Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf

Oncogene volume 22, pages 6257–6265 (2003)Cite this article

Abstract

Mutations in the Kras2 gene are seen in both human and mouse lung adenocarcinomas. The protein product (p21ras) encoded by the Kras2 gene must be post-translationally modified at a terminal CAAX motif in order to be biologically active. In this study, we systematically investigated the chemopreventive efficacy of two different farnesyltransferase inhibitors (FTIs): one is a peptidomimetic (FTI-276) and the other is an imidazole (L778–123). Both FTIs are designed to inhibit the post-translational modification of p21ras proteins with a terminal CAAX motif. In a complete chemoprevention study, where the inhibitor was administered before carcinogen was given, and throughout the study, FTI-276 treatment significantly reduced both the tumor multiplicity by 41.7% (P<0.005), and the total tumor volume by 79.4% (P<0.0001). In the late treatment study, where mice were treated with an inhibitor 12 to 20 weeks after carcinogen administration, FTI-276 treatment resulted in a 60% reduction in tumor multiplicity and 58% reduction in tumor volume. Next, we examined the chemopreventive efficacy of a new FTI, L-778,123, on lung tumor development in A/J mice and transgenic mice with a dominant-negative p53 mutation and/or heterozygous deletion of Ink4a/Arf. Treatment of mice with L-778,123 for a period of 10 weeks from 20 weeks to 30 weeks post carcinogen initiation resulted in an ∼50% decrease in tumor multiplicity in wild-type mice and mice with a dominant-negative p53 mutation and/or heterozygous deletion of the Ink4a/Arf tumor suppressor genes. Interestingly, tumor volume was decreased ∼50% in wild-type mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased ∼75% in animals with a dominant-negative p53 and in mice with both a p53 mutation and heterozygous deletion of Ink4a/Arf. This result suggests that FTI exhibited a significantly (P<0.05) more efficacious chemopreventive effect in animals with alterations of p53 and Ink4a/Arf as contrasted with wild-type mice. Thus, FTIs are potent lung chemopreventive agents in both A/J mice and transgenic mice harboring a dominant-negative p53 and heterozygous deletion of Ink4a/Arf. In fact, L-778,123 is more effective in inhibiting primary lung progression in mice with a p53 mutation and/or an Ink4a/Arf deletion than in wild-type animals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Barrington RE, Subler MA, Rands E, Omer CA, Miller PJ, Hundley JE, Koester SK, Troyer DA, Bearss DJ, Conner MW, Gibbs JB, Hamilton K, Koblan KS, Mosser SD, O'Neill TJ, Schaber MD, Senderak ET, Windle JJ, Oliff A and Kohl NE . (1998). Mol Cell. Biol., 18, 85–92.

  • Brassard DL, English JM, Malkowski M, Kirschmeier P, Nagabhushan TL and Bishop WR . (2002). Exp. Cell. Res., 15, 138–146.

  • Bos JL . (1989). Cancer Res., 49, 4682–4689.

  • Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW and Vogelstein B . (1999). J. Clin. Invest., 104, 263–269.

  • Casey PJ, Solski PA, Der CJ and Buss JE . (1989). Proc. Natl. Acad. Sci. USA, 86, 8323–8327.

  • Chiba I, Takahashi T, Nau MM, D'Amico D, Curiel DT, Mitsudomi T, Buchhagen DL, Carbone D, Piantadosi S and Koga H . (1990). Oncogene, 5, 1603–1610.

  • Crespo NC, Delarue F, Ohkanda J, Carrico D, Hamilton AD and Sebti SM . (2002). Cell Death Differ., 9, 702–709.

  • Du W, Lebowitz PF and Prendergast GC . (1999). Mol. Cell. Biol., 19, 1831–1840.

  • Gibbs JB, Pompliano DL, Mosser SD, Rands E, Lingham RB, Singh SB, Scolnick EM, Kohl NE and Oliff A . (1993). J. Biol. Chem., 268, 7617–7620.

  • Gu WZ, Tahir SK, Wang YC, Zhang HC, Cherian SP, O'Connor S, Leal JA, Rosenberg SH and Ng SC . (1999). Eur. J. Cancer, 35, 1394–1401.

  • Hancock JF, Magee AI, Childs JE and Marshall CJ . (1989). Cell, 57, 1167–1177.

  • Herzog CR, Lubet RA and You M . (1997). J. Cell Biochem., 28/29S, 49–63.

  • Herzog CR, Soloff EV, McDoniels AL, Tyson FL, Malkinson AM, Haugen-Strano A, Wiseman RW, Anderson MW and You M . (1996). Oncogene, 13, 1885–1891.

  • Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM and Cheng JQ . (2000). Mol. Cell. Biol., 20, 139–148.

  • Khosravi-Far R and Der CJ . (1994). Cancer Metastasis Rev., 13, 67–89.

  • Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP, Graham SL and Hamilton K et al. (1995). Nature Med., 1, 792–797.

  • Landis SH, Murray T, Bolden S and Wingo PA . (1998). CA Cancer J. Clin., 48, 6–29.

  • Lantry LE, Zhang Z, Crist KA, Wang Y, Hara M, Zeeck A, Lubet RA and You M . (2000a). Exp. Lung Res., 26, 773–790.

  • Lantry LE, Zhang Z, Yao R, Crist KA, Wang Y, Ohkanda J, Hamilton AD, Sebti SM, Lubet RA and You M . (2000b). Carcinogenesis, 21, 113–116.

  • Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J, Cox AD, Der CJ, Hamilton AD and Sebti SM . (1995a). J. Biol. Chem., 270, 26802–26806.

  • Lerner EC, Qian Y, Hamilton AD and Sebti SM . (1995b). J. Biol. Chem., 10, 26770–26773.

  • Lubet RA, Zhang Z, Wiseman RW and You M . (2000). Exp. Lung Res., 26, 581–593.

  • Mangues R, Corral T, Kohl NE, Symmans WF, Lu S, Malumbres M, Gibbs JB, Oliff A and Pellicer A . (1998). Cancer Res., 58, 1253–1259.

  • Markel P, Shu P, Ebeling C, Carlson GA, Nagle DL, Smutko JS and Moore KJ . (1997). Nat. Genet., 17, 280–284.

  • McDoniels-Silvers AL, Herzog CR, Tyson FL, Malkinson AM and You M . (2001). Exp. Lung Res., 27, 297–318.

  • Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB and Sidransky D . (1995). Nat. Med., 1, 686–692.

  • Minna JD, Pass H, Glatstein E and Ihde DC . (1989). Cancer Principles and Practice of Oncology. J.B. Lippiencott: Pjiladelphia, pp. 591–687.

    Google Scholar 

  • Nagasu T, Yoshimatsu K, Rowell C, Lewis MD and Garcia AM . (1995). Cancer Res., 55, 5310–5314.

  • Omer CA, Chen Z, Diehl RE, Conner MW, Chen HY, Trumbauer ME, Gopal-Truter S, Seeburger G, Bhimnathwala H, Abrams MT, Davide JP, Ellis MS, Gibbs JB, Greenberg I, Koblan KS, Kral AM, Liu D, Lobell RB, Miller PJ, Mosser SD, O'Neill TJ, Rands E, Schaber MD, Senderak ET, Oliff A and Kohl NE . (2000). Cancer Res, 60, 2680–2688.

  • Prendergast GC and Oliff A . (2000). Semin. Cancer Biol., 10, 443–452.

  • Reuter CW, Morgan MA and Bergmann L . (2000). Blood, 96, 1655–1669.

  • Rodenhuis S and Slebos RJC . (1992). Cancer Res., 52, 2665s–2669s.

  • Sebti SM and Hamilton AD . (2000). Expert Opin Investig Drugs, 9, 2767–2782.

  • Sellers TA, Potter JD, Bailey-Wilson JE, Rich SS, Rothschild H and Elston RC . (1992). Cancer Res., 52 (9 Suppl), 2694s–2697s.

  • Sun J, Qian Y, Hamilton AD and Sebti SM . (1995). Cancer Res., 55, 4243–4243.

  • Sun J, Qian Y, Hamilton AD and Sebti SM . (1998). Oncogene, 16, 1467–1473.

  • Tamanoi F . (1993). Trends Biochem. Sci., 18, 349–353.

  • Xu HJ, Hu SX, Cagle PT, Moore GE and Benedict WF . (1991). Cancer Res., 51, 2735–2739.

  • You M, Candrian U, Maronpot RR, Stoner GD and Anderson MW . (1989). Proc. Natl. Acad. Sci., 86, 3070–3074.

  • Zhang Z, Liu Q, Lantry LE, Wang Y, Kelloff GJ, Anderson MW, Wiseman RW, Lubet RA and You M . (2000). Cancer Res., 60, 901–907.

  • Zhang Z, Li J, Lantry LE, Wang Y, Wiseman RW, Lubet RA and You M . (2002a). Cancer Res., 62, 3024–3029.

  • Zhang Z, Wang Y, Herzog CR, Liu G, Lee HW, DePinho RA and You M . (2002b). Oncogene, 29, 5960–5966.

Download references

Acknowledgements

We are grateful to Dr Roger W Wiseman for providing the original UL53-3 mice and Dr Ronald A DePinho for the original Ink4a/Arf−/− mice and to Merck and Co., Inc. for supplying L-778,123. We acknowledge Dr William J Lemon and Sandya Liyanarachchi for statistical assistance. This work is supported by National Institutes of Health; Grants R01CA58554 and R01CA78797.

Author information

Author notes

  1. Zhongqiu Zhang and Yian Wang: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Surgery and The Alvin J. Siteman Cancer Center, Campus Box 8109, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA

    Zhongqiu Zhang, Yian Wang, Elizabeth Kastens & Ming You

  2. Department of Pathology, Medical College of Ohio, 43614, OH, USA

    Laura E Lantry & Gongjie Liu

  3. Department of Chemistry, Yale University, New Haven, Connecticut, USA

    Andrew D Hamilton

  4. Department of Oncology, Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA

    Said M Sebti

  5. Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, 20892, MD, USA

    Ronald A Lubet

Authors
  1. Zhongqiu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura E Lantry
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elizabeth Kastens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gongjie Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew D Hamilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Said M Sebti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ronald A Lubet
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ming You
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming You.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Z., Wang, Y., Lantry, L. et al. Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. Oncogene 22, 6257–6265 (2003). https://doi.org/10.1038/sj.onc.1206630

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206630

Keywords

This article is cited by

Search

Advanced search

Quick links