Deininger M, Buchdunger E, Druker BJ.. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105: 2640-2653

Oregon Health & Science University Cancer Institute, 3181 SW Sam Jackson Park Rd, Mailcode L592, Portland, OR 97239, USA.
Blood (Impact Factor: 10.45). 05/2005; 105(7):2640-53. DOI: 10.1182/blood-2004-08-3097
Source: PubMed


Imatinib has revolutionized drug therapy of chronic myeloid leukemia (CML). Preclinical studies were promising but the results of clinical trials by far exceeded expectations. Responses in chronic phase are unprecedented, with rates of complete cytogenetic response (CCR) of more than 40% in patients after failure of interferon-alpha (IFN) and more than 80% in newly diagnosed patients, a level of efficacy that led to regulatory approval in record time. While most of these responses are stable, resistance to treatment after an initial response is common in more advanced phases of the disease. Mutations in the kinase domain (KD) of BCR-ABL that impair imatinib binding have been identified as the leading cause of resistance. Patients with CCR who achieve a profound reduction of BCR-ABL mRNA have a very low risk of disease progression. However, residual disease usually remains detectable with reverse transcription-polymerase chain reaction (RT-PCR), indicating that disease eradication may pose a significant challenge. The mechanisms underlying the persistence of minimal residual disease are unknown. In this manuscript, we review the preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia.

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    • "Imatinib, a tyrosine kinase inhibitor specific to BCR-ABL also targets many off target kinases [8] [9] like v-Abl, c-Abl [10] [11], Tel-Abl [12], PDGFR-a, PDGFR-p, Tel-PDGFR [11] [13], c-Kit [1] [13], ARG [14], c-fms [15]. It becomes important to "

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    • "Tyrosine kinase (TK) inhibitors such as Imatinib, dasatinib, nilotinib, bosutinib etc, have been developed to decrease the amount of BCR-ABL transcripts or to inhibit tyrosine kinase activity. Among them Imatinib is widely used as the first line therapy, functions by preventing the binding of ATP to the activated tyrosine kinase and permit the differentiation of leukemic cells and undergoing apoptosis (Deininger et al, 2005). Despite the availability of targeted TK inhibitor therapy, leukemic cells develops resistance to imatinib has been a major disadvantage especially in the treatment of advanced stage CML (Talpaz et al, 2006). "
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    ABSTRACT: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm of the hematopoietic system, characterized by the presence of the BCR-ABL oncoprotein due to the chromosomal translocation t (9;22). This oncoprotein has elevated tyrosine kinase activity, which leads to enhanced proliferation, reduced differentiation and apoptosis, increased angiogenesis etc. Even though several targeted tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib etc. are being employed in treating CML, a proportion of patients (25-30%) exhibit resistance to TKIs leading to treatment failure and unchecked disease progression. Progression of CML may be due to genetic instability which include chromosomal translocations, mutations, polymorphisms and gene amplification which ultimately causes up and down regulation of genes in various pathways including angiogenesis. Increased angiogenesis is associated with CML due to the up regulation of various angiogenic factors and their transcriptional regulators, which in turn has been found to lead to disease progression to advanced phases, as the protein products of these genes may act synergistically with BCR-ABL oncoprotein in advancing the disease. Single nucleotide polymorphisms (SNPs) are one of the causes for up regulation of antigenic genes and are associated with susceptibility and progression of CML by affecting therapeutic outcome. This review focuses mainly on the role of upregulated pro-angiogenic factors-VEGF, IL-8 and their transcriptional regulators HIF1α, NF-kB and also the role of SNPs in these genes in disease susceptibility, progression, drug response, prognosis and survival in CML patients. Identification of SNPs and up regulated genes of angiogenesis may serve as biomarkers for predicting disease progression, drug response, prognosis etc. Anti-angiogenic therapy is aimed at targeting the new blood vessels that supply nutrients to rapidly growing tumor cells. Combinations of targeted therapy and anti-angiogenic therapy may serve as the novel therapeutic strategies in overcoming drug resistance and thereby preventing the disease progression in CML.
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    • "Imatinib, a tyrosine kinase inhibitor specific to BCR-ABL also targets many off target kinases [8] [9] like v-Abl, c-Abl [10] [11], Tel-Abl [12], PDGFR-a, PDGFR-p, Tel-PDGFR [11] [13], c-Kit [1] [13], ARG [14], c-fms [15]. It becomes important to "

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