Advances in the investigation of the molecular biology of cancer over several decades have made it possible to rationally design drugs to target oncogenic events with unprecedented specificity¹

Glivec® was the first tyrosine-kinase inhibitor available for clinical use and is thus the most established molecularly targeted agent of its class. It differs from interferon-alfa (IFN-α) and chemotherapeutic agents in having a specifically targeted mechanism of action and in exerting its effects on a particular abnormal protein within the leukemic cell, the Bcr-Abl tyrosine kinase.

CML was a good candidate disease for the rational design of a therapeutic drug aimed at a molecular pathogenetic target. The hallmark of CML, the Ph chromosome, contains the specific causative genetic abnormality that results in constitutive activation of the Bcr-Abl tyrosine kinase.

Glivec targets the molecular cause of CML to produce an effective and generally well-tolerated oral therapy. By inhibiting only the specific cause of the disease, Glivec brought to fruition the promise of molecularly targeted therapy.

Work in the field of targeted therapies in CML continues with the development of the next generation of signal transduction inhibitors, including dasatinib, which was approved in 2006, and nilotinib, known as Tasigna, which was developed by the makers of Glivec and is now approved in over 50 countries.

Tasigna represents an important therapeutic option for patients who become resistant or intolerant to Glivec. Tasigna is a highly specific and potent inhibitor of Bcr-Abl that was scientifically designed to bind more effectively than Glivec to Bcr-Abl². In fact, Tasigna is up to 20-50 times more potent than Glivec³.

• Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell. 2002;1:31-36.
• Manley PW, Cowan-Jacob SW, Mestan J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochimica et Biophysica Acta.
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• National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Chronic myelogenous leukemia. V.2.2009. http://www.nccn.org. Accessed June 9, 2009.

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