Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl :protein transferase inhibitor

摘要: For Ras oncoproteins to transform mammalian cells, they must be posttranslationally modified with a farnesyl group in reaction catalyzed by the enzyme farnesyl:protein transferase (FPTase). Inhibitors of FPTase have therefore been developed as potential anticancer agents. These compounds reverse many malignant phenotypes Ras-transformed cells culture and inhibit growth tumor xenografts nude mice. Furthermore, inhibitor (FTI) L-744,832 causes regression mouse mammary virus (MMTV)-v-Ha-ras transgenic mice stasis MMTV-N-ras Although these data support further development FTIs, it should noted that Ki-ras is ras gene most frequently mutated human cancers. Moreover, Ki-RasB binds more tightly than either Ha- or N-Ras, thus higher concentrations FTIs are competitive protein substrate may required Ki-Ras processing. Given unique biochemical biological features Ki-RasB, important evaluate efficacy any other modulator oncogenic function model systems expressing this oncoprotein. We strains carrying Ki-rasB cDNA an activating mutation (G12V) under control MMTV enhancer/promoter. The predominant pathological feature develops stochastic appearance adenocarcinomas. High levels transgene RNA detected tumors. Treatment MMTV-Ki-rasB caused inhibition absence systemic toxicity. activity was inhibited tumors from treated mice, unprocessed not detected. results demonstrate utility for testing Additionally, suggest although FTI can model, sole mediator effects FTI.