and showing lower plasma GH levels than Wistar rats. In a previous study, Mini rats showed a smaller femur size with lower mineral density and a reduction of the metaphyseal and diaphyseal bone mass. In the present study, Wistar rats were hypophysectomized (HX) and treated with GH, and then their bones were examined and compared with vehicle-treated intact age-matched Wistar rats and Mini rats. GH-treated (HX+GH) rats exhibited an increase in the mineral density of the tibia and increases in the length and mineral content of the femur and tibia. These changes in the HX+GH rats were attributable to an increase in the longitudinal growth and periosteal bone formation of the femur and tibia. When Mini rats and HX rats were compared with Wistar rats, both animals showed similar reductions in the bone length, mineral content, and mineral density of the femur, but the Mini rats showed a greater longitudinal growth rate, cancellous bone mass, and mineralizing surface than the HX rats, as well as less remarkable changes in body weight, relative organ weights, and hematological and blood chemical parameters. Therefore, Mini rats are considered to be a useful model for clarifying features of GH deficiency and examining effects of various treatments on the bone without any specific surgery or drug-administration.

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As a preliminary study to elucidate whether Plantago ovata forsk (PO) exhibits inhibiting effects on mammary carcinogenesis under a condition of hypercholesterolemia, 50 female Sprague-Dawley rats were first given a single intragastric dose of 200 mg/kg body weight of 7, 12-dimethylbenz[a]anthracene (DMBA). Ten of 50 rats died of acute toxicity of DMBA within one week. From one week later, the survived animals were divided into 4 groups: 13 rats in group 1 and 7 in group 2 received high cholesterol diets (HC) with and without 5% PO supplementation for 26 weeks, respectively. Eleven rats in group 3 and 9 in group 4 received basal diet (BD) with and without 5% PO supplementation for the same period, respectively. One to three rats in groups 1 to 4 died of mammary tumors, lymphomas and/or adrenal impairment attributable to DMBA treatment during the treatment period. Group 1 showed a tendency to decrease in the number of palpable mammary masses as compared with group 2, whereas group 3 showed a tendency to higher values compared with group 4. At the termination of the study, the serum levels of total cholesterol in group 1 were significantly lower than those in group 2 and the number of mammary masses was significantly decreased. Histopathologically, this decrease was mainly due to the decreased incidences of mammary adenocarcinomas, while no significant difference in the multiplicity of mammary tumor was observed between BD+PO and BD alone groups. The results of the present study suggest a possibility that PO exerts inhibiting effects on mammary carcinogenesis by decreasing circulating cholesterol levels in a rat two-stage mammary carcinogenesis model.

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Wistar-Furth-Osaka (WF/Osp) rat strain has been considered to induce spontaneous gastro-colonic adenocarcinoma. ACI rats, fosterbred by WF/Osp had developed the same type of colon adenocarcinoma. The serum from colon cancer-carrying WF/Osp rats induced the same tumors in Wistar/Shionogi (Wistar/Shi) rats. The serum from colon cancer-carrying WF/Osp rats also induced the analogous tumors in ACI rats by intra-peritoneal injection at newborn period respectively. Negative staining on solid-phase immune electron microscopy study revealed numerous particles in the tissue culture medium of transplantable gastric carcinoma. To bring to light, the amino acid sequence of virus antigen protein, using affinity chromatography column, we succeeded to obtain pure antigen on PVDF membrane. Protein structure of the antigen was analyzed, and amino acid sequence of Valine-Proline-Asparatic acid-Lysine-Threonine-Valine-Lysine-Tryptophan-Asparagine (VPDKTVKWN) turned out to be the novel structure among protein sequence by FASTA E-mail Server on GenomeNet.

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A spontaneous brain tumor was found in a 46-week-old male AKR/J Sea mouse. The tumor occupied the forebrain, and invaded the nasal mucosa of nose along the nerve. The tumor cells showed a wide variety of sizes and shapes; round, polygonal, oval, and fusiform with eosinophilic cytoplasm. Bizarre giant cells with multiple nuclei, foci of necrosis and hemorrhage, and mitotic figures were common findings. According to these findings, the tumor was diagnosed as glioblastoma multiforme, a highly malignant astrocytic neoplasm. The tumor cells reacted negatively against the antibody for glial fibrillary acidic protein (GFAP), and had no glial filaments under ultrastructural examination. It is presumed that those immunocytochemical and ultrastructural findings show poor differentiation in this case.

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A spontaneous ovarian cystadenocarcinoma with papillary growth to the serosa in a 66-week-old F344 rat was investigated morphologically and compared with a rat abdominal mesothelioma. Macroscopically, a large white soft mass was found in the right ovarian area with disseminated small nodules to the serosa and cloudy bloody-ascites in the abdominal cavity. Metastases to the lungs and lymph nodes were noted. Histologically, major growth patterns of the ovarian mass were tubular, cystic and/or papillary. The tubular areas were characterized by atypical cuboidal and/or columnar epithelial cells, with various amounts of stroma dividing glands. Cystic areas consisted of single or multiple cysts lined by uniform epithelial cells with intra-cystic papillary growth, supported by abundant hyaline-like stroma. Continuing from the ovarian mass, tumor cells were spread on the mesentery and omentum. Superficially, papillary projections resembling those of a mesothelioma were apparent. In deep areas, tubular structures consisting of epithelial cells were surrounded by various amounts of connective tissues. In the mesothelioma, collagen fibers were diffusely distributed around clustered or individual tumor cells. Since the histologic features strongly suggested a derivation from ovarian surface epithelium, we diagnosed this case as an ovarian cystadenocarcinoma with papillary growth to the serosa. Immunohistochemical results did not provide any clear specific reactions to distinguish ovarian cystadenocarcinomas from mesotheliomas.

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