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Molecular Targeted Therapy: Glivec® and CML Treatment
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 specificity12. One such drug, Glivec® (imatinib), has rapidly become the preferred pharmacotherapeutic option for chronic myeloid leukaemia (CML) treatment in all stages35, 63. Glivec is the first protein-tyrosine kinase inhibitor to reach the clinic and is thus the most established molecular targeted therapy agent of its class. It differs from interferon alfa (IFN-α) and chemotherapeutic agents in having a well-characterised mechanism of action and in exerting its effects on a particular abnormal protein within the leukaemic cell. In clinical trials, Glivec demonstrated efficacy in CML treatment superior to that achieved with previous systemic therapies, and it has been well tolerated by patients in all studies. The following section discusses Glivec in detail.
Chronic myeloid leukaemia is an eminent candidate disease for the rational design of a therapeutic drug aimed at a molecular pathogenetic target. The hallmark of CML, the Philadelphia (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 and is an effective and well-tolerated oral therapy. By inhibiting only the specific cause of the disease, Glivec brings to fruition the promise of molecular targeted therapy.
Glivec: The Paradigm of Molecular Targeted Therapy
Indication
For Philadelphia chromosome-positive (Ph+) CML treatment, Glivec is indicated for use in:
- Patients with newly diagnosed Ph+ CML for whom bone marrow transplantation is not considered as the first line of treatment
- Patients with Ph+ CML in chronic phase after failure of IFN-α therapy, or in accelerated phase or blast crisis4
The recommended starting doses for adult patients in whom Glivec therapy is indicated are 400 mg/d for chronic-phase CML treatment and 600 mg/d for accelerated-phase or blast-crisis disease. The recommended starting dosages for children with CML in whom Glivec targeted therapy is indicated are 260 mg/m2/d for chronic-phase CML and 340 mg/m2/d for accelerated-phase or blast-crisis disease. Please refer to local prescribing information for specific indications.
Mechanism of Action and Cellular Selectivity
Glivec is a member of the 2-phenylaminopyrimidine class of small molecules that has high affinity and selectivity for ABL (Figure 1)64, 66-68. Protein kinases, including ABL, contain within their catalytical domain a nucleotide-binding pocket and an activation loop, which controls activity. While the nucleotide-binding pocket among kinases is highly conserved, the molecular shapes of the activation loop in inactive kinases are diverse69, 70. Glivec, which binds to the ABL nucleotide-binding pocket, recognises and stabilises a distinctive inactive conformation of the activation loop of ABL and precludes ATP binding (Figure 2). Glivec prevents BCR-ABL from phosphorylating tyrosine residues of substrate proteins, thereby interrupting BCR-ABL signal transduction pathways that lead to leukaemic transformation. Although Glivec also inhibits wild-type ABL, it does not affect normal signal transduction pathways, presumably because of redundant signalling. No clinical evidence of inhibition of normal processes has been observed with Glivec therapy.
Figure 1 : Nucleotide-binding pocket
Click on the image to enlarge
Figure 2 : Glivec binding explainedIn addition to inhibiting ABL and BCR-ABL at concentrations in the micromolar range in vitro68, Glivec has also been shown to inhibit members of the class 3 family of receptor protein-tyrosine kinases: platelet-derived growth factor receptor-alpha (PDGFRα); PDGFRβ; KIT, the receptor for stem-cell factor or steel factor; and macrophage colony-stimulating factor receptor c-Fms4, 64, 68, 71-73. ARG, another cytoplasmic protein-tyrosine kinase structurally related to ABL, is also inhibited by Glivec (Table 1)74.
| Table 1. Glivec Selectively Inhibits Tyrosine Kinases in Addition to BCR-ABL and KIT | |||||||||||||||||||||||||||||||||
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Find out about efficacy, dosage, and safety in Prescribing Glivec.
