Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice

NE Kohl, CA Omer, MW Conner, NJ Anthony… - Nature medicine, 1995 - nature.com
NE Kohl, CA Omer, MW Conner, NJ Anthony, JP Davide, SJ Desolms, EA Giuliani…
Nature medicine, 1995nature.com
For Ras oncoproteins to transform mammalian cells, they must be post-translationally
modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein
transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer
agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is
added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing
palpable tumours, daily administration of L-744,832 caused tumour regression. Following …
Abstract
For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.
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