Search for protein farnesyltransferase inhibitors of microbial origin: our strategy and results as well as the results obtained by other groups.

Mutant ras oncogenes are associated with various human tumors, being found in approximately 25% of all human cancers. Since its identification, the enzyme Ras protein farnesyltransferase (PFTase), which catalyzes the initial step of Ras-processing, has been viewed as a most promising target for cancer therapy. Consequently, a number of synthetic and natural small molecules have been searched and developed according to this concept during the 1990s. Among these, microbial metabolites have provided diverse structural classes of compounds which exhibit PFTase inhibitory activity. This article reviews our work on PFTase inhibitors originating from microbial metabolites, and the results of similar works carried out by several other research groups.

Sclerosing effect of OC-108, a novel agent for hemorrhoids, is associated with granulomatous inflammation induced by aluminum.

OC-108 is a novel sclerosing agent for hemorrhoids, containing aluminum potassium sulfate (alum) and tannic acid as its main ingredients. In clinical studies, OC-108 injection therapy for severe internal hemorrhoids proved to be highly effective, not only on bleeding but also for prolapse, and the effects were comparable to hemorrhoidectomy. The aim of this study was to elucidate the mode of action by administrating the agent s.c. to mice and rats. In response to OC-108 injection, inflammation with necrosis developed at an early stage followed by granuloma formation with fibrosis at the injection site. Necrotic debris with aluminum was observed in the granuloma for a long period. Alum, as well as OC-108, induced vascular permeability, leukocyte infiltration, and granuloma formation; however, tannic acid did not. On the other hand, tannic acid inhibited leukocyte infiltration induced by alum but did not inhibit granuloma formation. These results indicate that OC-108 causes sclerosis and retraction of hemorrhoids through fibrosis associated with granulomatous chronic inflammation induced by the main active ingredient alum and that the adjunct ingredient tannic acid reduces excessive acute inflammation induced by alum.