Article

Refining targeted therapies in chronic myeloid leukemia: development and application of nilotinib, a step beyond imatinib.

Department of Cellular Biotechnology and Hematology, "Sapienza" University of Rome, Italy.
OncoTargets and Therapy (Impact Factor: 2.07). 01/2008; 1:49-58.
Source: PubMed

ABSTRACT The BCR-ABL kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia (CML). Despite the remarkable results achieved with imatinib for the treatment of CML, the emergence of resistance to this drug has become a significant problem. Mutations within the ABL kinase domain have been identified as the main mechanism of resistance to imatinib. Other mechanisms include genomic amplification of BCR-ABL and modulation of drug efflux or influx transporters. Several strategies have been developed to overcome the problem of imatinib resistance, including dose escalation of imatinib, combination treatments, or novel targeted agents. Nilotinib is a tyrosine kinase inhibitor 30-fold more potent than imatinib, active against a wide range of mutant clones, except T315I. Phase I-II trials of nilotinib showed high activity in imatinib-resistant CML and Ph+ acute lymphoblastic leukemia. We here review the development of nilotinib and the activity of this agent in CML patients and in other forms of sensitive neoplasms.

1 Bookmark
 · 
44 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The presence of acquired multidrug resistance (MDR) is one of the primary impediments to the success of chemotherapy. MDR is often a result of overexpression of ATP-binding cassette (ABC) transporters, which are involved in the extrusion of therapeutic drugs. Recently, it was shown that several ABC transporters could be modulated by specific tyrosine-kinase inhibitors (TKIs). Ponatinib, a multi-targeted TKI, inhibits the activity of BCR-ABL with very high potency and broad specificity, including the T315I mutation which confers resistance to other TKIs. It was reported that ponatinib was capable of reversing breast cancer resistance protein (BCRP)- and P-glycoprotein (P-gp)-mediated MDR. In the present study, we report for the first time that ponatinib also potentiates the cytotoxicity of widely used therapeutic substrates of MRP7, such as paclitaxel, docetaxel, vincristine and vinblastine. Ponatinib significantly enhances the accumulation of [3H]-paclitaxel in cells expressing MRP7. Furthermore, accumulation of [3H]-paclitaxel was achieved by inhibition of MRP7-mediated transport. Ponatinb limited drug export via MRP7 by multiple mechanisms. In addition to inhibition of pump function, ponatinib also downregulated MRP7 protein expression in a time- and concentration-dependent manner. Thus, ponatinib may represent a potential reversal agent for the treatment of MDR and may be useful for combination therapy in MDR cancer patients in clinical practice.
    Oncology Reports 01/2014; · 2.30 Impact Factor

Full-text (2 Sources)

View
15 Downloads
Available from
May 31, 2014