Type I interferon induces CX3CL1 (fractalkine) and CCL5 (RANTES) production in human pulmonary vascular endothelial cells.

Type I interferon (IFN) medications cause various adverse reactions, including vascular diseases. Although an association between chemokines and vascular diseases has also been reported, the relationship between type I IFN and chemokines in vascular endothelial cells (VEC) remains unclear. To provide clues to pathogenesis of the diseases, we analysed the effects of type I IFN on chemokine production in human VEC. Type I IFN induced higher CX3CL1 (fractalkine) mRNA expression and protein secretion in pulmonary arterial VEC than in umbilical vein VEC. Type I IFN also induced CCL5 [regulated upon activation normal T cell expressed and secreted (RANTES)] production in VEC, especially in lung micro-VEC. IFN-ß induced much higher chemokine production than IFN-α, and Janus protein tyrosine kinase (JAK) inhibitor I prevented type I IFN-induced chemokine secretion. Type I IFN-induced chemokines may be involved in the pathophysiology of pulmonary vascular diseases, and the JAK inhibitor may serve as a therapeutic option for these diseases.

Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND: Synchronous occurrence of intraductal papillary mucinous neoplasm (IPMN) and ductal carcinoma of the pancreas has been reported. Branch duct IPMNs with lower likelihood of malignancy are not submitted to resection but are followed-up, so ductal carcinoma may develop during the follow-up. The development of ductal carcinoma of the pancreas during follow-up of branch duct IPMNs was investigated. METHODS: 60 patients with branch duct IPMN who had an intraductal tumour of <10 mm on imaging examinations and a negative result for malignancy on cytological examination of the pancreatic juice were investigated. They were followed-up mainly by ultrasonography (US), and additionally by endoscopic ultrasonography (EUS), CT, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) with cytological examination of the pancreatic juice for an average period of 87 months. RESULTS: Ductal carcinoma of the pancreas distinct from IPMN developed in 5 of 60 (8%) branch duct IPMNs during follow-up. The 5-year rate of development of ductal carcinoma was 6.9% (95% CI 0.4% to 13.4%), the incidence of ductal carcinoma was 1.1% (95% CI 0.1% to 2.2%) per year and the standardised incidence ratio of development of ductal carcinoma was 26 (95% CI 3 to 48). Patients >70 years old developed ductal carcinoma significantly more frequently than those under 69. Four of five ductal carcinomas identified during follow-up were resectable. Cancer developed in IPMN in 2 of 60 (3%) branch duct IPMNs during follow-up. CONCLUSIONS: During follow-up of branch duct IPMNs, ductal carcinoma of the pancreas not infrequently developed distinct from IPMN. In the follow-up of IPMN, special attention should be paid to the development of ductal carcinoma of the pancreas.

Pre-medication with pronase reduces artefacts during endoscopic ultrasonography.

BACKGROUND: Gastric mucus usually induces artefacts during endoscopic ultrasonography. AIM: To investigate the effectiveness of pre-medication with the proteolytic enzyme, pronase, before endoscopic ultrasonography. METHODS: Out-patients scheduled for endoscopic ultrasonography were randomly assigned to oral pre-medication with the anti-foam agent, dimethylpolysiloxane, alone (treatment A; n = 29), with dimethylpolysiloxane plus sodium bicarbonate (treatment B; n = 29) or with dimethylpolysiloxane, sodium bicarbonate and pronase (treatment C; n = 29). All drinks were given about 10 min before the start of the procedure. After insertion of the endoscope, endoscopists recorded visibility scores before the procedure, imaging scores at endoscopic ultrasonography and the numbers of high-echo spots in the gastric cavity and on the gastric wall surface after the procedure. RESULTS: Pre-medication with pronase (treatment C) significantly reduced (both at P < 0.05) the visibility score (score 4, 46%) in comparison with that obtained for pre-medication without pronase (10% for both treatments A and B). Treatment with pronase significantly reduced (both at P < 0.05) the endoscopic ultrasonography score in the gastric cavity (score 4, 34%) in comparison with that found for treatments A (7%) and B (0%). It also significantly reduced (P < 0.05) the endoscopic ultrasonography score on the gastric wall surface (score 4, 14%) in comparison with that observed for treatment A (3%). The numbers of high-echo spots in the gastric cavity and on the gastric wall surface were significantly less (both at P < 0.001) for pre-medication with pronase (treatment C) than for pre-medication with treatments A and B. There were no complications associated with the solutions. CONCLUSIONS: Pre-treatment with pronase reduced the artefacts during endoscopic ultrasonography.

Does pleural lavage cytology before thoracic closure predict both patient's prognosis and site of cancer recurrence after resection of esophageal cancer?

BACKGROUND: Operative manipulation occasionally exfoliates and spreads cancer cells in the surgical field, and it is a matter of concern whether the exfoliated cancer cells actually affect the patient's prognosis and sites of cancer recurrence. METHODS: In 240 patients with esophageal cancers, lavage cytology (LC) of the right pleural cavity was performed before and after esophageal resection combined with regional lymphadenectomy. The cytologic results were compared with the pathologic factors associated with cancer extension, postoperative survival, and cause of surgical failure. RESULTS: Only 3 patients (1.3%) were LC positive before resection. Of the 237 LC-negative patients, LC was also negative after resection in 215 patients (90.7%) (LC-/-), but LC became positive after resection in 22 patients (9.3%) (LC-/+). The 3-year survival rate was 0% in the LC-/+ group versus 65% in the LC-/- group, and the median survival rates were 10.9 months and 25.0 months, respectively (P <.0001). Multivariate analysis revealed that LC-/+ was an independent prognostic factor (P =.0331), along with nodal involvement and depth of cancer invasion. However, there were no significant differences in the sites of cancer recurrence between the 2 groups. Only 1 patient was found to develop the first recurrence in the pleural cavity. The LC-/+ group had a higher incidence of bulky lymph-node metastasis (P =.0009). CONCLUSIONS: Pleural LC after resection of esophageal cancer seems to be a prognostic indicator of overall recurrence, but not necessarily in the pleural cavity. Patients with a positive LC after resection may benefit most by effective systemic adjuvant chemotherapy.

Suppression by verapamil of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in wistar rats.

BACKGROUND: The effects of combined administration of bombesin and verapamil hydrochloride (verapamil), a calcium channel blocker, on the incidence of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane (AOM) and the labeling index of intestinal cancers were investigated in male Wistar rats. METHODS: From the beginning of the experiment, rats were given 10 weekly subcutaneous injections of AOM (7.4 mg/kg body weight) and subcutaneous injections of bombesin (40 microg/kg body weight) every other day, and from week 16, intraperitoneal injections of verapamil (10 or 20 mg/kg body weight) every other day until the end fo the experiment in week 45. RESULTS: Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum. Although verapamil administered at either dose had little or no effect on the enhancement of intestinal carcinogenesis by bombesin or on the location, histologic type, depth of involvement, labeling index, apoptotic index or tumor vascularity of intestinal cancers, it significantly decreased the incidence of cancer metastasis. Verapamil also significantly decreased the incidence of lymphatic invasion of adenocarcinomas, which was enhanced by bombesin. CONCLUSION: These findings indicate that verapamil inhibits cancer metastasis through actions that do not affect the growth of intestinal cancers.

ras p21 Isoprenylation inhibition induces flat colon tumors in Wistar rats.

PURPOSE: The effect of pravastatin, an inhibitor of ras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associated ras p21 in colon tumors. CONCLUSIONS: These findings suggest that the ras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.

Inhibition by rat C-erbB-2/neu antisense oligonucleotide of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of a rat C-erbB-2/neu (C-erbB-2) antisense oligonucleotide on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the labeling and apoptotic indices of gastric cancer was examined in Wistar rats After oral treatment with MNNG for 25 weeks, the rats received intraperitoneal injections of a C-erbB-2 antisense-liposome complex or a sense-liposome complex at a dose of 50 microgram oligonucleotide/kg body weight every other day until the end of the experiment in week 52. In week 52, the incidence of gastric cancers was significantly lover in rats treated with the C-erbB-2 antisense oligonucleotide than in rats treated with the sense oligonucleotide. Administration of the C-erbB-2 antisense oligonucleotide also significantly decreased the bromodeoxyuridine-labeling index and significantly increased the apoptotic index of gastric cancers. The mean cellular fluorescence of gastric antral cells in MNNG-treated rats was positively correlated with the dose of FITC-labeled C-erbB-2 antisense oligonucleotide. Our findings indicate that the antisense oligonucleotide inhibits gastric carcinogenesis through decreased cell proliferation and increased apoptosis induction and suggest that antisense strategies may provide new treatment for gastric cancer.

Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations.

OBJECTIVE: Telomerase activity is reported to be specific and very frequent in human malignancy. K-ras mutations are also very frequently detected in pancreatic cancer, but their specificity for pancreatic cancer is controversial. We examined the telomerase activity and K-ras mutations in pancreatic juice from patients with pancreatic disease. METHODS: Pancreatic juice was obtained endoscopically at endoscopic retrograde pancreatography from 10 patients with pancreatic cancer, three with chronic pancreatitis, and three with a normal pancreas. The telomerase activity in pancreatic juice was assayed by telomeric repeat amplification protocol. K-ras mutations in exon 1 codon 12 were examined by the two-step polymerase chain reaction combined with restriction enzyme digestion, followed by single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Telomerase activity of >5.0 was detected in eight of 10 (80%) subjects with pancreatic cancer, but in none with chronic pancreatitis or normal pancreas. K-ras mutations were detected not only in eight of 10 (80%) subjects with pancreatic cancer but also in two of three with chronic pancreatitis and in one of three with a normal pancreas. CONCLUSIONS: It was shown that the detection of telomerase activity in pancreatic juice is a more useful diagnostic tool for pancreatic cancer than that of K-ras mutations.

Low-protein diet promotes sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

Sodium chloride (NaCl) initiates and promotes experimental carcinogenesis in rats. We recently found that a high-protein diet attenuates NaCl-enhanced gastric carcinogenesis in Wistar rats. To investigate the effect of a purified low-protein diet on NaCl-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Wistar rats, rats were fed a purified diet with an equalized caloric content containing 1% or 2% NaCl and 25% casein (normal-protein diet) or 10% casein (low-protein diet) after oral treatment with MNNG for 25 weeks. In week 52, neither 1% nor 2% NaCl had a significant effect on gastric carcinogenesis in rats fed a normal-protein diet. However, oral administration of 2%, but not 1%, NaCl significantly increased the incidence of gastric cancers in rats fed a low-protein diet. Oral administration of 2% NaCl also significantly increased the bromodeoxyuridine (BrdU)-labeling index and the ornithine decarboxylase (ODC) activity and decreased apoptosis of gastric cancers in rats fed a low-protein diet. However, 2% NaCl had no significant effect on these three parameters in rats fed a normal-protein diet. These findings indicate that a low-protein diet enhances the effect of NaCl in gastric carcinogenesis and that this enhancement may be mediated by increased cell proliferation and reduced apoptosis of gastric cancers.

Minute carcinoma of the pancreas measuring 1 cm or less in diameter--collective review of Japanese case reports.

BACKGROUND/AIMS: According to Tsuchiya's collective review on small pancreatic cancer measuring 2 cm or less in diameter (5), more than half of them had obstructive jaundice and the 5-year survival rate was as low as 30%. Thus, a more aggressive diagnostic approach is needed to detect a smaller and more curable cancer of the pancreas. METHODOLOGY: Thus, we collected 36 reported cases of "minute" pancreatic cancer measuring 1 cm or less in diameter, from Japanese medical literature, to analyze the relationships between the diagnostic processes and long-term results. RESULTS: Excluding 3 patients with obstructive jaundice, the other 33 patients did not show any specific initial symptoms. However, 28 (78%) out of 36 patients showed an elevation in serum pancreatic enzyme levels and/or glucose intolerance. Among the 35 patients who had received ultrasonography (US) and/or computed tomography (CT), 20 (57%) patients showed duct dilation alone, whereas only 9 patients (26%) showed tumor mass. Among 35 patients who received an endoscopic retrograde pancreatography (ERP), all patients showed positive findings such as obstruction/stenosis, filling defect or duct dilation. All 36 patients underwent pancreatectomy and the 5-year survival rate was 57%. However, the 5-year survival rate was 34% in the 13 patients with jaundice and/or tumor mass depicted in US/CT, while it was 69% for the 22 patients without these two findings (p < 0.05). CONCLUSIONS: These data lead us to conclude that an elevation of serum pancreatic enzyme levels, glucose intolerance, and duct dilation alone depicted by US/CT should not be overlooked. ERP should be more widely applied to such patients, instead of persisting in delineating the tumor mass by US/CT or follow-up by tumor marker.

Diagnosis of pancreatic cancer by cytology and measurement of oncogene and tumor markers in pure pancreatic juice aspirated by endoscopy.

BACKGROUND/AIMS: Cytological examination of pancreatic juice is useful in the diagnosis of an occult cancer of the pancreas. The early diagnosis of pancreatic carcinoma using traditional radiographic or ultrasonographic methods is extremely difficult. METHODOLOGY: In order to detect an early pancreatic cancer, cytological examination, measurement of tumor marker, and detection of K-ras point mutation were performed using the samples of pure pancreatic juice aspirated endoscopically in patients who had symptoms or findings that suggested pancreatic disease. RESULTS: By routine ERP-cytology, positive cytologic results were obtained in 15 (4%) out of 359 patients without a mass. With the aid of intra-operative cytodiagnosis, all 15 occult neoplasms of the pancreas were successfully resected. One patient died from another disease without evidence of recurrence. However, the other patients were alive with no evidence of recurrence for an average of 5.5 years following surgery. The patients who had negative ERP-cytology results were observed, but no further cases of pancreatic cancer were found. The CEA levels in the pure pancreatic juice were significantly higher in patients with pancreatic cancer than in those with pancreatitis. K-ras point mutation at codon 12 was detected not only in cases of pancreatic cancer, but also in cases of chronic pancreatitis as well as control subjects. CONCLUSIONS: Cytological examination of pancreatic juice is useful in the diagnosis of an early and potentially curable in situ cancer of the pancreas. The CEA levels in the pure pancreatic juice provided useful information for differentiating the pancreatic cancer from chronic pancreatitis. K-ras point mutation at codon 12 in pancreatic juice was considered to be useful in identifying patients at high risk for the development of pancreatic cancer.

Increased blood proinsulin and decreased C-peptide levels in patients with pancreatic cancer.

BACKGROUND/AIMS: Abnormal glucose tolerance during oral glucose tolerance test (OGTT) is frequently observed in patients with pancreatic cancer. The abnormality shown in previous studies, however, was characterized mainly by analyses based on immunoreactive insulin or C-peptide response during OGTT, despite their cross-reactivity with proinsulin. The mechanisms responsible for glucose intolerance in patients with pancreatic cancer remain controversial. METHODOLOGY: Both proinsulin and C-peptide responses during 75 g of OGTT were determined without influence of immunologic cross-reactivity in 32 patients with pancreatic cancer and 32 control subjects of similar age, sex, fasting blood glucose levels, and OGTT pattern. RESULTS: The pancreatic cancer patients had higher proinsulin and lower C-peptide levels than the control subjects both in the non-diabetic and diabetic groups. The ratio of the sum of five proinsulin values observed at 0, 30, 60, 120, and 180 min to that of the five C-peptide values (sigma proinsulin/sigma C-peptide ratio) was 6.1 +/- 3.2% in patients with pancreatic cancer and 2.5 +/- 1.0% in control subjects (p < 0.05), while it was not associated with the diabetic pattern in OGTT. The sigma proinsulin/sigma C-peptide ratio was not associated with tumor size, location or resectability but was associated with the number of islets left within or close to cancer stroma. The increased sigma proinsulin/sigma C-peptide ratio decreased after tumor removal. CONCLUSIONS: Patients with pancreatic cancer are characterized by increased proinsulin secretion and decreased C-peptide production during OGTT probably due to impaired proinsulin conversion. Although further studies are required in a large scale of patients, measurement of proinsulin and C-peptide levels during OGTT should serve as an early marker to identify high risk groups of the disease.

Attenuation by all-trans-retinoic acid of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of all-trans-retinoic acid (RA) on sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labelling and apoptotic indices and immunoreactivity of transforming growth factor (TGF) alpha in the gastric cancers was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats were given chow pellets containing 10% sodium chloride and subcutaneous injections of RA at doses of 0.75 or 1.5 mg kg(-1) body weight every other day. In week 52, oral supplementation with sodium chloride significantly increased the incidence of gastric cancers compared with the untreated controls. Long-term administration of RA at both doses significantly reduced the incidence of gastric cancers, which was enhanced by oral administration of sodium chloride. RA at both doses significantly decreased the labelling index and TGF-alpha immunoreactivity of gastric cancers, which were enhanced by administration of sodium chloride, and significantly increased the apoptotic index of cancers, which was lowered by administration of sodium chloride. These findings suggest that RA attenuates gastric carcinogenesis, enhanced by sodium chloride, by increasing apoptosis, decreasing DNA synthesis, and reducing TGF-alpha expression in gastric cancers.

Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effects of prolonged administration of genistein, a tyrosine-kinase inhibitor, on sodium-chloride-enhanced induction of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labeling and apoptotic indices and vessel counts in the gastric mucosa and gastric cancers, were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were fed chow pellets containing 10% sodium chloride and were given s.c. injections of genistein at dosages of 15 mg/kg or 30 mg/kg body weight every other day. In week 52, the incidence of gastric cancers was significantly greater in rats fed sodium chloride than in untreated control rats. Prolonged administration of genistein at a dosage of 30 mg/kg, but not 15 mg/kg, body weight significantly reduced the incidence of gastric cancers, which was increased by oral treatment with sodium chloride. Genistein at the higher dose significantly decreased the labeling index and vessel counts of the antral mucosa and the gastric cancers (which were increased by treatment with sodium chloride) and significantly increased the apoptotic index of the antral mucosa and the cancers (which was lowered by the treatment with sodium chloride). These findings suggest that genistein attenuates gastric carcinogenesis promoted by sodium chloride, by inducing increased apoptosis and lower cell proliferation and angiogenesis of antral mucosa and gastric cancers.

Inhibition by transforming growth factor (34-43)-alpha, a TGF-alpha antagonist, of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of transforming growth factor (34-43)-alpha, an antagonist of TGF-alpha, on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the labelling and apoptotic indices and TGF-alpha immunoreactivity of gastric mucosa and gastric cancers was examined in Wistar rats. The rats received intraperitoneal injections of 10 or 20 microg kg(-1) body weight of TGF(34-43)-alpha every other day after oral treatment with MNNG for 25 weeks. Long-term administration of TGF(34-43)-alpha at both doses significantly reduced the incidence of gastric cancers at the end of the experiment in week 52. However, TGF(34-43)-alpha had no significant effect on the number, histological type or depth of involvement of gastric cancers. Administration of TGF(34-43)-alpha also significantly decreased the bromodeoxyuridine labelling index and TGF-alpha immunoreactivity, and significantly increased the apoptotic index of antral mucosa and gastric cancers. These findings indicate that TGF(34-43)-alpha inhibits gastric carcinogenesis, and that its effects are mediated through decreased cell proliferation and TGF-alpha immunoreactivity and increased apoptosis induction in the gastric cancers.

Inhibition of experimental gastric carcinogenesis, induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats, by sodium nitroprusside, a nitric oxide generator.

The effects of prolonged administration of sodium nitroprusside (SNP), a generator of nitric oxide (NO), on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and the labelling index of the gastric mucosa were investigated in male Wistar rats. The rats received intra-peritoneal injections of 2 or 4 mg/kg body weight of SNP every other day after 25 weeks' oral treatment with the carcinogen. Prolonged administration of SNP at 4 mg/kg body weight, but not at 2 mg/kg body weight, significantly decreased the incidence of gastric cancers in experimental week 52. However, it did not affect the histological types or depths of involvement of gastric cancers. SNP at 4 mg/kg body weight, but not at 2 mg/kg body weight, also significantly decreased the bromodeoxyuridine labelling index of the antral epithelial cells. These findings indicate that SNP inhibits gastric carcinogenesis and suggest that this effect may be related to the suppression of proliferation of the antral epithelial cells.

[A measure to continue intra-arterial infusion chemotherapy long-term for locally advanced pancreatic cancer].

For locally advanced non-resectable cancer of the pancreas, we have routinely performed intra-arterial chemotherapy: Each catheter is placed in the splenic artery and gastroduodenal artery during laparotomy, and a mixture of Methotrexate and Angiotensin-II is infused within 30 minutes. This treatment is repeated weekly at our outpatient clinic as long as possible. However, obstruction of the catheter or corresponding artery is the major cause of interruption of treatment. The present paper reports a case in which intra-arterial chemotherapy was possible by repeated catheterization for the catheter obstruction. A 54-year-old woman with non-resectable pancreatic cancer underwent catheter placement during laparotomy, but they became occluded one month later. Another catheter was placed into the common hepatic artery by the Seldinger method. After this catheter was occluded again, another catheter was placed into the inferior pancreaticoduodenal artery via the superior mesenteric artery by the Seldinger method. By repeating this catheter placement, we succeeded in continuing the intra-arterial chemotherapy, and the patient has remained alive (30 postoperative months) without losing her quality of life.

Alpha1-adrenoceptor stimulation enhances experimental gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of the norepinephrine-mimicking agent metaraminol, the alpha1-adrenergic agonist phenylephrine and the alpha2-adrenergic agonist clonidine on the incidence of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the ornithine decarboxylase activity of the gastric cancer and the labeling index of the gastric mucosa were investigated in Wistar rats. Rats received s.c. injections of metaraminol, phenylephrine or clonidine every other day after 20 weeks of oral treatment with MNNG. At week 52, administration of metaraminol and phenylephrine at the higher dose significantly increased the incidence of gastric cancers, the ornithine decarboxylase activity of the gastric cancers and the labeling index of the antral epithelial cells. Administration of phenylephrine at the lower dose and clonidine at both doses had no significant effect on the incidence of gastric cancers, the ornithine decarboxylase activity of the gastric cancers or the labeling index of the gastric mucosa. Our results suggest that adrenoreceptor stimulation enhances gastric carcinogenesis and that such enhancement is mediated through alpha1-adrenoceptors without alpha2-adrenoceptor involvement.

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.