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

Nat Med. 1995 Aug;1(8):792-7. doi: 10.1038/nm0895-792.

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.

MeSH terms

  • Alkyl and Aryl Transferases*
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / therapeutic use*
  • Enzyme Inhibitors / toxicity
  • Female
  • Genes, ras
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / pathology
  • Methionine / administration & dosage
  • Methionine / analogs & derivatives*
  • Methionine / therapeutic use
  • Methionine / toxicity
  • Mice
  • Mice, Transgenic
  • Salivary Gland Neoplasms / drug therapy*
  • Transferases / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • L 744832
  • Methionine
  • Transferases
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase