| Co-Investigator(Kenkyū-buntansha) |
OZAWA Keiya Jichi Medical School, Department of hematology Professor, 医学部, 教授 (30137707)
KOBAYASHI Hiroshi Hamamatsu University School of Medicine, Department of Obstetrica and Gynecology assistant professor, 医学部, 講師 (40178330)
SUZUKI Mitsuaki Jichi Medical School, Department of Obstericts and Gynecology Professor, 医学部, 教授 (50110870)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
To establish tumor dormancy therapy, which does not completely cure cancer but inhibits metastasis and expansion of invasion, we focused on NK4 which was a hepatocyte growth factor (HGF) antagonist, urinary trypsin inhibitor (UTI), and IL-10 which was a one of immunosuppressive cytokines. We investigated the inhibition of metastasis/invasion by these substances. In addition, we evaluated a new gene therapy for ovarian cancer using an adeno-associated virus (AAV) vector. Ovarian cancer cell lines HRA and SHIN-3 were used for preparation of models of ovarian cancer peritoneal dissemination. We prepared NK4-expressing plasmid vector and UTI-expressing plasmid vector, and transduced ovarian cancer cells with these vectors. In HRA/NK4 cells, in vitro migration of the cells was decreased in scratch wound healing assay. When HRA/NK4 cells were intraperitoneally inoculated in mice, peritoneal dissemination was inhibited compared to that in the control. In the experiment with HRA/UTI, marked in
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hibition of migration and infiltration was observed and ascites production was also inhibited. We isolated the active region of UTI, HI-8, and successfully prepared ATF-HI-8-expressing plasmid vector. HRA was transduced with this plasmid vector, and inhibition of migration and infiltration was observed as in HRA/UTI. With regard to IL-10, expression vector was prepared for SHIN-3 and conversion to AAV vector was also successful. AAV-IL-10 was intramuscularly inoculated into mice, and angiogenesis, peritoneal dissemination, and ascites production were inhibited. Furthermore, the survival period extended. Tumor suppressor gene PTEN increased the sensitivity to irinotecan hydrochloride in a gene transduction experiment. Cell migration was inhibited in HRA/PTEN. We transduced cervical cancer cell line SKG-II with thymidylate synthase (TS) DNA and successfully prepared a cell line highly expressing TS. In SKG-II/TS, radiosensitivity was decreased compared with the control, and sensitivity to 5-FU was also decreased.
The above findings may lead to dormancy therapy and gene therapy for ovarian cancer, and selection of effective chemotherapy. Less
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