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Farnesylation of ras is essential for its membrane

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Unformatted text preview: ntial for its membrane localization and thereby for its signaling function and cell transforming activity. This lipid modification is catalyzed by farnesyltransferase. The first strategy to inhibit RAS activity in tumor cells was the development of farnesyltransferase inhibitors (FTIs), which prevent RAS localization. FTIs appeared to have anti-tumor effects in different studies. As single agents, FTIs have significant activity in myeloid leukemia’s, but in solid tumors the effects appear to be modest (16). The nature of the FTI effects is highly complex. It appears that KRAS and NRAS proteins can also be modified by geranylgeranyl protein transferase, particularly when cells are treated with FTIs. This geranylgeranyl modification enables KRAS and NRAS to remain associated with the cell membrane. In addition, it has become clear that cell types with no RAS mutation are also sensitive to FTIs. Therefore, it is likely that the anti-tumor effects of FTIs are mediated by the inhibition of farnesylation of other proteins in addition to RAS (105). Antisense inhibition of RAS protein expression appeared to have partial anti-tumor effects in human lung cancer cells and transformed fibroblast. The therapeutic use of these antisense oligonucleotides was limited, since they were rapidly degraded by intracellular nucleases. Moreover, they appeared to have sequence independent cytotoxic and antiproliferative effects (16). The different approaches to inhibit Ras signaling in cancer cells are not specific for oncogenic RAS. A technique that can be used to differentiate between mutated and wild-type transcripts is RNA interference (RNAi). RNAi is a sequence specific posttranscriptional gene silencing mechanism induced by double-stranded RNA (dsRNA) molecules. A major advantage of RNAi-mediated anti-RAS cancer therapy, in contrast to other RAS based therapies, is the specific targeting of oncogenic RAS. This might be crucial, since inhibition of wild type RAS function in cells could interfere 25 with normal cell viability. The targeting of oncogenic...
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