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Synergistic activity of the Src/Abl inhibitor bosutinib in combination with imatinib

Leukemia volume 24, pages 1223–1227 (2010)Cite this article

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Chronic myeloid leukemia (CML) is a hematopoietic disorder caused by a translocation occurring between chromosome 22 and chromosome 9, leading to the formation of the Philadelphia chromosome (Ph) and the BCR-ABL fusion gene. The oncogenic protein tyrosine kinase expressed by this gene fusion, Bcr-Abl, is the underlying cause of CML.

The Abl kinase inhibitor imatinib was registered for clinical use in 2001 and is now the current first-line treatment for CML. Beside the activity against Abl, imatinib can also inhibit platelet-derived growth factor receptor-β and c-Kit, which is believed to contribute to a number of side effects such as edema, muscle cramps, skin rash, pigmentation and low-grade inhibition of normal hemopoiesis. In addition, imatinib is unable to eradicate the leukemic cells and resistance to it can develop, especially in advanced patients, thus leading to short-term remissions.1 Resistant clones carrying point mutations on Bcr-Abl protein sequence can be found in approximately 50% of patients with advanced disease.

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References

  1. Gambacorti-Passerini C, Gunby R, Piazza R, Galietta A, Rostagno R, Scapozza L . Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 2003; 4: 75–85.

    Article  PubMed  Google Scholar 

  2. Puttini M, Coluccia AML, Boschelli F, Cleris L, Marchesi E, Donella-Deana A et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res 2006; 66: 11314–11322.

    Article  CAS  PubMed  Google Scholar 

  3. Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 2009; 27: 469–471.

    Article  CAS  PubMed  Google Scholar 

  4. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia 2009; 23: 477–485.

    Article  CAS  PubMed  Google Scholar 

  5. Chou TC . Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006; 58: 621–681.

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Apperley J . Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1018–1029.

    Article  CAS  PubMed  Google Scholar 

  8. Weisberg E, Catley L, Wright RD, Moreno D, Banerji L, Ray A et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood 2007; 109: 2112–2120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007; 110: 4064–4072.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded by AIRC, EU (LSHB-CT-2004-503467), MIUR-PRIN program (2008), Ministry of health–Integrated program of oncology (RFPS-2006-2-333974).

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Authors and Affiliations

  1. Department of Clinical Medicine and Prevention, University of Milano-Bicocca, S.Gerardo Hospital, Monza, Italy

    S Redaelli, P Perini, A Pirola, M Viltadi & C Gambacorti-Passerini

  2. Center for Integrative Biology and Therapeutics, Pfizer Research, Pearl River, NY, USA. E-mail carlo.gambacorti@unimib.it,

    F Boschelli

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  1. S Redaelli
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Competing interests

Dr Frank Boschelli is employee at Pfizer Research, which is developing bosutinib for treatment of CML. No other conflict of interest to disclose.

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Redaelli, S., Boschelli, F., Perini, P. et al. Synergistic activity of the Src/Abl inhibitor bosutinib in combination with imatinib. Leukemia 24, 1223–1227 (2010). https://doi.org/10.1038/leu.2010.79

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