Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The introduction of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec; Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most patients with CML receiving imatinib still harbour molecular residual disease and some develop resistance associated with ABL kinase domain mutations. The second-generation BCR-ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol-Myers Squibb) have shown significant activity after imatinib failure in clinical trials, but still face similar obstacles to imatinib, including negligible activity against the frequent BCR-ABL T315I mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts, in part aided by structural studies of the ABL kinase-imatinib complex have resulted in the synthesis of a new generation of BCR-ABL inhibitors, some of which have shown encouraging preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML.
...
PMID:Flying under the radar: the new wave of BCR-ABL inhibitors. 1785 1

Autografting was first attempted for patients with chronic myeloid leukemia (CML) in transformation in order to restore a second chronic phase (CP). The principal rationale for autografting in CP resides on the reduction of the tumor burden and the number of leukemic cells at risk of developing blastic transformation, and the possibility of eradicating already mutated cells. In a European Group for Blood and Marrow Transplantation (EBMT) Registry survey, patients with CML in CP, undergoing autologous stem cell transplantation (auto-SCT) for the first time, had an overall survival of 65% at 5 years from transplant with more than 50% of all patients remaining in CP. The main point made by this retrospective study was that in patients refractory to interferon-alpha (IFN), 70% achieved a cytogenetic response post autografting, which was complete or major in 31%. Since the advent of imatinib, autografting in CML has experienced a substantial decline. Theoretically, there are several possible ways of using auto-SCT in combination with imatinib: (1) to reverse resistance to imatinib; (2) to eliminate a Ph-positive clone bearing a BCR-ABL kinase domain mutation; and (3) to reduce the level of residual disease after a cytogenetic response to imatinib in patients in whom Ph-negative cells had been harvested. The exact role of auto-SCT in the present management of CML remains unanswered.
...
PMID:Autologous stem cell transplantation in chronic myeloid leukemia. 1796 24

The introduction of selective tyrosine-kinase inhibitors (TKIs) for the treatment of chronic myeloid leukaemia has changed patient outcome and, consequently, management of this disease. Imatinib is now the treatment of choice for most newly diagnosed patients. Excellent responses, in terms of symptom control and haematological parameters, are usually obtained. However, failure to completely eradicate leukaemic cells and the escape of these cells from previous control has led to an intensive search for the mechanisms of resistance and subsequent treatments by which to overcome this resistance. Up to now, there has been considerable focus on the role of ABL-kinase-domain mutations as mediators of resistance to imatinib, thereby encouraging the development of a second generation of TKIs capable of inhibiting these mutant proteins. However, studies have increasingly shown that these mutations do not account for all cases of resistance and have a negligible role in the inability of TKIs to eradicate residual disease in patients who are good responders. More recently, attention has turned to the relative roles of drug bioavailability and drug efflux and drug influx proteins in the development of resistance to imatinib. This review is the first of two papers and discusses imatinib resistance and its potential causes. The second paper will focus on the assessment and subsequent management of patients with less than optimum responses to imatinib.
...
PMID:Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. 1797 12

The majority of patients with chronic-phase (CP) chronic myeloid leukemia (CML) who are treated with Bcr-Abl tyrosine kinase inhibitors such as imatinib and dasatinib achieve cytogenetic disease remission (ie, Philadelphia chromosome-positive cells undetectable by cytogenetic evaluation). However, more sensitive methods are required for monitoring residual disease (ie, molecular monitoring of BCR-ABL transcript levels). It is generally accepted that molecular responses have prognostic significance. Patients with CP CML who achieve early molecular responses are more likely to achieve durable cytogenetic responses and are less likely to experience disease progression. Rising BCR-ABL transcript levels also indicate loss of response, often as a consequence of developing BCR-ABL mutations. However, some studies have suggested that patients who achieve complete cytogenetic disease remission may not derive an additional prognostic benefit from achieving a major molecular response. Practical issues also exist for molecular monitoring with respect to restricted access and variability in methodologies and data reporting. Although molecular monitoring has a clear role in assessing residual disease and determining the risk of disease progression in patients with CML, the importance of cytogenetic monitoring should not be ignored.
...
PMID:Molecular monitoring in chronic myeloid leukemia: response to tyrosine kinase inhibitors and prognostic implications. 1834 94

Patients with newly diagnosed chronic phase chronic myeloid leukemia were treated with imatinib mesylate (IM) for 6 to 12 months to establish disease control, before reduced intensity stem cell transplantation (RISCT). Escalating doses of donor lymphocyte infusions were given from 6 months after transplantation to eradicate residual disease. A total of 18 patients entered the study and 15 received RISCT (median follow-up, 31 months). RISCT was well tolerated with rapid engraftment, short inpatient stays, and few readmissions. Viral reactivation was common, although extensive graft-versus-host disease occurred infrequently. Donor lymphocyte infusions were given as part of the RISCT protocol in 13 of 15 patients. BCR-ABL transcripts continued to decrease after RISCT, and 8 (53%) patients achieved sustained undetectable levels. All patients are currently off IM. Although IM is now established as first-line therapy for chronic phase chronic myeloid leukemia, this protocol is a safe, well-tolerated, and effective strategy in these patients. This study is registered at http://www.controlled-trials.com as ISRCTN86187144.
...
PMID:Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia. 1837 54

Clinical studies of patients with chronic myeloid leukemia revealed that a common pattern of response is a dramatic fall in the circulating population of blast cells, with a minimal or delayed decrease in marrow blasts, suggesting a protective environment. These observations suggest that a greater understanding of the interaction of stromal cells with leukemic cells is essential. Here, we present an in vivo system for monitoring relative tumor accumulation in leukemic mice and residual disease in leukemic mice treated with a tyrosine kinase inhibitor and an in vitro system for identifying integral factors involved in stromal-mediated cytoprotection. Using the in vivo model, we observed high tumor burden/residual disease in tissues characterized as significant sources of hematopoiesis-promoting stroma, with bone marrow stroma most frequently showing the highest accumulation of leukemia in untreated and nilotinib-treated mice as well as partial protection of leukemic cells from the inhibitory effects of nilotinib. These studies, which showed a pattern of leukemia distribution consistent with what is observed in imatinib- and nilotinib-treated chronic myeloid leukemia patients, were followed by a more in-depth analysis of stroma-leukemia cell interactions that lead to protection of leukemia cells from nilotinib-induced cytotoxicity. For the latter, we used the human BCR-ABL-positive cell line, KU812F, and the human bone marrow stroma cell line, HS-5, to more closely approximate the bone marrow-associated cytoprotection observed in drug-treated leukemia patients. This in vitro system helped to elucidate stromal-secreted viability factors that may play a role in stromal-mediated cytoprotection of tyrosine kinase inhibitor-treated leukemia cells.
...
PMID:Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells. 1844 57

Interferon-alpha (IFN-alpha) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-alpha-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-alpha-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-alpha-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6(+) to 18(+) months, and persisted after pegylated IFN-alpha-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-alpha-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.
...
PMID:Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. 1865 Apr 51

The majority of patients with chronic phase chronic myeloid leukaemia (CP-CML) treated with imatinib achieves cytogenetic disease remission. Molecular monitoring for residual disease has prognostic significance: rising BCR-ABL levels may provide earliest indication that a patient has become resistant to treatment. The emergence of resistance to imatinib has dampened the enthusiasm for this drug. The most common cause of resistance is the selection of leukemic clones mutated in ABL kinase domain due to amino acid substitutions with prevention of appropriate binding of the drug. Amplification and over-expression of BCR-ABL, acquired cytogenetic aberrations and modulation of drug efflux or influx transporters have been reported. These observations have established the rationale for the creation of new compounds that have been explored in clinical trials. This review will discuss the underlying mechanisms of imatinib-resistance and new strategies to avoid and overcome this phenomenon.
...
PMID:Resistance to imatinib in chronic myeloid leukemia and therapeutic approaches to circumvent the problem. 1927 74

Patients with chronic myelogenous leukemia have a t(9;22)(q34;q11.2) or variant translocation that results in a BCR-ABL fusion gene. BCR-ABL detection by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) is the standard practice for monitoring residual disease in patients with chronic myelogenous leukemia who receive tyrosine kinase inhibitor therapies. In this study, we describe a patient who tested positive for the BCR-ABL translocation by fluorescence in situ hybridization and cytogenetic analysis but tested negative by qRT-PCR molecular analysis at the time of diagnosis. Further PCR analysis and DNA sequencing with alternative primer sets demonstrated the presence of an e14a3 (also known as b3a3) BCR-ABL fusion. The e14a3 fusion is rare, but may be underreported as a result of many commercially available and laboratory-developed primer sets that fail to detect breakpoints in the ABL gene that are downstream of intron 1. For this patient, if the qRT-PCR assay had been used to monitor disease response/progression after treatment and not in conjunction with fluorescence in situ hybridization or cytogenetics at the time of diagnosis, the negative result would have been misinterpreted as molecular remission.
...
PMID:A rare e14a3 (b3a3) BCR-ABL fusion transcript in chronic myeloid leukemia: diagnostic challenges in clinical laboratory practice. 1949 89

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a triphasic clinical course, the morphologic expansion of a terminally differentiated myeloid cell and the presence of the BCR-ABL1 fusion gene, the hallmark of CML. The fusion gene is usually, but not always, associated with a Philadelphia chromosome, the result of a reciprocal exchange of genetic material between chromosome 22 and chromosome 9, which leads to the production of the activated BCR-ABL1 gene and oncoprotein. The breakpoint in the BCR gene occurs commonly downstream of exons e13 or e14 (M-BCR) and less frequently downstream of exons e1 and e2 (m-BCR). Less than 1% of cases carry a breakpoint downstream of exon 6 or 8 ("variant fusion genes") or exon 19 (mu-BCR). Breakpoints in the ABL1 gene cluster upstream of exon a2 (or of exon a3 in less than 5% of patients with CML). Conventional cytogenetic, fluorescence in situ hybridization, and molecular testing for the BCR-ABL1 fusion gene are key investigations for the diagnosis and monitoring of CML. Treatment using tyrosine kinase inhibitors has revolutionized the management of CML with hematologic and cytogenetic response within 12-18 months observed in >85% of patients. Nevertheless, between 15 and 20% of patients may evolve to blastic phase. Measurement of low level or "minimal" residual disease using molecular tests is becoming the gold-standard approach to measure response to therapy due to its higher sensitivity compared to other routine techniques. The technical aspects and clinical applications of molecular monitoring will be the main focus of this article.
...
PMID:Technical aspects and clinical applications of measuring BCR-ABL1 transcripts number in chronic myeloid leukemia. 1954 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---