KOBAYASHI Hiroshi Hamamatsu University School of Medicine, Department of Obstetrics and Gynecology, Associate professor, 医学部, 助教授 (40178330)
OZAWA Keiya Jichi Medical School, Department of Center for Molecular Medicine, Professor, 医学部, 教授 (30137707)
OHWADA Michitaka Jichi Medical School, Department of Obstetrics and Gynecology, Associate professor, 医学部, 助教授 (40203955)
|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
To establish molecular targeting therapy and gene therapy for ovarian cancer targeting inhibition of peritoneal dissemination and angiogenesis, we performed a basic study of various molecular targeting factors.
1)An antagonist of hepatocyte growth factor, HGF/NK4, exhibited inhibitory effects on cell migration in vitro and peritoneal dissemination in vivo.
2)A urinary trypsin inhibitor, bikunin, exhibited inhibitory effects on cancer cell invasion and metastasis. We successfully prepared a hybrid gene, ATF-HI8, in which the active site of bikunin, HI8, was bound to ATF that has high affinity for cancer cells. ATF-HI8 markedly inhibited cell migration and invasion.
3)An inflammation-suppressing cytokine, IL-10, inhibited angiogenesis, and tumor growth and peritoneal dissemination were inhibited through the inhibition of angiogenesis in ovarian cancer-bearing mice. We prepared IL-10-expressing AAV vectors(AAV-IL-10), and investigated the effect in vivo. Intramuscular injection of AAV-IL-10 into skeletal muscle decreased the numbers of new blood vessels and peritoneally disseminating tumors in ovarian cancer-bearing mice, and the survival period of the tumor-bearing mice was extended.
4)Theeffects of sFlt-1, the soluble form of a VEGF receptor, Flt-1, were also investigated. Inhibition of tumor growth and peritoneal dissemination through inhibition of angiogenesis was observed in ovarian cancer-bearing mice. sFLT-1-expressing AAV vectors (AAV-sFlt-1) were prepared, and administered in vivo, and the numbers of new blood vessels and peritoneally disseminating tumors were decreased.
The above findings clarified that molecular targeting factors, HGFINK4, bikunin (ATF-HI8), IL-b, and sFlt-1, inhibit peritoneal dissemination of ovarian cancer through inhibition of tumor angiogenesis and migration/invasion. In addition, therapeutic AAV vectors expressing IL-10 and sFlt-1 were successfully prepared, which may lead to gene therapy for ovarian cancer.