Tetsuya Okino

In situ Gene Transfer and Suicide Gene Therapy of Gastric Cancer Induced by N-Ethyl-N′-nitro-N-nitrosoguanidine in Dogs

Gene therapy could potentially revolutionize the treatment of gastrointestinal (GI) tract cancer. The aim of this study was to establish a practical method of gene transfer which would be applicable to human gastric cancer. Retrovirus or/and adenovirus vectors carrying the lacZ marker gene were transferred in situ by needle through an endoscopic biopsy channel into primary gastric cancer in six male beagle dogs that had been treated with N‐ethyl‐N′‐nitro‐N‐nitrosoguanidine (ENNG). In addition, an adenovirus vector carrying the herpes simplex virus thymidine kinase (Ad.CAGHSV‐TK) gene was introduced in situ into cancer tissues in the stomach of three dog, and the animals were treated with intravenous ganciclovir (GCV). Retrovirus‐producing cells which expressed the lacZ gene were specifically localized to the injection site in the stomach. The lacZ gene was more widely transferred into the tumor by the adenovirus vector than by retrovirus‐producing cells. Improvement of the needle used for gene transfer and the use of multiple injections per tumor led to more diffuse transfer of the vector into the tumor. The Ad.CAG lacZ gene was also transferred into regional lymph nodes of the stomach. Moderate to diffuse degeneration of the primary cancer tissues of the stomach was found after Ad.CAGHSV‐TK/GCV gene therapy. Moreover, almost complete tissue degeneration was observed in the regional lymph nodes of the stomach. An adverse effect of HSV‐TK/GCV gene therapy was acute hepatotoxicity, which was not found after Ad.CAG lacZ gene transfer, but was found after high‐titer Ad.CAGHSV‐TK gene transfer followed by GCV. These findings suggest that in situ gene transfer of a suicide gene followed by prodrug treatment may be applicable not only to primary tumors, but also to lymph node metastases of gastric cancer, though further study of both beneficial and adverse effects is required before clinical usage.

Sequential Histopathological Changes in vivo after Suicide Gene Therapy of Gastric Cancer Induced by N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine in Rats

Gastrointestinal cancer is the most important clinical target of gene therapy. Suicide gene therapy, such as with the herpes simplex virus type 1 thymidine kinase (HSV‐TK) gene, has been shown to exert antitumor efficacy in various cancer models in vitro. We previously reported in situ gene transfer and gene therapy for gastric cancer induced by N‐ethyl‐.N′‐nitro‐.N‐nitrosoguanidine (ENNG) in dogs. Here, we describe the sequential histopathological changes after suicide gene therapy of N‐methyl‐.N′‐nitro‐.N nitrosoguanidine (MNNG)‐induced gastric cancer in rats. Gastric tumors were induced by MNNG in 38/73 (52%) of Wistar strain rats. The suicide gene therapy group (14 rats) was subjected to in situ gene transfer with a recombinant adenovirus vector carrying the HSV‐TK gene driven by CAG promoter (Ad.CAGHSV‐TK) in gastric tumor, followed by the antiviral drug ganciclovir (GCV). To observe the histopathological changes at various tunes after HSV‐TK/GCV gene therapy, groups of animals were sacrificed at 3, 8, and 30 days after gene transfer. Apoptosis in the gastric tumors was detected by the TUNEL method to assess the efficacy of HSV‐TK/GCV gene therapy, and it was marked in the 8‐ and 30‐day treatment groups compared to the sham operation controls (P<0.001). Various histopathological changes, degeneration of cancer tissue and fibrosis after necrosis and apoptosis were significantly greater in the 30‐day treatment group. The HSV‐TK gene was detectable in peripheral blood by PCR until 30 days after gene transfer. These results may be useful in devising a method of suicide gene therapy for humans.

Multiple early gastric cancer with duodenal invasion

BackgroundEarly gastric cancers with duodenal invasion are rare, and no previous case of multiple early gastric cancer, one invading the duodenal bulb, has been reported.Case presentationA 79-year-old woman was investigated for upper abdominal discomfort. Endoscopic examination revealed an irregular nodulated lesion in the antrum area, and a reddish aggregated-type semi-circumferential nodulated lesion extending from the prepyloric area to the duodenal bulb through the normal mucosa with the antrum lesion. Biopsy revealed a tubular adenoma for the antrum lesion and a well-differentiated tubular adenocarcinoma for the prepyloric lesion. Distal gastrectomy with sufficient duodenal resection was performed. Microscopically, the antrum lesion appeared as a papillary adenocarcinoma, and the prepyloric lesion as a mainly papillary adenocarcinoma which partially invaded the submucosa without any sequential elongation for endoscopic findings. The lesion extended into the duodenal bulb, and was 12 mm in length from the oral end of Brunners glands area and limited within the duodenal mucosa.ConclusionHere, we present an unusual case of multiple early gastric cancer, one of which invaded the duodenum with relative wide mucosal spreading. This case illustrates that even early stage cancers located in the gastric antrum, particularly in the prepyloric area can invade the duodenum directly.

7190 Endoscopic examination of mucosal atrophy/ intestinal metaplasia and h.pyloriinfection in the stomach among different populations in asia.

Close correlation between mucosal atrophy/intestinal metaplasia (IM) and gastric cancer has been reported. Recently, etiological relation between H. pyloriinfection and gastric cancer has been elucidated. Aim of this study is to clarify the geographical differences of mucosal atrophy/IM and H. pyloriinfection in the stomach among different populations in Asia, i.e. Japanese (Tokyo) 4260 cases, Chinese (Beijing) 257 cases, Vietnamese(Ho Chi-ming) 223 cases and Thai (Chaing Mai) 437 cases. Under the endoscopic examination, 3 biopsy specimens were taken from #1 antrum, #2 upper corpus and #3 angulus regions and grading of atrophy, IM and H. pyloriinfection were undergone by the Sydney System. Results showed most geographical differences in biopsy specimens taken from #3 angulus region. H. pyloriinfection was most high in Thai population in all generation, followed by Chinese, Japanese and Vietnamese in younger generation; and Japanese, Chinese and Vietnamese in elder generation. Mucosal atrophy was most high in Japanese followed by Vietnamese, Chinese and Thai; and IM was most high in Japanese followed by Chinese, Vietnamese and Thai in all generation. In conclusion, H. pyloriinfection correlated with mucosal atrophy/IM in Japanese but not in Thai population. These differences of stomach mucosa may attribute to high and low incidence of gastric cancer in Japan and Thai population, respectively.