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 Manuscript
  • Published:

Experimental Therapeutics: STI571

Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells

Abstract

The ABL-specific tyrosine kinase inhibitor STI571 (formerly CGP57148B) induced cytogenetic remissions in 33% of chronic myelogenous leukemia (CML) patients in a phase I trial (Druker et al 1999). Combination therapy may increase this proportion. We tested whether combinations of STI571 and cytarabine or other chemotherapeutic agents such as hydroxyurea, mafosfamide or etoposide would display synergistic activity in BCR-ABL-positive chronic myelogenous leukemia (CML) cell lines derived from patients in blast crisis. In addition, the toxicity of these combinations on BCR-ABL-negative cells was investigated. A tetrazolium-based MTT assay was used to quantify growth inhibition after 48 h of exposure to cytotoxic agents alone and in simultaneous combination with STI571. The drug interactions were analyzed using the median-effect method of Chou and Talalay. The combination index (CI) was calculated according to the classic isobologram equation. At growth inhibition levels of over 50%, STI571 + cytarabine as well as STI571 + etoposide were significantly synergistic (CI < 1, P < 0.05) in the BCR-ABL-positive cell lines evaluated. At 60% inhibition or higher, a similar synergistic pattern became apparent for STI571 + mafosfamide (P < 0.05), while STI571 + hydroxyurea showed ambiguous, cell line-dependent synergism (BV173), additivity (EM-3) or antagonism (K562) in CML cell lines. Furthermore, the BCR-ABL-negative HL-60, KG1A and normal CD34+ progenitor cells were not affected by 0.8 μM STI571, a concentration which produced more than 50% growth inhibition in all BCR-ABL-positive cells tested, and no potentiation of growth inhibition was observed in these BCR-ABL-negative cells when STI571 was combined with chemotherapeutic agents. Our in vitro data with CML blast crisis cell lines strongly suggest that combinations of STI571 with cytarabine or etoposide be rapidly considered for clinical testing.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

  1. Sawyers CL . Chronic myeloid leukemia N Engl J Med 1999 340: 1330–1340

    Article  CAS  PubMed  Google Scholar 

  2. Druker BJ, Talpaz M, Resta D, Peng B, Buchdunger E, Ford J, Sawyers CL . Clinical efficacy and safety of an Abl-specific tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia Blood 1999 94: (Suppl. 1) 368a

    Google Scholar 

  3. Kasper B, Fruehauf S, Schiedlmeier B, Buchdunger E, Ho AD, Zeller WJ . Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors Cancer Chemother Pharmacol 1999 44: 433–438

    Article  CAS  PubMed  Google Scholar 

  4. Schiedlmeier B, Kühlcke K, Eckert HG, Baum C, Zeller WJ, Fruehauf S . Quantitative assessment of retroviral transfer of the human multidrug resistance 1 gene to human mobilized peripheral blood progenitor cells engrafted in nonobese diabetic/severe combined immunodeficient mice Blood 2000 95: 1237–1248

    CAS  PubMed  Google Scholar 

  5. Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, Tura S . An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology Blood 1999 94: 1517–1536

    CAS  PubMed  Google Scholar 

  6. Carlo-Stella C, Mangoni L, Almici C, Caramatti C, Cottafavi L, Dotti GP, Rizzoli V . Autologous transplant for chronic myelogenous leukemia using marrow treated ex vivo with mafosfamide Bone Marrow Transplant 1994 14: 425–432

    CAS  PubMed  Google Scholar 

  7. Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay J Immunol Meth 1983 65: 55–63

    Article  CAS  Google Scholar 

  8. Finlay GJ, Wilson WR, Baguley BC . Comparison of in vitro activity of cytotoxic drugs towards human carcinoma and leukemia cell lines Eur J Cancer Clin Oncol 1986 22: 655–662

    Article  CAS  PubMed  Google Scholar 

  9. Pieters B, Huismans DR, Leyva A, Veerman AJP . Adaptation of the rapid automated tetrazolium dye based (MTT) assay for chemosensitivity testing in childhood leukemia Cancer Letters 1988 41: 323–332

    Article  CAS  PubMed  Google Scholar 

  10. Chou TC, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors Adv Enzyme Regul 1984 22: 27–55

    Article  CAS  PubMed  Google Scholar 

  11. Nowell PC, Hungerford DA . A minute chromosome in chronic granulocytic leukemia Science 1960 132: 1497–1501

    Google Scholar 

  12. Rowley JD . A new consistant chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine, fluorescence and Giemsa staining Nature 1973 243: 290–293

    Article  CAS  PubMed  Google Scholar 

  13. Konopka JB, Watanabe SM, Witte ON . An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity Cell 1984 37: 1035–1042

    Article  CAS  PubMed  Google Scholar 

  14. Sawyers CL, Denny CT, Witte ON . Leukemia and the disruption of normal hematopoiesis Cell 1991 64: 337–350

    Article  CAS  PubMed  Google Scholar 

  15. Warmuth M, Danhauser-Riedl S, Hallek M . Molecular pathogenesis of chronic myeloid leukemia: implications for new therapeutic strategies Ann Hematol 1999 78: 49–64

    Article  CAS  PubMed  Google Scholar 

  16. McGahon A, Bissonette R, Schmitt M, Cotter KM, Green DR, Cotter TG . BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death Blood 1994 83: 1179–1187

    CAS  PubMed  Google Scholar 

  17. Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS, Akhtar AJ, Hilton J, Jones RJ . BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents Blood 1995 86: 1148–1158

    CAS  PubMed  Google Scholar 

  18. Nishii K, Kabarowski JH, Gibbons DL, Griffiths SD, Titley I, Wiedemann LM, Greaves MF . ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block Oncogene 1996 13: 2225–2234

    CAS  PubMed  Google Scholar 

  19. McGahon AJ, Nishioka WK, Martin SJ, Mahboubi A, Cotter TG, Green DR . Regulation of the Fas apoptotic cell death pathway by Abl J Biol Chem 1995 270: 22625–22631

    Article  CAS  PubMed  Google Scholar 

  20. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ . Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia Blood 1994 83: 2038–2044

    CAS  PubMed  Google Scholar 

  21. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB . Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of bcr/abl positive cells Nat Med 1996 2: 561–566

    Article  CAS  PubMed  Google Scholar 

  22. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB . Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative Cancer Res 1996 56: 100–104

    CAS  PubMed  Google Scholar 

  23. Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB, Gilliland DG, Druker BJ . CGP57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL and TEL-PDGFR fusion proteins Blood 1997 90: 4947–4952

    CAS  PubMed  Google Scholar 

  24. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB . Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors J Pharmacol Exp Ther 2000 295: 139–145

    CAS  PubMed  Google Scholar 

  25. Gambacorti-Passerini C, le Coutre P, Mologni L, Fanelli M, Bertazzoli C, Marchesi E, Di Nicola M, Biondi A, Corneo GM, Belotti D, Pogliani E, Lydon NB . Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis Blood Cells Mol Dis 1997 23: 380–394

    Article  CAS  PubMed  Google Scholar 

  26. Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL . Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL J Exp Med 2000 191: 977–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C . Induction of resistance to the abelson inhibitor STI571 in human leukemic cells through gene amplification Blood 2000 95: 1758–1766

    CAS  PubMed  Google Scholar 

  28. Mahon FX, Deininger DWN, Schultheis B, Goldman JM, Melo JV . Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the signal transduction inhibitor STI571: mechanisms of resistance Blood 1999 94: (Suppl. 1) 656a

    Google Scholar 

  29. Lin CK, Nguyen TT, Morgan TL, Mei RL, Kaptein JS, Kalunta CI, Yen CF, Park E, Zou HY, Lad PM . Apoptosis may be either suppressed or enhanced with strategic combinations of antineoplastic drugs or anti-IgM Exp Cell Res 1998 244: 1–13

    Article  CAS  PubMed  Google Scholar 

  30. Johnson KR, Young KK, Fan W . Antagonistic interplay between antimitotic and G1-S arresting agents observed in experimental combination therapy Clin Cancer Res 1999 5: 2559–2565

    CAS  PubMed  Google Scholar 

  31. Zeller WJ, Berger M, Schmähl D . Synergistic action of vincristine and adriamycin in the treatment of experimental rat leukemia L5222 Cancer Res 1979 39: 1071–1073

    CAS  PubMed  Google Scholar 

  32. Zeller WJ, Berger MR, Henne T, Weber E . More than additive toxicity of the combination of 1-methyl-1-nitrosourea plus 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat Cancer Res 1986 46: 1714–1716

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciate the continuing support of Prof AD Ho (Department of Internal Medicine V, University of Heidelberg, Germany). We are grateful to S Heil, B Berkus, and HJ Engel for expert technical assistance (German Cancer Research Center, Heidelberg, Germany), to Dr E Buchdunger and B Willi (Novartis Pharma AG, Basel, Switzerland) for supplying STI571 and to Dr J Pohl (ASTA Medica, Frankfurt am Main, Germany) for supplying mafosfamide. This work was supported in part by grant DJCLS-R00/03 of the Deutsche José Carreras Leukämie Stiftung eV.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Topaly, J., Zeller, W. & Fruehauf, S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia 15, 342–347 (2001). https://doi.org/10.1038/sj.leu.2402041

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402041

Keywords

This article is cited by

Search

Quick links