Attenuation by ambroxol of monochloramine-enhanced gastric carcinogenesis: a possible prevention against Helicobacter pylori-associated gastric carcinogenesis.

The effects of combined administration of a reactive oxidant, monochloramine, and a mucoregulatory agent, ambroxol, on the development of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in inbred Wistar rats. After receiving oral MNNG and regular chow pellets for 25 weeks, rats received regular chow pellets or chow pellets containing 20% ammonium acetate, and normal tap water or water containing 30 mM sodium hypochlorite, with or without subcutaneous injection of ambroxol at high or low doses, until the end of the experiment at week 52. Treatment with both ammonium acetate and sodium hypochlorite, which produce monochloramine, significantly increased the incidence of gastric cancers at week 52, whereas concomitant administration of ambroxol with ammonium acetate and sodium hypochlorite significantly attenuated this enhanced gastric carcinogenesis. Results also revealed that ambroxol scavenged monochloramine. Because monochloramine is closely related to Helicobacter pylori-associated gastric carcinogenesis, these findings suggest that ambroxol may prevent H. pylori-associated gastric carcinogenesis.

[A clinical study of bladder cancer in adolescent patients].

PURPOSE: We have reviewed clinical characteristics of bladder cancer in adolescent patients. MATERIALS AND METHODS: Between 1978 and 1997, we have experienced eight bladder cancer patients of 7 men and 1 woman under 30 years old. Two patients were less than 20 years old and six patient were more than 20 years old. We have reviewed initial symptoms, diagnostic methods, cystoscopic findings, methods of treatment, pathological findings, and prognosis of these patients. RESULTS: The most common chief complaint was asymptomatic macroscopic hematuria. Cystoscopically, all tumors were papillary and solitary except in one case. All of tumors were superficial transitional cell carcinomas and treated with transurethral resection (TUR). Although the tumors in patients of less than 20 years old were pathologically grade 1 and 2, two cases of grade 3 tumors were found in patients more than 20 years old. The prognosis of these patients were good, for none of them was dead and the recurrence rate after TUR was 12.5% (1/8). CONCLUSIONS: We considered that characteristics of bladder cancer in adolescent patients were low stage, low grade, and good prognosis. But it was found that high grade tumors were contained in patients more than 20 years old.

Slow rate of free radical scavenging in the gastric antral mucosa of male Wistar rats: a possible mechanism of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine.

We previously suggested that hydroxyl free radical (-OH) production may play a role in carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MNNG-induced gastric cancer in rats and human gastric carcinoma occur most often in the antral mucosa and rarely in the normal fundic mucosa. We hypothesized that regional differences in anti-oxidant activity may be responsible. In the present study, we examined anti-oxidant activity by comparing the relative rates of reduction of a nitroxide free radical, 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol), in the antral and fundic mucosa of male Wistar rats using ESR. The relative rate of Tempol reduction was significantly slower in the antral portion of the wall than in the fundic portion when Tempol [4 x 10(-6) mole/mg wet weight of gastric wall] in HEPES buffer (pH 7.4) was spread over the mucosal surface of a section of the gastric wall. Addition of a sulfhydryl group modulator, N-ethylmaleimide, to the mucosal surface before treatment with Tempol removed the significant difference observed in the rates of reduction in the antral and fundic portions of the gastric wall. No signals were detected in the muscle layer. Our results indicate that the relative rate of free radical reduction by sulfhydryl groups was significantly slower in the antral mucosa than in the fundic mucosa. We therefore conclude that a regional difference in the rates of reduction of free radicals by sulfhydryl groups may result in the site susceptible to development of MNNG-induced gastric cancer.

Attenuation by methionine of monochloramine-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

Helicobacter pylori appears to play a major role in the development of gastric cancer in humans. The mechanism behind the carcinogenic or co-carcinogenic effects of H. pylori has not been established. Ammonia, generated by urea from H. pylori, has been studied as a possible cause. However, the ammonia-monochloramine system has been shown to play a more important role in H. pylori-associated mucosal injury. Therefore, the effects of combined administration of monochloramine and methionine, singly or together, on the development of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in inbred Wistar rats. After receiving oral MNNG and regular chow pellet for 25 weeks, rats received regular chow pellets or chow pellets containing 20% ammonium acetate, and normal tap water or water containing 30 mM sodium hypochlorite, with or without a subcutaneous injection of methionine, until the end of the experiment (week 52). Treatment with both ammonium acetate and sodium hypochlorite, which produce monochloramine, significantly increased the incidence of gastric cancers in week 52, whereas the concomitant administration of methionine with ammonium acetate and sodium hypochlorite significantly attenuated such enhanced gastric carcinogenesis. Spectrophotometric examination revealed that methionine scavenged monochloramine. Our findings suggest that H. pylori-associated gastric carcinogenesis may be mediated by monochloramine.

Enhancement by monochloramine of the development of gastric cancers in rats: a possible mechanism of Helicobacter pylori-associated gastric carcinogenesis.

The effects of cytotoxic monochloramine on the development of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in Wistar rats. After oral administration of drinking water containing the carcinogen and regular chow pellets for 25 weeks, rats received regular chow pellets or chow pellets containing 20% ammonium acetate, and normal tap water or water containing 30 mM sodium hypochlorite, with or without s.c. injection of taurine, until the end of the experiment in week 52. Treatment with both ammonium acetate and sodium hypochlorite significantly increased the incidence of gastric cancers in week 52, while the concomitant use of taurine with ammonium acetate and sodium hypochlorite significantly attenuated the enhanced gastric carcinogenesis. Spectrophotometric examinations revealed that taurine scavenged monochloramine. These findings suggest that Helicobacter pylori-associated gastric carcinogenesis may be mediated by monochloramine.

[Clinical evaluation of the long-term treatment with chlormadinone acetate in patients with benign prostatic hypertrophy].

Fifty patients with benign prostatic hypertrophy were treated with chlormadinone acetate (CMA) at the dose of 50 mg/day for 12 months. Subjective symptoms and objective findings were evaluated before, and after 4 and 12 months of treatment. Better improvement was observed in all of the subjective symptoms and in almost all the parameters of objective findings, in proportion to the period of CMA treatment. Generally speaking, 12 months of treatment was more effective than 4 months of treatment. Two patients had impotence (4.0%). Both of them complained of side effects within 4 months after treatment, but they were not severe. In conclusion, long-term treatment of benign prostatic hypertrophy with CMA was useful.

Production of the thiyl free radical by the reaction of N-methyl-N'-nitro-N-nitrosoguanidine with L-cysteine.

The thiyl free radical is formed in the L-cysteine/N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) system (pH 7.8) without exposure to light as detected by the ESR spin trapping technique. The formation of N-methyl-N'-nitroguanidine in the system is identified by thin-layer chromatography. The hypothesis that the thiyl radical is formed by the attack of the nucleophilic reagent L-cysteine on the nitroso group of MNNG is verified by these results.

Effects of propranolol and cimetidine on cysteamine inhibition of gastric carcinogenesis induced in Wistar rats by N-methyl-N'-nitro-N-nitrosoguanidine.

The effects of propranolol and cimetidine on inhibition by cysteamine (2-aminoethanethiol hydrochloride) of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on gastric acid secretion, serum gastrin level, and labelling index of the gastric mucosa were investigated in inbred Wistar rats. Rats received alternate-day injections of cysteamine (25 mg/kg body weight) with or without propranolol (dl-propranolol hydrochloride) (2 mg/kg bw) or cimetidine (50 mg/kg bw) in depot form after 25 weeks of oral treatment with MNNG. Prolonged administration of cysteamine significantly reduced the incidence of adenocarcinoma of the glandular stomach. A combination of cysteamine and propranolol significantly accelerated the inhibitory effect of cysteamine on gastric carcinogenesis. However, with concomitant administration of cysteamine and cimetidine, the incidence of adenocarcinoma was slightly but not significantly increased as compared to that after treatment with cysteamine alone. Administration of cysteamine caused a significant increase in gastric acid secretion and serum gastrin level, and a significant decrease in the labelling index of the antral mucosa. A combination of cysteamine and propranolol significantly increased gastric acid secretion by cysteamine alone and significantly decreased the labelling index of the antral mucosa. With this treatment, the serum gastrin level was significantly higher than the basal level, but the stimulated serum gastrin level was significantly lower than observed that after administration of cysteamine alone. In contrast, concomitant administration of cysteamine and cimetidine caused a significant decrease in gastric acid secretion and significant increase in the serum gastrin level as compared to the levels seen after treatment with cysteamine alone, but had no influence on the labelling index of the antral mucosa. These findings indicate that hypersecretion of acid, but not hypergastrinemia associated with hyposecretion of acid or achlorhydria, exerts a protective effect against gastric carcinogenesis, and that this effect may be related to its activity in decreasing proliferation of the antral mucosa.

Inhibitory effect of prolonged administration of cysteamine on experimental carcinogenesis in rat stomach induced by N-methyl-N'-nitro-N-nitrosoguanidine.

The effect of cysteamine (2-aminoethanethiol hydrochloride) on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in inbred Wistar rats. Prolonged administration of 25 or 50 mg per kg body weight of cysteamine after treatment with MNNG for 25 weeks significantly reduced the incidence and number of adenocarcinomas of the glandular stomach. Histological examination showed that the adenocarcinomas that did develop in rats treated with these 2 doses of cysteamine had high mucin-producing activity. Furthermore, treatment with cysteamine caused significant increases in serum gastrin level and gastric acid secretion, together with significant decreases in the antral mucosal pH and the labelling indices of pyloric and oxyntic gland mucosae and gastric cancer. These findings indicate that cysteamine inhibits the development of gastric adenocarcinomas and that its effect may be related to decreasing proliferation of cells in the gastric mucosae.

Scavenging effect of butylated hydroxytoluene on the production of free radicals by the reaction of hydrogen peroxide with N-methyl-N'-nitro-N-nitrosoguanidine.

The scavenging effects of the antioxidant butylated hydroxytoluene (BHT) on a hydroxyl free radical (.OH) produced in the reaction of H2O2 with N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] and on free radicals derived from MNNG (.MNNG) were examined by electron spin resonance with the use of the spin-trapping agent 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). BHT was added to the H2O2-MNNG-DMPO system in 50% acetonitrile and exposed to a tungsten-halogen lamp at an intensity of 0.3 mW/cm2 for 3 minutes at 3 degrees C for the first 2 minutes of irradiation. The amounts of .OH and .MNNG in the system decreased and reached constant levels with increase in BHT concentration. The spectrum of the H2O2-MNNG-BHT system showed the specific signal of BHT, whereas the spectra of the BHT solution and the H2O2-MNNG system did not show any signal. These findings indicate that BHT scavenged .OH and .MNNG, and in its reaction with them formed a stable free radical.

[A fundamental and clinical study of ferritin 'Eiken' radioimmunoassay kit].

We have measured serum ferritin level using double antibody radioimmunoassay kit (Eiken ICL) and evaluated the characteristics of the kit and clinical usefulness. Satisfactory results were observed in standard curve, reproducibility, dilution and recovery test. In clinical evaluation, we have measured in normal subjects and patients with various diseases. The range in normal males and females were 13.0-158.7 ng/ml and 7.3-73.0 ng/ml, respectively. Serum ferritin level was elevated in patients with hepatoma, biliary cancer, lung cancer and other malignant diseases. Measurement of serum ferritin value would be useful in the monitoring of cancer patients.

Production of hydroxyl-free radical by reaction of hydrogen peroxide with N-methyl-N'-nitro-N-nitrosoguanidine.

Production of a hydroxyl free radical (.OH) by reaction of hydrogen peroxide (H2O2) with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was examined by electron spin resonance using the X OH spin trapping agent 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). The electron spin resonance spectra of the H2O2-MNNG-DMPO system after exposure to light at an intensity of 0.03 mW/cm2 for 5 min, and the DMPO- (.OH) spin adduct (2-hydroxy-5,5-dimethyl-1-pyrroline-1-oxide) generated by use of Fenton's reagent showed the same hyperfine structure and g-value. The signal of the DMPO adduct obtained in the H2O2-MNNG-DMPO system disappeared on addition of the .OH scavenger sodium benzoate. The addition of another .OH scavenger, ethanol, resulted in the appearance of a new signal due to trapping of the alpha-hydroxyethyl radical. These results show that .OH was formed in the H2O2-MNNG-DMPO system. The typical signal of the DMPO-(.OH) spin adduct was not observed in the system in the absence of light. The amount of DMPO-(.OH) spin adduct increased with increase in the concentration of H2O2 when the MNNG level was kept constant, and it changed with the concentration of MNNG at a constant H2O2 level, indicating that .OH was produced by the interaction of MNNG with H2O2. In the absence of H2O2, complicated trapped signals appeared in the spectrum of the MNNG-DMPO system in the light, but these signals were not observed when the system was kept in the dark. In the absence of MNNG, the H2O2-DMPO system did not show any signal, even in the light. These results indicate that interaction of free radicals derived from MNNG with H2O2 on exposure to light resulted in .OH production.

[Clinical statistics on inpatients and operations in the Urological Department of the Wakayama Red Cross Hospital (April, 1979 to March, 1983)].

Statistical observations made on the 1,102 inpatients and 1,127 operations at our clinic between April 1979 and March 1983 were reviewed. The patients were most frequently in their sixties, and lately patients under 10 are increasing. The most frequent diseases of the inpatients were benign prostatic hypertrophies, ureteral calculi, undescended testicles and bladder tumors. The frequently performed operations were those for bladder tumors, phimosis and benign prostatic hypertrophies in order of frequency.

[Gynecological urologic disease: a summary of clinical experience during the last 4 years at Wakayama Red Cross Hospital].

From April 1979 to March 1983, sixty seven patients with gynecological urologic disease were experienced at our department. Forty one of them were inpatients, i.e., 15.3% of the total number of female in patients admitted during the same period. Thirty three urologic operations were performed on them which corresponded to 16.1% of the total operations on female patients. Ten of these patients had ureteral obstruction following gynecological operation, 8 had ureteral fistula, 7 had vesicovaginal fistula, 11 had tumor invasion to urinary tract, 14 had radiation cystitis, 16 had neurogenic bladder dysfunction, and 1 had other complication. The treatment of these patients and the results are summarized and discussed.

Protective effect of butylated hydroxytoluene against induction of gastric cancer by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effects of butylated hydroxytoluene (BHT) on the incidence and histology of gastric cancers induced by oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats. Oral administration of 1.0% BHT in regular chow pellets during treatment with MNNG for 25 weeks significantly reduced the incidence of gastric cancers in experimental week 40. BHT had no influence on the histological type of adenocarcinomas induced in MNNG-treated rats. BHT alone induced slight glandular hyperplasia, but not moderate glandular hyperplasia or gastric cancer.