シュジュツ フノウ シンコウ イガン ニ タイスル カガク リョウホウ

Although the incidence of gastric cancer is declining in Japan, it is still the second common cancer. After ２０００ year, several new anticancer drugs for gastric cancer have been developed, and overall response rate and survival have been ７‐５１％ and ６‐１２ months respectively. However, these are still unsatisfactory results and the majority of the metastatic gastric cancer is incurable. We proposed a triplet regimen consisting of docetaxel, cisplatin and S‐１（DCS）, and performed phase I and II study. The results showed that response rate was８７．１％ and overall survival was ２２ months. Now, phase III study is under way. In addition, recently efficacy of herceptin, an antibody agent against HER２, was proved for HER２ positive gastric cancer. This is the first molecular targeting drug that was approved for gastric cancer. In future, combination of herceptin and cytotoxic anticancer drugs such as DCS regimen will be tested

Mnagement of Information about Advarse Events in Clinical Trials

金沢大学医学部附属病院薬剤

Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice

Chronic exposure to methamphetamine causes adaptive changes in brain, which underlie dependence symptoms. We have found that the transmembrane protein 168 (TMEM168) is overexpressed in the nucleus accumbens of mice upon repeated methamphetamine administration. Here, we firstly demonstrate the inhibitory effect of TMEM168 on methamphetamine-induced behavioral changes in mice, and attempt to elucidate the mechanism of this inhibition. We overexpressed TMEM168 in the nucleus accumbens of mice by using an adeno-associated virus vector (NAc-TMEM mice). Methamphetamine-induced hyperlocomotion and conditioned place preference were attenuated in NAc-TMEM mice. Additionally, methamphetamine-induced extracellular dopamine elevation was suppressed in the nucleus accumbens of NAc-TMEM mice. Next, we identified extracellular matrix protein osteopontin as an interacting partner of TMEM168, by conducting immunoprecipitation in cultured COS-7 cells. TMEM168 overexpression in COS-7 cells induced the enhancement of extracellular and intracellular osteopontin. Similarly, osteopontin enhancement was also observed in the nucleus accumbens of NAc-TMEM mice, in in vivo studies. Furthermore, the infusion of osteopontin proteins into the nucleus accumbens of mice was found to inhibit methamphetamine-induced hyperlocomotion and conditioned place preference. Our studies suggest that the TMEM168-regulated osteopontin system is a novel target pathway for the therapy of methamphetamine dependence, via regulating the dopaminergic function in the nucleus accumbens

1997年岡山県下に発生した集団食中毒患者から分離された腸管出血性大腸菌EHEC O157 : H7のパルスフィールドゲル電気泳動法による遺伝子解析

Thirteen enterohemorrhagic Escherichia coli O157 : H7 (EHEC) isolates derived from the patients of an outbreak in the R-hospital in Okayama Japan and one isolated from the ingredients of Japanese noodles in June 1997 were analyzed by molecular typing using pulsed-field gel electrophoresis (PFGE). The PFGE patterns of the patients were almost the same as the patterns of the Japanese noodle ingredients. Therefore, the EHEC O157 : H7 derived from the food was considered to have caused the outbreak in the R-hospital. The molecular typing of isolates from the patients and the Japanese noodle ingredients was almost the same as that of isolates from outbreaks in Hiroshima and Fukuoka prefectures classified as type Ia in 1996 by PFGE analysis. These results indicate that EHEC O157 : H7 strains with a similar PFGE type Ia pattern have already spread throughout western Japan since last year.1997年6月に岡山県下のR-病院で腸管出血性大腸菌EHEC O157 : H7による集団食中毒が発生した｡その患者および食材である日本そばから分離されたEHEC O157 : H7の菌株をパルスフィールドゲル電気泳動法(PFGE)を使用して遺伝子解析を行った｡13名の患者から分離された菌株の遺伝子型は日本 そばから分離された菌株と一致した｡従って日本そばから分散されたEHEC O157 : H7が集団食中毒の原因であることが解った｡さらにこれらの菌株の遺伝子型は1996年に広島県および福岡県の西日本に集団食中毒が発生した菌株のタイプIa型と類似していた｡このことはこの遺伝子タイプの類似した菌株の感染が西日本で去年から広がっていることを示している

キンダイ イコウ ニオケル アシダガワ チュウカリュウイキ ノ シンスイイキ ノ ヘンセン ト ソノ ヨウイン ノ ケントウ

P(論文)departmental bulletin pape

Monitoring method for transgene expression in target tissue by blood sampling

In this study, we have developed a novel method to monitor transgene expression in tissues by blood sampling. We administered plasmid DNA (pDNA) encoding non-secretory form of firefly luciferase as a reporter gene and pDNA encoding secretable Gaussia princeps luciferase as a monitor gene simultaneously into mice. Good positive correlations were found between log-transgene expression of the reporter gene and the monitor gene in the treated muscle, between the monitor gene in the treated muscle and plasma, and consequently between the reporter gene in the treated muscle and the monitor gene in plasma after naked pDNA transfer into the muscle of mice. Such positive correlations were also found with gastric serosal surface instillation of naked pDNA, intravenous injection of lipoplex, and hydrodynamics-based injection of naked pDNA. We developed monitoring method of transgene expression in tissues by blood sampling, which was named ‘Therapeutic transgene monitoring (TTM)’, after ‘Therapeutic drug monitoring (TDM)’

Response Predictors of DCS Therapy in Gastric Cancer

Objectives: The aim of this study was to identify biomarkers for predicting the efficacy of docetaxel, cisplatin, and S-1 (DCS) therapy for advanced gastric cancer using microarrays of biopsy specimens before chemotherapy. Methods: Nineteen samples were taken from 19 patients with unresectable metastatic gastric cancer who received DCS as a first-line therapy. Laser capture microdissection was performed, and total cellular RNA was extracted from each microdissected sample. Whole-gene expression was analyzed by microarray, and the difference in mRNA expression observed with the microarrays was confirmed by quantitative real-time PCR. Immunohistochemical staining was performed using clinical tissue sections obtained by endoscopic biopsy. Results: Eleven patients were identified as early responders and 8 patients as nonresponders to DCS therapy. Twenty-nine genes showed significant differences in relative expression ratios between tumor and normal tissues. A classifier set of 29 genes had high accuracy (94.7%) for distinguishing gene expression between 11 early responders and 8 nonresponders. Decreasing the size of the classifier set to 4 genes (PDGFB, PCGF3, CISH, and ANXA5) increased the accuracy to 100%. Expression levels by real-time PCR for validation were well correlated with those 4 genes in microarrays. Conclusion: The genes identified may serve as efficient biomarkers for personalized cancer-targeted therapy