BBI Japanese Editor

TOKYO, Japan – Takenori Ochiai, professor in the department of surgery at the Chiba University School of Medicine, discussed clinical applications of gene therapy for cancer of the esophagus during the 87th Japan Gastroenterology Society general meeting, held here this past spring. Basic studies on gene therapy for cancer of the esophagus began in 1994, and its protocol has been approved by the Bureau of Pharmaceutical Safety in the Ministry of Health, Labor and Welfare and is scheduled for clinical implementation beginning this fall.

Cytokine genes, cancer suppressor gene p53, and suicide genes are engineered into vectors, respectively, esophageal carcinoma colony cells are established, and the respective anti-tumor effects were compared. Ochiai said cells impregnated with IL-2 and GM-CSF genes, respectively, have shown meaningful suppression effect of tumor proliferation. Esophageal colony cells impregnated with typical herpes simplex virus-thymidine kinase (HSV-tk) were subcutaneously implanted in nude mice, upon which ganciclovir was administered intra-abdominally to compare the increase of tumor volume over the control group. Meaningful suppression of tumor proliferation was observed, which eventually have involuted. Normal type p53 genes were introduced into esophageal carcinoma cells using retrovirus vector, and comparisons were made against a group introduced with control genes. In vitro examination confirmed that the proliferation was meaningfully suppressed and had triggered apoptosis. Susceptibilities to chemotherapy agents and radiation also were confirmed.

Kohzoh Imai, professor in the department of internal medicine at Sapporo Medical University, reported on abnormalities in apoptosis-related genes with cancers of the digestive organs. As it is known that occurrence of mutation with p53 gene in microsatellite instability (MIS) positive large bowel cancer is low, Imai examined the (G)8 sequence of the Bax gene, which induces apoptosis whose transcription was accelerated by the p53 gene to determine whether there is any mutation or not. His finding was that frame shift mutations were detected in more than half of MIS-positive large bowel cancer cases. While Bax gene mutations also were observed in high frequencies with MIS-positive cancer of the stomach and familial non-polyposis cancer of the large intestine (HNPCC), it was clear that frequencies of mutations of p53 genes are low, indicating that Bax gene mutation is playing an important role in oncogenesis and evolution.

Norio Hayashi, professor in the department of molecular science and therapeutics at Osaka University Graduate School of Medicine, spoke about host genes related to the onset of chronic hepatitis C and reactivity to Interferon therapy. In hepatitis C patients, persistent infection occurs despite low viral load and progresses into hepatic cirrhosis and eventually to hepatic carcinoma. It is therefore necessary to clarify the mechanism of this persistent infection and eliminate the virus in order to hinder progression into hepatic carcinoma. It has been indicated that TAP2 gene polymorphisms is associated with factors that regulate degree of hepatic damage and that LMP7 gene polymorphisms is linked to significant effects on INF treatment. The unraveling of these gene polymorphisms is expected to be useful not only in projection of diagnostic significance or effect of INF treatment, but also in clarifying mechanisms of chronic hepatic damage and the development of more effective treatment methods.

Shuichi Kaneko, of the department of internal medicine at Kanazawa University Graduate School of Medicine, described the status of gene diagnosis and gene therapy for hepatic diseases. Gene diagnosis of hepatic diseases consists of one category in which DNA is analyzed and the other category in which RNA is analyzed. The university has conducted base sequence analysis, homology analysis and gene identifications with all expressed genes in excess of 350,000 collected from normal livers. As a result of these studies, types and frequencies of genes expressed in normal livers became clear.

Minoru Tada, MD, of the department of digestive internal medicine at the University of Tokyo, described gene diagnosis and gene therapies of digestive organ diseases. Studies have revealed that abnormalities of K-ras, p53, p16 and DPC4 genes exist in high frequency with gall bladder cancer and cancer of the pancreas. Teromerase activity resulting from the abnormalities of teromerase genes related to immortalization of cells also was observed. On the other hand, fewer APC gene convulsion and microsatellite instability were observed with gall bladder cancer and cancer of the pancreas. Based on these characteristics, methods of gene diagnosis have been reported for detecting gene abnormalities from clinically collected samples, including pancreatic juice. Requirements for cancer diagnosis are that those genetic abnormalities can be observed in high frequencies under relatively simple analysis methods from minute amounts of samples. Genetic diagnosis will become important in the future as a means for selecting appropriate methods of treatment.