Effects of different types of diet and sodium saccharin on proliferation at the limiting ridge of the rat forestomach

Sodium saccharin, at high doses in the diet, has been reported to cause hyperplasia of the forestomach (squamous portion of stomach), at the limiting ridge in F344 rats, in addition to its potential to induce proliferative effects on the urinary bladder epithelium. We have characterized this hyperplasia of the squamous epithelium of the forestomach at the limiting ridge in F344 and Sprague-Dawley rats given various doses of sodium saccharin for 4 to 95 wk. With increasing doses of sodium saccharin, the limiting ridge of the forestomach showed dose-related morphological changes: basal-cell hyperplasia, early papillary hyperplasia with basal-cell hyperplasia and papillary hyperplasia. Calcium saccharin in Prolab diet caused hyperplasia of the forestomach at the limiting ridge, similar to that caused by sodium saccharin. The severity of hyperplasia was influenced by the type of diet and by the strain of rats. AIN-76A diet without added sodium saccharin caused basal-cell hyperplasia in F344 rats, whereas Prolab, Purina and NIH-07 diets without added sodium saccharin had little or no effect on the forestomach. The effect of AIN-76A diet alone persisted through 95 wk of feeding without any evidence of tumour formation. In Sprague-Dawley rats, which appeared more sensitive to effects on the forestomach than F344 rats, Prolab 3200 and Purina diets without sodium saccharin caused basal-cell hyperplasia in more than half of the treated rats. The forestomach hyperplasia associated with AIN-76A or saccharin administration appears to be mild, limited in extent to the limiting ridge, and not associated with carcinogenesis.     

A combined treatment with 8 MHz radiofrequency hyperthermia, HPC-adriamycin, immunotherapy, radiation, systemic chemotherapy and irradiation for invasive bladder carcinoma

Hyperthermia was induced for the treatment of invasive bladder carcinoma in order to study its usefulness. The subjects were 12 cases of invasive bladder cancer; including 5 cases of T2, 3 cases of T3, 2 cases of T4, and 2 cases of recurrence after total cystectomy. As previous treatment, 4 patients received radiotherapy and the other received TUR, systemic chemotherapy, and intravesical injection of anticancer drugs. For hyperthermia treatment, a Thermotron RF-8 was used for heating a deep seated tumor. Each case received hyperthermia 2 to 10 times. Combined therapy included injection of HPC-adriamycin into the urinary bladder in 5 cases, immunotherapy in 3 cases, M-VAC therapy in one case, radiotherapy in one case, radiotherapy and intra-arterial injection in one case, and Peplomycin and OK-432 local injection in one case. The treatment results showed a 75% effectiveness; with CR in 4 cases, PR in 5 cases, MR in 2 cases and PD in one case. Three patients died and 9 survived. Of four patients who had received radiotherapy as a previous treatment 3 cases obtained CR and one case MR. Therefore, it was considered that a favorable treatment effect with hyperthermia could be obtained after radiotherapy.     

Studies on the retention of the mucous-membrane-adhesive anticancer agent hydroxypropylcellulose doxorubicin.

Incorporation of hydroxypropylcellulose (HPC-)doxorubicin, which we developed as a mucous-membrane-adhesive drug preparation, was instilled into the urinary bladder in 10 clinical cases. Tumor of the urinary bladder was a single tumor in all 10 cases, and preclinical histology showed transitional cell carcinoma, grade 1 or 2, and a lower stage than T1. HPC-doxorubicin, 20 mg/20 ml, was administered in 5 cases, and the other 5 cases received the conventional aqueous doxorubicin, 20 mg/20 ml by way of a catheter and the urethra. Cold punch biopsy was performed after 3 days of instillation, and the incorporation of doxorubicin into both tumorous and normal tissue was measured by high-pressure liquid chromatography. After 3 days, it was found that in the HPC-doxorubicin-administered group, doxorubicin was detected in both tumorous and normal tissue, but it was not detected in either tissue after aqueous doxorubicin administration. In 5 cases of the HPC-doxorubicin group, doxorubicin levels in the tumorous and normal tissue were examined, and it was found that significantly more doxorubicin was detected in the tumorous tissues. Thus, it may be said that our HPC-doxorubicin remained longer within the urinary bladder than the conventional aqueous doxorubicin preparation. Instilled HPC-doxorubicin is more highly concentrated in the tumorous tissue than in the normal bladder tissue, and thus, HPC-compounded anticancer drugs may be therapeutically more useful.     

Preneoplastic and neoplastic growth of xenotransplanted lung-derived human cell lines using deepithelialized rat tracheas

The human lung tumor-derived cell lines A549, Calu-1, Calu-3, HuT292, and SW900 and the transformed human bronchial epithelial cell line TBE-1, that was transfected with the v-Harvey-ras oncogene, were inoculated into deepithelialized Fisher 344 rat tracheas (5 X 10(5) cells/trachea). After the ends of the tracheas were sealed, the tracheas were transplanted into s.c. tissues of nude mice. In a parallel experiment, 1 X 10(6) cells from each of these cell lines were injected s.c. Histological examination of the tracheal transplants 2, 4, 8, 12, and 16 weeks after cell inoculation proved to be of greater usefulness than either clinical or histological observation of the s.c. injection sites. A549, Calu-1, and TBE-1 produced intratracheal neoplastic nodules as early as 2 weeks after cell inoculation. Calu-3, HuT292, and SW900 grew relatively slowly in the tracheas, and simple or stratified epithelia with slight or moderate atypia (preneoplastic lesions) were seen at 2 weeks. After the 4th week, they produced tumor nodules in the tracheal transplants, whereas no tumor cells could be seen at the s.c. injection sites. The human derivation of the cells was confirmed by in situ hybridization using human-specific DNA probes. The intratracheal inoculation and xenotransplantation of human-derived cell lines offers a time-saving alternative to the s.c. inoculation assay for tumorigenicity and is at the same time a potentially valuable approach to studying preneoplastic and neoplastic progression with human cell subpopulations.     

Reperfused myocardial infarctions on T1- and susceptibility-enhanced MRI: Evidence for loss of compartmentalization of contrast media

The purpose of this study was to characterize the contrast caused by a susceptibility MRI contrast agents, on spin echo T₂-weighted imaging of reperfused myocardial infarction. Our interest in this model focused on the expected requirement that such agents be compartmentalized in the tissue to cause signal loss on spin echo images, a condition which may not be present in reperfused infarcted myocardium. Accordingly, nine rats were subjected to 2 h of left coronary artery occlusion followed by 3 ± 0.5 h of reperfusion prior to administration of contrast media. Three sets of MR images were acquired: (a) baseline axial images at the midventricle, both T₁-weighted (TR/TE = 300/20) and T₂-weighted (TR/TE = 1500/60); (b) T₁-weighted images after administering a T₁-enhancing agent, Gd-DTPA-BMA (0.2 mmol/kg), to document that contrast media is delivered to the reperfused infarction; and (c) T₂-weighted images after administering the susceptibility agent, Dy-DTPA-BMA (1.0 mmol/kg). Gadolinium-enhanced T₁ images depicted reperfused infarction as regions with greatly enhanced signal intensity compared with unin-farcted myocardium, indicating that contrast agent was delivered to the infarcted zone. Dysprosium-enhanced T₁ images depicted the injury as a region of persistent signal intensity relative to depletion of signal in normal myocardium, consistent with failure of the contrast agent to cause signal loss. Similar infarction sizes were observed for unenhanced T₂-weighted images (33 ± 5%), gadolinium-enhanced T₁ weighted images (36 ± 5%) and postmortem staining (30 ± 6%); strong correlations (r > 0.9) were noted in comparisons of these data. Dysprosium-enhanced images exhibited a smaller region of differential signal presumed to be infarction (20 ± 5%, P < 0.05) and weak correlations (r < 0.75) with the other measurements. We conclude that the smaller infarction depicted on dysprosium-enhanced images is a subregion of the true infarction in which myocardial necrosis is sufficiently advanced that the agent is homogeneously distributed throughout all tissue compartments, preventing T₂*-dependent phase loss on spin echo images.     

Treatment strategies for hepatic metastasis from colorectal cancer

Hepatic micrometastases of the parenchyma adjacent to a macroscopic lesion were detected in 17 of 31 resected liver metastases. Fifty-nine micrometastatic lesions were detected in total; 26 lesions were situated in the portal vein (PV), 22 in the central vein (CV), 5 in the bile duct (BD), and 6 in the sinusoid (SS). A histological study confirmed the direct invasion of the macrometastatic cancer cells into the adjacent PV, CV, BD, and SS. According to the tumor doubling time, the mean diameter of the macrometastases in 19 remnant livers was calculated to have been 0.57±0.87 cm at the time of the primary resection. The calculated diameter of 3 of these 19 macrometastases was found to be less than 0.01 cm, the minimum implantable size, indicating that the cancer recurrence in these specimens may have developed from macroscopic metastatic lesions as a satellite, and not from the primary tumor. In 13 patients who received doses of 5250 mg or more of 5 fluorouracil (FU) via the hepatic artery, the cumulative disease-free rate 2 years postoperatively was 100%; this value was 47.6% in 11 patients who received less than 5250 mg of 5 FU via the hepatic artery, and 0% in 39 patients who received no chemotherapy (P<0.005). These results suggest that anatomical hepatic resection for satellite lesions, combined with prophylactic hepatic arterial chemotherapy for micrometastases, decreases the recurrence rate of hepatic metastases in the remnant liver.     

Generation of fractal patterns for probing the visual memory.

The effective use of computer-generated pictures as a trial-unique probe for studying the visual memory is described. The shape of the pattern is determined by means of a fractal algorithm with pseudorandom parameters. This method enables us to easily obtain thousands of moderately complex and sufficiently diversified pictures in series from a given number which serves as the seed of a pseudorandom number generator. We can thereby create a new and unique set of pictures if a new seed is given, as well as retrieve exactly the same pictures in the same sequence as when the original seed is given. These properties eliminate the demand for the massive memory space in a computer otherwise needed to store the entire set of stimulus pictures.     

WS009 A and B, new endothelin receptor antagonists isolated from Streptomyces sp. no. 89009. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

WS009 A and B novel endothelin receptor antagonists, have been isolated from the fermentation broth of Streptomyces sp. No. 89009. These antagonists were purified from the culture filtrate followed by Diaion SP-207, DEAE Toyopearl column chromatography and HPLC. WS009 A and B showed selective activity in an endothelin receptor binding assay with IC50 of 5.8 x 10(-6) M and 6.7 x 10(-7) M, respectively. On the basis of spectroscopic and chemical evidence, the structures of WS009 A and B have been established as 1 and 3, and are highly hydroxylated benz[a]anthraquinone chromophores.     

Effect of vitamin E in gastric mucosal injury induced by ischaemia-reperfusion in nitric oxide-depleted rats

BACKGROUND: Neutrophil infiltration and lipid peroxide accumulation are involved in reperfusion-induced gastric mucosal injury in nitric oxide-depleted rats. AIM: To assess the effect of vitamin E on this injury. METHODS: After ischaemia-reperfusion, the total area of erosions, lipid peroxide contents in gastric mucosa, and gastric neutrophil accumulation were compared between nitric oxide-depleted rats with deficient, normal, and increased vitamin E intake over 8 weeks. Thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity were measured in gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. RESULTS: The total area of erosions was significantly increased in the vitamin E-deficient group compared with the sufficient-intake and vitamin-supplemented groups. Both thiobarbituric acid-reactive substances and myeloperoxidase activity also were significantly increased in the vitamin E-deficient group compared with others. The total area of erosions closely paralleled the increases in both thiobarbituric acid-reactive substances and myeloperoxidase activity. CONCLUSION: These results indicate that the inhibition of lipid peroxidation and interference with neutrophil infiltration by vitamin E may be responsible for its cytoprotective effect in ischaemia-reperfusion.