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The roles of cyclooxygenase-2 (COX-2) in the development of gastric cancer are unknown. We investigated the effects of nonsteroidal antiinflammatory drugs (NSAIDs). which are specific and nonspecific inhibitors of COX-2, on proliferation of the gastric cancer cell lines KATOIII, MKN28, and MKN45. The protein level of COX-2 was examined in these cell lines by Western analysis, and mRNA levels of COX-1/2 by Northern analysis. These cell lines expressed comparable levels of COX-I mRNA. However, mRNA and protein expression of COX-2 in these cell lines was different. MKN45 expressed higher levels of COX-2 mRNA and protein than KATOIII and MKN28. We also examined the effects of NS-398 and indomethacin. specific and nonspecific inhibitors of COX-2. on the increase in cell number and [ 3 H]thymidine uptake of these cell lines. NS-398 and indomethacin suppressed proliferation of MKN45 cells that overexpressed COX-2, although they exerted minimal effects on proliferation of KATOIII and MKN28, which expressed lower levels of COX-2. These results are consistent with the hypothesis that COX-2 is expressed in certain groups of gastric cancers and is related to their cell proliferation. It was proposed that COX-2 plays an important role in development of gastric cancer cells. Furthermore, NSAIDs may exert antiproliferative activity against gastric adenocarcinomas that overexpress COX-2.

We examined the effects of lansoprazole and famotidine on gastric basic fibroblast growth factor (bFGF) levels and ulcer healing in patients with gastric ulcer. Sixteen patients with active gastric ulcer were divided into two groups and received treatment with lansoprazole 30 mg/day or famotidine 40 mg/day. They were examined endoscopically at 2, 4, and 8 weeks to measure gastric bFGF levels at the ulcer margin and to assess ulcer healing. Helicobacter pylori infection was determined by a rapid urease test. The two groups were comparable with regard to age, male :female ratio, H. pylori infection rates, and bFGF levels. During treatment, bFGF levels did not change significantly in the famotidine group, whereas they increased by a factor of 2.2 to 2.6 in the lansoprazole group. Cumulative healing rates were also significantly lower in the famotidine group than in the lansoprazole group. These results indicate that lansoprazole increases tissue bFGF levels and promotes gastric ulcer healing in humans.

This article consists of three independent studies regarding Helicobacter pylori-related gastric carcinogenesis. Ammonia, a Helicobacter product, promoted chemically induced gastric carcinogenesis in animals. Moreover. an extract of Helicobacter stimulated inflammatory production of nitric oxide (NO), a potent mutagen that causes G:C → A:T transition. Meta-analysis of recent studies demonstrated that G:C → A:T transition is one of the most common mutations in the p53 tumor suppressor gene in early phases of human gastric carcinogenesis. Therefore, bacterial factors such as ammonia and host factors, including inflammatory NO production, might play important roles in H. pylori-induced gastric carcinogenesis.

This study examined the mRNA level of cyclooxygenase-2 (cox-2) in a rat gastric mucosal cell line after growth stimulation in vitro and in rat gastric mucosa before and after acid-induced injury in vivo. RGMI cells were stimulated with fetal calf serum in the in vitro study. Thereafter, the cox-2 mRNA level was examined by Northern analysis. Effects of NS-398, a specific inhibitor of cox-2, and indomethacin on prostaglandin production and cell proliferation were examined in RGM1 cells. In the in vivo study, rats were given 1 ml of 0.6 N hydrochloric acid into the stomach. The level of cox-2 mRNA was examined in rat gastric mucosa after acid administration. Cox-2 mRNA increased 20-60 min after growth stimulation in RGMI1 cells. Both NS-398 and indomethacin suppressed prostaglandin production and cell proliferation after growth stimulation. Expression of cox-2 mRNA was observed 40 and 60 min after administration of 0.6 N HCl. Gastric lesions developed within 60 min after HCI administration and healed significantly within 48 h. The present study shows the expression of cox-2 in gastric epithelial cells in vitro and in gastric mucosa after injury in vivo. The results also suggest that cox-2 is involved in de novo synthesis of prostaglandins and cell proliferation in gastric epithelium.

The protective effect of prostaglandin D2 (PGD2) in ethanol-, HCl-, or NaCl-induced gastric mucosal injury was investigated. To clarify the mechanism, the gastric mucosal hemodynamics were also investigated using reflectance spectrophotometry and laser Doppler flowmetry in anesthetized rats. PGD2 administered orally significantly reduced the ethanol-induced mucosal injury. Although it did not reach any significance, PGD2 also reduced 0.6 N HCl-induced mucosal damage, and slightly reduced 25% NaCl-induced mucosal damage. Topical application of PGD2 did not affect gastric mucosal hemodynamics at steady state before the administration of necrotizing agent. However, PGD2 significantly improved the gastric mucosal microcirculatory congestion caused by ethanol, and partly improved 0.6 N HCl-induced ischemia. However, it did not improve the 25% NaCl-induced mucosal congestion. The results indicated that PGD2 had a protective effect in the ethanol-induced gastric mucosal injury through the improvement of gastric mucosal microcirculation. However, further investigations are needed to clarify the precise effect of PGD2 in 0.6 N HCl- or 25% NaCl-induced mucosal damage.

To clarify the roles of endogenous leukotrienes and prostaglandins in the ethanol-induced gastric mucosal injury, the effect of AA-861 (a selective 5-lipoxygenase inhibitor) and indomethacin (a cyclooxygenase inhibitor) on the ethanol-induced gastric mucosal lesions was investigated in fasted rats. Furthermore, the effect of these agents on the gastric mucosal microcirculatory disturbance induced by ethanol was also investigated using laser Doppler velocimetry and reflectance spectrophotometry. Forty percent ethanol caused mucosal microcirculatory stasis and mucosal hypoxemia, followed by mucosal injury. The pretreatment with AA-861 reduced the mucosal injury and significantly reduced the mucosal congestion and hypoxia induced by 40% ethanol. The pretreatment with indomethacin did not reduce the gastric mucosal damage or influence the mucosal blood flow stasis and the mucosal hypoxemia induced by ethanol. These results suggested that the increase of endogenous leukotrienes after intragastric administration of ethanol is responsible for the mucosal microcirculatory disturbance and mucosal tissue hypoxemia resulting in the mucosal injury, and that the decrease of prostaglandins alone may not play an important role in ethanol-induced mucosal injury.

The gastric microcirculation was investigated with the in vivo microscopic analyzing system and reflectance spectrophotometry. The topical administration of either ethanol (greater than or equal to 20%), indomethacin (0.1 mg/kg), leukotriene C4 (0.1 microgram), and platelet activating factor (PAF) (125 micrograms) decreased mucosal blood flow and mucosal blood oxygenation. The subsequent reperfusion of blood and/or addition of hydrocholoride (0.2 N) induced the gastric bleeding and ulceration. Pretreatment with calcium channel blockers (verapamil, flunaridine, and diltiazem) significantly reduced the gastric lesions induced by mucosal ischemia followed by reperfusion. Lipid peroxidation increased only after reperfusion, which was also blocked by pretreatment with calcium channel blockers. Thus, the calcium ion influx and the membrane lipid peroxidation followed by mucosal hypoxia might have a role in the mucosal cell death. The results indicate that the gastric surface mucosal circulation plays an important role in the mucosal protection against high concentrations of ethanol, nonsteroidal anti-inflammatory drugs (NSAIDs), PAF, and leukotriene C4.