A novel antitumor bicyclic depsipeptide, FR901228, was isolated from a broth culture of Chromobacteriumviolaceum No. 968 as colorless prisms and the molecular formula was determined as C24H36N4O6S2. This antibiotic reverted the transformed morphology of a Ha-ras transformant to normal, and exhibited prominent antitumor activities against murine and humantumor cell lines both in vitro and in vivo. 301 Recent studies showed that a family of ras oncogenes was frequently found to harbor mutations in human tumors1}. The presence of these genes in human tumors play an important role in the development of tumors. A relationship between the levels of expression of the H&-ras oncogene and tumorigenic potential was clearly demonstrated2>3). In addition, it was shownthat morphological reversion of the ras transformed phenotype was achieved through micro-injection of antibodies specific for the Ha-ras gene product4*. Consequently, activated ras expression is thought to be critical in maintaining the transformed phenotype. These data show that if an agent selectively reversed the phenotype of a ras transformant, it would be a new class of anticancer drug targeting the components of ras-mediated signaling transduction pathways. For this reason, we have searched for novel products from fermentation broths which would reverse a r

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Previously, we discovered that RANKL expression is induced in compressed periodontal ligament cells, and that this promotes osteoclastogenesis on the compression side in orthodontic tooth movement. We hypothesized that local OPG gene transfer to the periodontium would neutralize the RANKL activity induced by mechanical compressive force, thereby inhibiting osteoclastogenesis and diminishing tooth movement. The upper first molars of six-week-old male Wistar rats were moved palatally by means of a fixed-orthodontic wire. A mouse OPG expression plasmid [pcDNA3.1(+)-mOPG] was constructed, and the production of functional OPG protein was confirmed in vitro. The inactivated HVJ envelope vector containing pcDNA3.1(+)-mOPG or PBS was injected periodically into the palatal periodontal tissue of upper first molars. When this local OPG gene transfer was performed, OPG production was induced, and osteoclastogenesis was inhibited. Local OPG gene transfer significantly diminished tooth movement. In this study, we report that OPG gene transfer to periodontal tissue inhibited RANKL-mediated osteoclastogenesis and inhibited experimental tooth movement.

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