Article

Tyrosine kinase inhibitors: the first decade.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Current Hematologic Malignancy Reports 04/2010; 5(2):70-80. DOI: 10.1007/s11899-010-0045-y
Source: PubMed

ABSTRACT The treatment of chronic myeloid leukemia (CML) drastically changed with the introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), in 1998. By directly targeting this leukemogenic protein kinase, imatinib affords patients with CML sustained chromosomal remissions, which translate into prolonged survival. However, there has been concern over the emergence of resistance to imatinib, and some patients fail to respond or are intolerant of imatinib therapy because of untoward toxicity. This has spurred interest in developing novel TKIs to overcome the mechanisms of resistance that lead to treatment failure-most importantly, Bcr-Abl1 kinase domain mutations. Two of these second-generation TKIs, nilotinib and dasatinib, are approved worldwide for the treatment of CML after imatinib failure or intolerance. Although these agents are active, they fail in many patients because of the development of highly resistant mutations such as the T315I, against which several novel agents are currently being tested in clinical trials. This review provides an account of the progress made in the field of TKI therapy for CML over the past decade.

0 Bookmarks
 · 
79 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of chronic myeloid leukemia (CML). Even though TKI therapy does not necessarily eliminate all leukemic cells, a small proportion of CML patients is able to discontinue the treatment successfully and be considered cured. Besides inhibiting the actual target BCR-ABL1 kinase in leukemic cells, TKIs inhibit several off-target kinases in normal healthy cells, such as lymphocytes. To date, little is known about the long-term in vivo effects of TKI treatment on the function of the immune system. However, constantly growing evidence suggests that some TKIs have a dual-mode of action; the direct cytotoxic effects induced by oncokinase inhibition are accompanied by the activation of immune system 2 , which is potentially relevant for the long-term control of CML. In this review, we have summarized the reported immunomodulatory effects of the three TKIs, which currently are accepted for first-line use in CML (imatinib, dasatinib and nilotinib). Understanding the mechanisms of TKI-induced functional cure and the role of immune system in this process will hopefully not only benefit CML patients, but also patients with other malignant diseases in the future.
    07/2013;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many new chemotherapeutic agents are under preclinical investigation and, despite efforts to more selectively target cancer cells, limitations such as toxicity and inherent resistance are often encountered. Therefore, alternative strategies are needed to treat cancer and overcome such limitations. We describe novel cyclohexylpiperazine derivatives, designed as mixed affinity ligands for sigma (σ) receptors and human Δ₈-Δ₇ sterol isomerase (HSI) ligands, which also exhibit P-glycoprotein (P-gp) inhibitory activity, with the aim of exploiting the antiproliferative effects mediated by σ and HSI sites while overcoming P-gp-mediated resistance. All of the compounds displayed high affinities for σ receptors and HSI sites, P-gp inhibitory activity, and σ₂ receptor agonist antiproliferative activity. Antiproliferative activity was also tested in PC-3 cells to establish σ₁ and HSI contribution. Compound cis-11, which displayed the best antiproliferative and P-gp inhibitory activities, was co-administered with 0.1 μM doxorubicin in MDCK-MDR1 cells. Compound cis-11 caused 70 % and 90 % cell death when co-administered at 30 μM and 50 μm, respectively. When administered alone, cis-11 resulted in 50 % cell death, demonstrating its single agent antitumor properties in a tumor cell line overexpressing P-gp.
    ChemMedChem 11/2010; 6(1):73-80. · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nilotinib, formally known as AMN107, is a second-generation tyrosine kinase inhibitor, rationally designed from its revolutionary parent compound imatinib, to produce a 30-40-fold enhancement in the inhibition of the BCR-ABL1-derived oncoprotein associated with chronic myeloid leukemia. In clinical trials, nilotinib has proven to be a useful agent in the treatment of imatinib-refractory disease and was initially approved by both the US FDA and EMA in 2007 for use in adults as a second-line therapy. More recently, data from the first randomized controlled trials of the front-line use of nilotinib in newly diagnosed patients with chronic phase chronic myeloid leukemia have demonstrated superiority in the rates of major molecular responses at 12 months over the gold standard-imatinib 400 mg. As such, in June 2010, the FDA granted accelerated approval for its use in newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia. Nilotinib is well tolerated, with a favorable side-effect profile. With the emergence of supportive trial data, it is likely to have a leading role both in the front-line management of newly presenting patients and in the second-line treatment of patients resistant to or intolerant of imatinib and other second-line agents.
    Future Oncology 02/2011; 7(2):201-18. · 3.20 Impact Factor