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 Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16 deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16 deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1 defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorithm for an optimal management of these patients.
...
PMID:A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. 1565 57

We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.
...
PMID:In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia. 1593 Aug 91

Although most patients with adult acute lymphoblastic leukaemia (ALL) can achieve a remission when treated with conventional, DNA-damaging chemotherapy, in more than half of all cases the disease relapses and ultimately results in death. Therefore, there is a substantial need for new antileukaemic drugs. Recent advances in the understanding of the molecular alterations in ALL have lead to the identification of new targets and the arrival of molecular-targeted therapies in the clinical setting. The prototype for this approach is the treatment of Philadelphia chromosome-positive ALL with imatinib mesylate. Here, the targeting of a molecular abnormality--inhibition of BCR-ABL tyrosine kinase--has turned a very poor-prognosis disease into one in which promising results are achieved. Promising new therapies are under development that target various goals, including the NOTCH signalling pathway, purine nucleoside phosphorylase activity, mammalian target of rapamycin and tyrosine kinase. This review outlines recent advances in the development of emerging drugs for the treatment of adult ALL. The recent advances in the understanding of the biology and pathogenesis of ALL have helped to determine prognosis and to plan the therapy of adult patients with ALL. Still, despite improved complete remission rates of 65-90% with current therapy, only 20-40% of patients can be considered cured. New therapeutic alternatives are needed to improve these results. With a better understanding of the disease, more target-specific therapies could be designed. The aim of this review is to highlight new pharmacotherapies and those emerging drug treatments for patients with adult ALL.
...
PMID:Emerging drugs for adult acute lymphoblastic leukaemia. 1608 31

The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.
...
PMID:Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. 1706 30

In the early 1980s, adult acute lymphoblastic leukemia (ALL) was a rarely curable disease with overall survival < 10%. After adapting combinations employed by pediatric groups, the outcome improved to 30-40%. A period of stagnation followed with improvement only in distinct subgroups. In the past 5 years, however, striking new developments have been noticeable. Progress has been made in molecular diagnostics of ALL. Improvements to standard therapy including stem cell transplantation (SCT) have occurred and a variety of new drugs for ALL are under evaluation. Rapid diagnosis and classification of ALL is increasingly important to identify prognostic factors and molecular genetic subsets that will be the focus of "targeted" therapies as we enter the era of subset specific treatment. In the following review we will discuss treatment of adult ALL (excluding elderly patients,(1) adolescents(2) and patients with Ph/BCR-ABL positive ALL(3)).
...
PMID:Treatment of adult acute lymphoblastic leukemia. 1712 52

Acute lymphocytic leukemia (ALL) is a heterogeneous group of disorders that are associated with a cure rate of > 80% in children. The prognosis in adults is considerably inferior, with age, disease bulk, leukemia karyotype and immune phenotype being prognostically relevant. Adult ALL treatment programs include induction, intensified consolidation and maintenance phases with CNS prophylaxis. The addition of imatinib in patients with BCR-ABL-positive ALL has improved the prognosis of this subgroup, but their survival is still poor. Initial data on the second-generation BCR-ABL inhibitors, dasatinib and nilotinib, indicate a potentially greater efficacy than imatinib, but the improvement is likely to be modest. The overall efforts in terms of developmental therapeutics in ALL are very modest and not in keeping with the urgent need for improvement. Most agents being investigated have mechanisms of action similar to those of existing agents for ALL therapy and thus represent modest opportunities to improve results. Of such agents, data on BCR-ABL inhibitors, sphingosomal vincristine, pemetrexed, talotrexin, annamycin and ABT-751 are reviewed.
...
PMID:Emerging therapeutic options for Philadelphia-positive acute lymphocytic leukemia. 1735 21

Session 4 of the 2005 Society of Hematopathology/European Association for Haematopathology Workshop focused on case presentations of precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (pre-T ALL/LBL) and acute biphenotypic leukemia. Pre-T ALL represents approximately 15% of childhood and 25% of adult ALL cases. Pre-T LBL comprises 85% to 90% of LBL and frequently manifests as a mediastinal mass. Gene expression studies have shown distinct subtypes of LYL1+, HOX11+, TAL1+, and MLL+ pre-T ALL/LBL. HOX11 overexpression may correlate with a good prognosis in adult pre-T ALL. ABL gene amplification and NOTCH1 gene mutations in subsets of pre-T ALL/LBL suggest patients may benefit from therapy with tyrosine kinase and gamma-secretase inhibitors, respectively. Acute biphenotypic leukemias are characterized by a single population of blasts that express myeloid, T- or B-lineage antigens in various combinations and account for fewer than 4% of all acute leukemias. The blasts have a high incidence of chromosome abnormalities. An accurate diagnosis of pre-T ALL/LBL and acute biphenotypic leukemia requires a multiparametric approach, including examination of morphologic features, immunophenotype, clinical characteristics, and cytogenetic and molecular findings.
...
PMID:Precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma and acute biphenotypic leukemias. 1736 28

Acquired imatinib resistance in advanced Philadelphia-positive acute lymphoblastic leukemia (Ph(+) ALL) has been associated with mutations in the kinase domain (KD) of BCR-ABL. We examined the prevalence of KD mutations in newly diagnosed and imatinib-naive Ph(+) ALL patients and assessed their clinical relevance in the setting of uniform frontline therapy with imatinib in combination with chemotherapy. Patients enrolled in the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) trial ADE10 for newly diagnosed elderly Ph(+) ALL were retrospectively examined for the presence of BCR-ABL KD mutations by denaturing high-performance liquid chromatography (D-HPLC), cDNA sequencing, and allele-specific polymerase chain reaction (PCR). A KD mutation was detected in a minor subpopulation of leukemic cells in 40% of newly diagnosed and imatinib-naive patients. At relapse, the dominant cell clone harbored an identical mutation in 90% of cases, the overall prevalence of mutations at relapse was 80%. P-loop mutations predominated and were not associated with an inferior hematologic or molecular remission rate or shorter remission duration compared with unmutated BCR-ABL. BCR-ABL mutations conferring high-level imatinib resistance are present in a substantial proportion of patients with de novo Ph(+) ALL and eventually give rise to relapse. This provides a rationale for the frontline use of kinase inhibitors active against these BCR-ABL mutants.
...
PMID:Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). 1740 7

Acute lymphocytic leukaemia (ALL) is a heterogeneous group of disorders that result from the clonal proliferation and expansion of malignant lymphoid cells in the bone marrow, blood and other organs. Distinct clinicopathological ALL entities have been identified, resulting in the adoption of risk-oriented treatment approaches. Advances in ALL therapy have led to long-term survival rates of >80% in children. However, only approximate, approximately 30-40% of adults achieve long-term disease-free survival. Contemporary ALL treatment programmes include induction, intensified consolidation, maintenance phases and CNS prophylaxis. The optimal treatment of Philadelphia chromosome-positive patients requires the addition of BCR-ABL tyrosine kinase inhibitors, such as imatinib, whereas allogeneic stem-cell transplantation remains the preferred approach for high-risk patients in first remission. Since only approximate, approximately 38% of adult ALL patients are free of disease 5 years after diagnosis and the outcome of salvage chemotherapy is very poor (complete remission rates of 20-30%, median survival of 3-6 months), novel agents are desperately required. Of those currently in clinical studies, the outlook for sphingosomal vincristine, pegylated asparaginase (pegaspargase), liposomal annamycin, ABT-751, pemetrexed, talotrexin, nelarabine and the novel BCR-ABL kinase inhibitors is discussed.
...
PMID:Treatment of acute lymphoblastic leukaemia : a new era. 1792 82

RT-PCR detects chimeric BCR-ABL mRNA in approximately 25% of adult acute lymphoblastic leukemia (ALL) cases. Minor breakpoint transcripts (e1a2) are found in about 70% of positive cases and major breakpoint transcripts (e13a2, e14a2) in about 30% of cases. However, other atypical transcripts are sometimes observed. We report experience gained in the GMALL Study Group and identified 8 BCR-ABL-positive adult ALL cases with such atypical transcripts: 5 with e1a3, 2 with e13a3 (b2a3), and 1 with e6a2. This corresponds to a prevalence of 1-2% of all BCR-ABL-positive cases. The clinical courses are reported and diagnostic proposals are made.
...
PMID:Atypical BCR-ABL mRNA transcripts in adult acute lymphoblastic leukemia. 1805 96


<< Previous 1 2 3 4 5 6 7 Next >>

---