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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Barbacid, M. Ras genes. Annu. Rev. Biochem. 56, 779–827 (1987).

  2. 2

    Lowy, D.R. & Willumsen, B.M. Function and regulation of ras . Annu. Rev. Biochem. 62, 851–891 (1993).

  3. 3

    Adams, J.M. & Cory, S. Transgenic models of tumor development. Science 254, 1161–1167 (1991).

  4. 4

    Clark, G.J. & Der, C.J. Ras proto-oncogene activation in human malignancy. in Cellular Cancer Markers (eds Garrett, C.T. & Sell, S.) 17–52 (Humana Press, Totowa, New Jersey, 1995).

  5. 5

    Bos, J.L. Ras oncogenes in human cancer: A review. Cancer Res. 49, 4682–4689 (1989).

  6. 6

    Gibbs, J.B., C-terminal processing enzymes—new drug targets? Cell 65, 1–4 (1991).

  7. 7

    Clarke, S. Protein isoprenylation and methylation at carboxyl-terminal cysteine residues. Annu. Rev. Biochem. 61, 355–386 (1992).

  8. 8

    Gibbs, J.B., Oliff, A. & Kohl, N.E. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77, 175–178 (1994).

  9. 9

    Patel, D.V. et al. Phosphinyl acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase. J. med. Chem. 38, 435–442 (1995).

  10. 10

    Kohl, N.E. et al. Farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc. natn. Acad. Sci. U.S.A. 91, 9141–9145 (1994).

  11. 11

    Sinn, E. et al. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenes in vivo. Cell 49, 465–475 (1987).

  12. 12

    Dexter, D.L., Diamond, M., Creveling, J. & Chen, S.-F. Chemotherapy of mammary carcinomas arising in ras transgenic mice. Invest, new Drugs 11, 161–168 (1993).

  13. 13

    James, G.L. et al. Benzodiazepine peptidomimetics: Potent inhibitors of Ras farnesylation in animal cells. Science 260, 1937–1942 (1993).

  14. 14

    Prendergast, G.C. et al. Farnesyltransferase inhibition causes morphological reversion of Ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Molec. cell. Biol. 14, 4193–4202 (1994).

  15. 15

    James, G.L., Goldstein, J.L., Pathak, R.K., Anderson, R.G.W. & Brown, M.S. A prenylated protein of peroxisomes. J. biol. Chem. 269, 14182–14190 (1994).

  16. 16

    Vogelstein, B. & Kinzler, K.W. The multistep nature of cancer. Trends Genet. 9, 138–141 (1993).

  17. 17

    Yamada, H., Yoshida, T., Sakamoto, H., Terada, M. & Sugimura, T. Establishment of a human pancreatic adenocarcinoma cell line (PSN-1) with amplification of both c-myc and activated c-Ki-ras by a point mutation. Biochem. biophys. Res. Commun. 140, 167–173 (1986).

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Further reading