Effect of Helicobacter pylori infection on the N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in mongolian gerbils.
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The effect of Helicobacter pylori infection on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer was studied using a Mongolian gerbil model. Five-week-old male Mongolian gerbils were divided into four groups of 25-30 animals each and challenged for 20 weeks with H.pylori, MNNG, a combination of H.pylori and MNNG, or neither of them. Four to 20 animals from each group were killed at 16, 24 and 52 weeks after H.pylori inoculation, and histopathological changes in their stomachs were examined. A well-differentiated adenocarcinoma was first observed 24 weeks after inoculation in the combination group. At 52 weeks, only six of 15 animals were colonized with H.pylori persistently, and four of them showed well-differentiated adenocarcinomas; on the other hand, neither of the animals with disappearance of H.pylori from the combination group showed adenocarcinoma. At the same observation time, three of 17 animals from MNNG group showed poorly differentiated adenocarcinomas. The incidence of gastric carcinoma in the combination group was significantly higher than that in the MNNG group (P < 0.05). However, no tumors were seen in the control and H.pylori groups. The present findings demonstrate that H.pylori infection enhances the carcinogenic action of MNNG. (+info)
High inter- and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion.
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The purpose of the study was to examine inter- and intrapatient variation in 5-fluorouracil (5-FU) plasma concentrations in adult cancer patients receiving a 3-day drug infusion. Fourteen patients received 1266 mg/m2 N-(phosphonacetyl)-L-aspartate (PALA) infused i.v. over 15 min on day 1, followed immediately by a loading dose of 500 mg/m2 calcium leucovorin over 30 min. Then a prolonged infusion of leucovorin at 500 mg/m2/day and 5-FU at 1750 mg/m2/day was administered as either a constant rate or as a circadian infusion over 72 h. During constant rate infusions, 5-FU concentrations within individuals varied by 1.7-fold, but no uniform time of peak or trough concentration was observed. Transformation of these data by setting the time of peak to 0 h and by expressing concentrations as the percentage of the 24-h mean value revealed a nonrandom distribution of the time from peak to trough with a median time of 12 h (P = 0.027). These transformed data were also successfully fit to a circadian cosinor function (P < 0.001). During multiple constant rate 5-FU infusions, the intrapatient variability was high; the times of peak 5-FU concentration occurred at the same approximate sampling time 43% of the time, and troughs coincided 17% of the time. No difference in clinical toxicity was observed when matched constant rate and circadian infusions of 5-FU were compared. High inter- and intrapatient variability exists in 5-FU plasma concentrations in adult cancer patients during constant rate infusions with no evidence of a consistent circadian rhythm in untransformed data. (+info)
Enhanced expression of inducible nitric oxide synthase and nitrotyrosine in gastric mucosa of gastric cancer patients.
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Recent studies (K. Komoto et al., Am. J. Gastroenterol., 93: 1271-1276, 1998) have shown that Helicobacter pylori infection is associated with gastric cancer. However, the mechanism of H. pylori in carcinogenesis has not been clarified. H. pylori infection leads to a sustained production of reactive nitrogen species that may contribute to cause DNA damage. In this study, we examined the expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine in gastric mucosa. The expression of iNOS and nitrotyrosine was examined by immunohistochemistry in 93 patients who initially underwent gastric biopsies between 1975 and 1992. Thirty-four individuals were later found to have gastric cancer at least 2 years after the initial biopsies (group A). The other 59 subjects have shown no evidence of gastric cancer during long-term follow-up. Fifty-one of these patients were positive for H. pylori (group B), and eight were negative for H. pylori (group C). The expression of iNOS and nitrotyrosine in the gastric mucosa was significantly higher in H. pylori-positive groups A and B than in H. pylori-negative group C. Among the H. pylori-positive patients, the expression of iNOS and nitrotyrosine was significantly higher in group A than in group B. These results suggest that high production of iNOS and nitrotyrosine in the gastric mucosa infected with H. pylori may contribute to the carcinogenesis of gastric cancer. (+info)
Infrequent germ-line mutation of the E-cadherin gene in Japanese familial gastric cancer kindreds.
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Germ-line mutation of the E-cadherin gene was reported in familial gastric cancer (FGC) kindreds from New Zealand. Therefore, we analyzed all of the exons of E-cadherin by PCR-single-strand conformational polymorphism analysis in 16 patients from 14 Japanese FGC kindreds. However, no germ-line mutation was detected, suggesting that a predisposition to FGCs by E-cadherin gene mutation is infrequent in Japanese cases. (+info)
Expression of nuclear retinoid receptors in normal, premalignant and malignant gastric tissues determined by in situ hybridization.
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Retinoids exhibit multiple functions through interaction with nuclear retinoid receptors and have growth-suppressive activity on gastric cancer cells. To better understand the roles of nuclear retinoid receptors during gastric carcinogenesis, we have used in situ hybridization to investigate expression of retinoic acid receptors (RARs) and retinoid x receptors (RXRs) in premalignant and malignant formalin-fixed paraffin-embedded gastric tissues. Histological sections of eight normal, 17 distal normal and nine gastric cancer tissues were hybridized with non-radioactive RNA probes for subtypes of RAR and RXR. Expression of RAR alpha, RAR beta, RAR gamma, RXR alpha and RXR beta was found in most cell types in gastric mucosa tissues from normal individuals as well as in distal normal tissues from cancer patients. Expression of RAR alpha and RAR beta were found in three and seven cancer tissues, respectively, and levels of RXR alpha mRNA were significantly decreased in poorly differentiated cancer tissues. Among the five investigated nuclear retinoid receptors, only expression of RAR alpha mRNA was significantly decreased in intestinal metaplasia, dysplasia and cancer tissues when compared to adjacent normal tissues. In conclusion, normal gastric mucosa expressed both RARs and RXRs, which supports the physiological role of retinoic acid on normal gastric mucosa. The decrease in RAR alpha expression in premalignant and malignant gastric tissues suggests a significant role of RAR alpha during gastric carcinogenesis. (+info)
Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial.
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We report the final results of a prospectively randomized study that compared the combination of epirubicin, cisplatin and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin and methotrexate (FAMTX) in previously untreated patients with advanced oesophagogastric cancer. Between 1992 and 1995, 274 patients with adenocarcinoma or undifferentiated carcinoma were randomized from eight oncology centres in the UK and analysed for response and survival. The overall response rate was 46% (95% confidence interval (CI), 37-55%) with ECF, and 21% (95% CI, 13-28%) with FAMTX (P = 0.00003). The median survival was 8.7 months with ECF and 6.1 months with FAMTX (P = 0.0005). The 2-year survival rates were 14% (95% CI, 8-20%) for the ECF arm, and 5% (95% CI, 2-10%) for the FAMTX arm (P = 0.03). Histologically complete surgical resection following chemotherapy was achieved in ten patients in the ECF arm (three pathological complete responses to chemotherapy) and three patients in the FAMTX arm (no pathological complete responses). The ECF regimen resulted in a response and survival advantage compared with FAMTX chemotherapy. The probability of long-term survival following surgical resection of residual disease is increased by this treatment. The high response rates seen with ECF support its use in the neoadjuvant setting. (+info)
Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer.
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Adenomatous polyposis coli (APC) mutations are present in >70% of colon cancers. The APC protein binds to beta-catenin (beta-cat), a protein first identified because of its role in E-cadherin (E-cad) cell adhesion. In some colon cancers lacking APC defects, mutations in presumptive glycogen synthase kinase 3beta phosphorylation sites near the beta-cat NH2 terminus appear to render beta-cat resistant to regulation by APC and glycogen synthase kinase 3beta. In cells with APC or beta-cat defects, beta-cat is stabilized and, in turn, binds to and activates T-cell factor (Tcf)/lymphoid enhancer factor (Lef) transcription factors. To further explore the role of APC, beta-cat, Tcf, and E-cad defects in gastrointestinal cancers, we assessed gastric and pancreatic cancers for constitutive Tcf transcriptional activity (CTTA). Two of four gastric and two of eight pancreatic cancer lines showed CTTA. One gastric and one pancreatic cancer had mutations in the NH2-terminal phosphorylation sites of beta-cat. The other gastric cancer with CTTA had a missense mutation at serine 28 of gamma-cat, a potential phosphorylation site in this beta-cat-related protein. Although E-cad is an important binding partner for beta-cat and gamma-cat, E-cad inactivation did not result in CTTA. The beta-cat and gamma-cat mutant proteins identified in our studies strongly activated Tcf transcription in vitro, whereas beta-cat mutant proteins with large NH2-terminal deletions had only modest effects on Tcf. Our results suggest a role for Tcf deregulation in gastric and pancreatic cancer, resulting from beta-cat and gamma-cat mutations in some cases and, in others, from yet to be defined defects. Furthermore, these data imply that the consequences of APC and beta-cat mutations are distinct from the effects of E-cad inactivation. (+info)
Expression of c-erbB-2 oncoprotein in gastric carcinoma: correlation with histopathologic characteristics and analysis of Ki-67.
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Amplification and overexpression of the c-erbB-2 gene has been demonstrated in several tumors and thought to be important determinants of biologic behaviors of carcinomas. In this study, correlation between c-erbB-2 expression und histopathologic parameters, including proliferative activity of gastric carcinomas was evaluated. Paraffin-embedded tissue sections from 62 patients who underwent curative resection of gastric carcinoma were analyzed immunohistochemically for the expression of c-erbB-2 and Ki-67. Strong membrane staining for c-erbB-2 was detected in 11 of 62 gastric carcinomas (17,7%) and no positive reaction was evident in noncancerous tissue. The incidence of c-erbB-2 positivity in intestinal type carcinomas (24,3%) was higher than that of diffuse type carcinomas (4,76%). Positive staining for c-erbB-2 was present in one of the 9 (11,1%) early gastric carcinomas and 10 of 53 (18, 8%) advanced gastric carcinomas. However, no statistically significant relationships were found between c-erbB-2 expression and histopathologic type, depth on invasion, the tumor size or lymph node metastases. Among the metastatic lymph nodes, 3 were positively stained with c-erbB-2 whereas the primary tumors of two cases had been found to be negative. Additionally, no correlation was found between c-erbB-2 reactivity and proliferative activity of carcinoma cells. The results suggest that expression of c-erbB-2 protein may occur selectively in intestinal type of gastric carcinomas. However, c-erbB-2 expression is not a reliable marker of malignant potential in gastric carcinomas. (+info)