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)

Targeted therapies for hematological malignancies have come of age since the advent of all trans retinoic acid (ATRA) for treating APL and STI571/Imatinib Mesylate/Gleevec for CML. There are good molecular targets for other malignancies and several new drugs are in clinical trials. In this review, we will concentrate on individual abnormalities that exist in the myelodysplastic syndromes (MDS) and myeloid leukemias that are targets for small molecule therapies (summarised in Fig. 1). We will cover fusion proteins that are produced as a result of translocations, including BCR-ABL, the FLT3 tyrosine kinase receptor and RAS. Progression of diseases such as MDS to secondary AML occur as a result of changes in the balance between cell proliferation and apoptosis and we will review targets in both these areas, including reversal of epigenetic silencing of genes such as p15(INK4B).
...
PMID:Targeted therapies in myeloid leukemia. 1475 35

Iatrogenic causes for palpebral edema are rarely suspected and must be specifically sought. The authors report a case of palpebral edema in a patient treated with a specific inhibitor of the BCR-ABL tyrosine kinase (Glivec) for chronic myeloid leukemia. Histopathological analysis of specimens of the excised upper eyelid tissue revealed the absence of leukemic infiltration, suggesting the toxic effect of the treatment. This side effect should be noted so that patients are informed and biopsy is proposed to eliminate tumoral infiltration.
...
PMID:[Palpebral edema secondary to treatment by a specific inhibitor of tyrosine kinase: Glivec. A case report]. 1496 89

Abnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR/ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model. Rapamycin/Imatinib combinations also inhibit Imatinib-resistant mutants of BCR/ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or -resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor/rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and/or overexpressed PTKs.
...
PMID:Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. 1497 43

The new knowledge in molecular biology and pathophysiology of chronic myeloid leukemia enabled the development of imatinib mesylate (Glivec, formerly STI571). Imatinib potently inhibits several protein tyrosine kinases, including BCR-ABL, c-Kit, and PDGF receptor. Imatinib blocks the phosphorylation of downstream target proteins and interrupts the malignant transformation leading to the development of CML. Phase I and II studies demonstrated that imatinib is highly effective and well tolerated in all phase of CML. We got our experience with imatinib on more than two-year monitoring 34 patients within the Expanded Access Study CST1571 0113. Imatinib 400 mg/d was administered orally to 10 women and 24 men in median age of 53 years (22-70) who were hematologically (n = 9) or cytogenetically (n = 13) resistant, cytogenetically refractory (n = 3) or intolerant (n = 9) to interferon alpha. The median follow-up time was 97.5 weeks (23-115), the median time from CML diagnosis to the start of the study was 32.3 months (6-140.5). Complete hematologic response was achieved in 33 of 34 (97%) pts, total major cytogenetic response (complete plus major) in 21 of 33 (63%) pts. Cytogenetic relapse was observed in 2 of 33 pts (6%), cytogenetic progression in 4 (12%) pts. Non-hematologic toxicity was mild (grade 1 or 2) and no patient was excluded from the study due to it. Hematological toxicity grade 3 limited dose of imatinib in 26% of patients and probably caused lower rate of cytogenetic responses in heavy pretreated patients. Both quantitative RT-PCR methods (competitive RT-PCR and real-time RT-PCR Light-Cycler) were found useful to monitor patients with CML on imatinib therapy. Our results confirmed high efficacy and safety of imatinib in late-chronic phase CML patients failing prior interferon therapy. The lower incidence of hematological toxicity and higher rate of cytogenetic responses in patients treated with imatinib in early-chronic phase CML justify according to our opinion the recommendation to administer imatinib early after the diagnosis of CML in patients who are not indicated for allogeneic transplantation.
...
PMID:[Imatinib mesylate (Glivec) in treatment of chronic phase chronic myeloid leukemia]. 1501 23

Chronic myeloid leukemia (CML) is a clonal stem cells disorder and belongs to the myeloproliferative diseases. Over the past decades seminal discoveries in the field of CML research have greatly contributed to our knowledge of leukemogenesis. The hallmark of the disease is the presence of the Philadelphia chromosome, the first described acquired non-random cytogenetic abnormality in human malignancies. This chromosomal abnormality is the result of a reciprocal translocation between chromosomes 9 and 22, t(9;22). At the molecular level this involves the fusion of the ABL protooncogene on chromosome 9 with the BCR (breakpoint cluster region) gene on chromosome 22. The fusion protein has increased tyrosine kinase activity and is a key event in the malignant transformation of a given progenitor cell in the bone marrow. Diagnosis of CML is based on the peripheral blood smear, bone marrow examination, the presence of the Philadelphia chromosome and its molecular correlate, the BCR-ABL transcript. Remarkable progress has been made in the treatment options over the last years which as a result rendered the therapeutic choices more complex and challenging. The current knowledge of treatment options is reviewed with particular emphasis on the newly introduced tyrosine kinase inhibitor Imatinib which opened an as yet unexpected promising avenue in the treatment of CML.
...
PMID:[Chronic myeloid leukemia--update]. 1501 97

The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases. Analysis of CML patients resistant to BCR-ABL suppression by Imatinib mesylate coupled with the crystallographic structure of ABL complexed to this inhibitor have shown how structural mutations in ABL can circumvent an otherwise potent anticancer drug. The successes and limitations of Imatinib mesylate hold general lessons for the development of alternative molecular targeted therapies in oncology.
...
PMID:The BCR-ABL story: bench to bedside and back. 1503 71

Resistance against STI571 (Imatinib) appears to be multifactorial, but the most likely mechanisms can be broadly categorized as interference with the pharmacologic activity of STI571 or genetic changes which alter the biologic behaviour of the leukemic cells. In Ph + ALL, responses to STI571 are not sustained, and in the overwhelming majority of patients development of resistance is rapid. Clinically, two types of resistance to STI571 can be distinguished: 'primary resistance', corresponding to a failure to achieve fewer than 5% blasts in the bone marrow, and 'secondary resistance' in patients with STI571-induced complete remission who relapse despite continued STI571 treatment. Attempts to identify mechanisms by which Ph + ALL acquire resistance to STI571 have already been successful. Mutations in the ATP binding site of ABL are frequent events which counteract the antileukemic effect of STI571. Gene expression profiling has been shown to discriminate between resistant and sensitive leukemic cells. Application of this technique has also generated several hypotheses regarding the ability of leukemic cells to bypass the BCR-ABL signal transduction pathway. This may result in the proliferation of Ph + leukemic cells even in the presence of STI571.
...
PMID:Mechanisms of resistance to STI571 (Imatinib) in Philadelphia-chromosome positive acute lymphoblastic leukemia. 1516 Sep 36

Imatinib mesylate, a novel, molecularly targeted agent for the treatment of chronic myeloid leukemia (CML), has expanded the management options for this disease and provided a paradigm for the treatment of other cancers. Imatinib is a potent, specific inhibitor of BCR-ABL, the constitutively active protein tyrosine kinase critical to the pathogenesis of CML. A randomized, phase III comparison of imatinib with interferon-alfa plus cytarabine as initial treatment for newly diagnosed chronic-phase CML, which demonstrated significantly higher rates of disease response with less toxicity, better quality of life, and a significantly longer progression-free survival time, provided the most persuasive data supporting a major role for imatinib. Currently, allogeneic stem cell transplantation is the only treatment modality with long-term data demonstrating curative potential in CML. An option for less than half of CML patients and associated with substantial morbidity and mortality, transplantation may still be appropriate initial therapy for certain patients. Busulfan and hydroxyurea have no demonstrable effect on disease natural history. The interferon-plus-cytarabine combination can induce durable cytogenetic remissions and was previously the CML pharmacotherapy standard of care, but it is often poorly tolerated. Imatinib is now indicated as first-line therapy for CML in all phases.
...
PMID:Optimizing treatment of chronic myeloid leukemia: a rational approach. 1516 81

Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.
...
PMID:Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. 1562 54

Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. Several clinical trials have demonstrated the efficacy of imatinib in different phases of this disease. On the other hand, imatinib is also active against other tyrosine kinases, such as ABL, the stem cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this regard, imatinib has already shown a remarkable activity in patients with hypereosinophilic syndrome and gastrointestinal stromal tumours. Imatinib is an example of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a molecular-targeted therapy.
...
PMID:Imatinib mesylate (Gleevec/Glivec) a molecular-targeted therapy for chronic myeloid leukaemia and other malignancies. 1520 9


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

---