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.

  • Molecular Targets For Therapy (MTT)
  • Published:

Molecular Targets for Therapy (MTT)

A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl

Leukemia volume 18, pages 23–28 (2004)Cite this article

Abstract

Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity.

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

Relevant articles

Open Access articles citing this article.

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 5
Figure 2
Figure 3
Figure 4

References

  1. Heisterkamp N, Groffen J . BCR/ABL gene structure and BCR function. In: Carella AM, Daley GQ, Eaves CJ, Goldman JM, Hehlman R (eds) Chronic Myeloid Leukemia: Biology and Treatment. London, UK: Martin Dunitz, 2001, pp 3–17.

    Google Scholar 

  2. Smith JM, Mayer BJ . Abl: mechanisms of regulation and activation. Front Biosci 2002; 7: d31–d42.

    Article  CAS  Google Scholar 

  3. Shet AS, Jahagirdar BN, Verfaillie CM . Chronic myelogenous leukemia: mechanisms underlying disease progression. Leukemia 2002; 16: 1402–1411.

    Article  CAS  Google Scholar 

  4. Faderl S, Garcia-Manero G, Thomas DA, Kantarjian HM . Philadelphia chromosome-positive acute lymphoblastic leukemia – current concepts and future perspectives. Rev Clin Exp Hematol 2002; 6: 142–160.

    Article  CAS  Google Scholar 

  5. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002; 100: 1965–1971.

    Article  CAS  Google Scholar 

  6. Campbell LJ, Patsouris C, Rayeroux KC, Somana K, Januszewicz EH, Szer J . BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. Cancer Genet Cytogenet 2002; 139: 30–33.

    Article  CAS  Google Scholar 

  7. le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000; 95: 1758–1766.

    CAS  PubMed  Google Scholar 

  8. Druker BJ . Imatinib and chronic myeloid leukemia: validating the promise of molecularly targeted therapy. Eur J Cancer 2002; 38: S70–S76.

    Article  Google Scholar 

  9. Schiffer CA, Hehlmann R, Larson R . Perspectives on the treatment of chronic phase and advanced phase CML and Philadelphia chromosome positive ALL. Leukemia 2003; 17: 691–699.

    Article  CAS  Google Scholar 

  10. Cox AD . Farnesyltransferase inhibitors: potential role in the treatment of cancer. Drugs 2001; 61: 723–732.

    Article  CAS  Google Scholar 

  11. Kelland LR . Farnesyltransferase inhibitors in the treatment of breast cancer. Expert Opin Investig Drugs 2003; 12: 413–421.

    Article  CAS  Google Scholar 

  12. Cortes JE, Kurzrock R, Kantarjian HM . Farnesyltransferase inhibitors: novel compounds in the development for the treatment of myeloid malignancies. Semin Hematol 2003; 39: 26–30.

    Article  Google Scholar 

  13. Le DT, Shannon KM . Ras processing as a therapeutic target in hematologic malignancies. Curr Poin Hematol 2002; 9: 308–315.

    Article  Google Scholar 

  14. Haluska P, Dy GK, Adjei AA . Farnesyltransferase inhibitors as anticancer agents. Eur J Cancer 2002; 38: 1685–1700.

    Article  CAS  Google Scholar 

  15. Choy E, Chiu VK, Silletti J, Feoktistov M, Morimoto T, Michaelson D et al. Endomembrane trafficking of Ras: the CAAX motive targets proteins to the ER and Golgi. Cell 1999; 98: 69–80.

    Article  CAS  Google Scholar 

  16. Du W, Lebowitz PF, Prendergast GC . Cell growth inhibition by farnesyltransferase inhibitor is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 1999; 19: 1831–1840.

    Article  CAS  Google Scholar 

  17. Norgaard P, Law B, Joseph H, Page DL, Shyr Y, Mays D et al. Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis. Clin Cancer Res 1999; 5: 35–42.

    CAS  PubMed  Google Scholar 

  18. Barrington RE, Subler MA, Rands E, Omer CA, Miller PJ, Hundley JE et al. A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis. Mol Cell Biol 1998; 18: 85–92.

    Article  CAS  Google Scholar 

  19. Crespo NC, Ohkanda J, Yen TJ, Hamilton AD, Sebti SM . The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J Biol Chem 2001; 276: 16161–16167.

    Article  CAS  Google Scholar 

  20. Prendergast GC, Oliff A . Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action and clinical properties. Semin Cancer Biol 2000; 10: 443–452.

    Article  CAS  Google Scholar 

  21. Falugi C, Trombino S, Granone P, Margaritora S, Russo P . Increasing complexity of farnesyltransferase inhibitors activity: role in chromosome instability. Curr Cancer Drug Targets 2003; 3: 109–118.

    Article  CAS  Google Scholar 

  22. Cox AD, Der CJ . Ras family signaling. Cancer Biol Ther 2002; 1: 599–600.

    Article  CAS  Google Scholar 

  23. Reichert A, Heisterkamp N, Daley GQ, Groffen J . Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyltransferase inhibitor SCH66336. Blood 2001; 97: 1399–1403.

    Article  CAS  Google Scholar 

  24. Peters DG, Hoover RR, Gerlach MJ, Koh EY, Zhang H, Choe K et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood 2001; 97: 1404–1412.

    Article  CAS  Google Scholar 

  25. Voncken J-W, Griffiths S, Greaves MF, Pattengale PK, Heisterkamp N, Groffen J . Restricted oncogenicity of BCR/ABL P190 in transgenic mice. Cancer Res 1992; 52: 4534–4539.

    CAS  PubMed  Google Scholar 

  26. Adjei AA, Erlichman C, Davis JN, Cutler DL, Sloan JA, Marks RS et al. A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res 2000; 60: 1871–1877.

    CAS  PubMed  Google Scholar 

  27. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P et al. Antitumor activity of SCH66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and Wap-ras transgenic mice. Cancer Res 1998; 58: 4946–4947.

    Google Scholar 

  28. le Coutre P, Mologni L, Cleris L, Marchesi E, Buchdunger E, Giardini R et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1999; 91: 163–168.

    Article  CAS  Google Scholar 

  29. Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci USA 2002; 99: 7622–7627.

    Article  CAS  Google Scholar 

  30. Wolff NC, Ilaria Jr RL . Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571. Blood 2001; 98: 2808–2816.

    Article  CAS  Google Scholar 

  31. Adjei AA, Davis JN, Erlichman C, Svingen PA, Kaufmann SH . Comparison of potential markers of farnesyltransferase inhibition. Clin Cancer Res 2000; 6: 2318–2325.

    CAS  PubMed  Google Scholar 

  32. Karp JE, Lancet JE, Kaufmann SH, End DW, Wright JJ, Bol K et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 2001; 97: 3361–3369.

    Article  CAS  Google Scholar 

  33. Schmitt CA, Rosenthal CT, Lowe SW . Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med 2000; 6: 1029–1035.

    Article  CAS  Google Scholar 

  34. Voncken JW, Morris C, Pattengale P, Dennert G, Kikly C, Groffen J et al. Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice. Blood 1992; 79: 1029–1036.

    CAS  PubMed  Google Scholar 

  35. Smith V, Rowlands MG, Barrie E, Workman P, Kelland LR . Establishment and characterization of acquired resistance to the farnesyl protein transferease inhibitor R115777 in a human colon cancer cell line. Clin Cancer Res 2002; 8: 2002–2009.

    CAS  PubMed  Google Scholar 

  36. Hofmann W-K, Komor M, Wassmann B, Jones LC, Gschaidmeier H, Hoelzer D et al. Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood 2003; 102: 659–661.

    Article  CAS  Google Scholar 

  37. Hoover RR, Mahon F-X, Melo JV, Daley GQ . Overcoming STI571 resistance with the farnesyltransferase inhibitor SCH66336. Blood 2002; 100: 1068–1071.

    Article  CAS  Google Scholar 

  38. Nakajima A, Tauchi T, Sumi M, Bishop WR, Ohyashiki K . Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with Imatinib against BCR-ABL-positive cells. Mol Cancer Ther 2003; 2: 219–224.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Bianca Hemmeryckx for help in establishing culture conditions for PLC1 and for help with the figures and Jan Willem Voncken for establishing growth of the S2-3 cells. This study was supported by the Kenneth T and Eileen L Norris Foundation (SM, BZ, and JG) and PHS NIH grants CA50248 and CA90321 (NH).

Author information

Author notes

  1. S Mishra and B Zhang: These authors should be considered equal first authors

Authors and Affiliations

  1. Division of Hematology/Oncology, Section of Molecular Carcinogenesis, Childrens Hospital of Los Angeles Research Institute, Los Angeles, CA, USA

    S Mishra, B Zhang, J Groffen & N Heisterkamp

Authors
  1. S Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Groffen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Heisterkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N Heisterkamp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mishra, S., Zhang, B., Groffen, J. et al. A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl. Leukemia 18, 23–28 (2004). https://doi.org/10.1038/sj.leu.2403203

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403203

Keywords

This article is cited by

Search

Advanced search

Quick links