Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) blocks the constitutively activated Bcr-Abl tyrosine kinase that is characteristic of chronic myeloid leukemia (CML). Molecular analysis for the presence of residual Bcr-Abl-positive cells in patients with a cytogenetic response following treatment with imatinib mesylate reveals that some patients have undetectable disease using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assays capable of detecting 1 in 10(5) Philadelphia chromosome-positive (Ph(+)) cells. To examine whether the leukemia is still Bcr-Abl-dependent in patients who have responded to imatinib mesylate but have relapsed, a quantitative assay that directly measures enzymatic activity of Bcr-Abl toward one of its major signaling substrates has been developed. This assay allows monitoring both of the imatinib mesylate sensitivity of patient cells in vitro, and of the endogenous inhibition of Bcr-Abl kinase activity during imatinib mesylate treatment and relapse. Studies show that imatinib mesylate resistance is associated with restored activation of the Bcr-Abl signal transduction pathway in the majority of cases, indicating that Bcr-Abl remains a valid target for therapeutic intervention. Understanding resistance mechanisms of Ph(+) leukemia to imatinib mesylate will allow design of therapies to overcome such barriers to efficacy.
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PMID:Molecular studies in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. 1152 97

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (Gleevec) (formerly STI571) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs in patients with chronic phase (CP) and advanced disease. A cohort of 72 patients with CML in myeloid blast crisis (BC) (n = 34), lymphoid BC (n = 2), accelerated phase (AP) (n = 16), CP (n = 18), and BCR-ABL(+) acute lymphoblastic leukemia (ALL) (n = 2) resistant to imatinib were investigated. Median levels of BCR-ABL transcripts, determined by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), were not significantly changed at the time of resistance, but seven of 55 patients showed a greater than 10-fold increase in BCR-ABL levels. Genomic amplification of BCR-ABL was found in two of 32 patients evaluated by fluorescence in situ hybridization (FISH). Additional chromosomal aberrations were observed in 19 of 36 patients and point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 29 of 72 patients. Resistance may be caused by BCR-ABL-independent or BCR-ABL-dependent mechanisms. A thorough evaluation of resistant cases is required to suggest therapeutic measures in the individual case. Clonal selection of resistant cells harboring a BCR-ABL mutation might be reversed by stopping imatinib therapy and switching to chemotherapy. Combination therapy from the start of treatment to reduce the frequency of resistance is currently being evaluated with several drugs.
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PMID:Cytogenetic and molecular mechanisms of resistance to imatinib. 1278 79

Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of chronic myeloid leukemia (CML) patients. Early prediction of response to imatinib cannot be anticipated. We used a standardized quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) for BCR-ABL transcripts on 191 out of 200 late-chronic phase CML patients enrolled in a phase II clinical trial with imatinib 400 mg/day. Bone marrow samples were collected before treatment, after 12, 20 and at the end of study treatment (52 weeks) while peripheral blood samples were obtained after 2, 3, 6, 10, 14, 20 and 52 weeks of therapy. The amount of BCR-ABL transcript was expressed as the ratio of BCR-ABL to beta2-microglobulin (beta2M). We show that, following initiation of imatinib, the early BCR-ABL level trends in both bone marrow and peripheral blood samples made it possible to predict the subsequent cytogenetic outcome and response. We propose this method as the method of choice for monitoring patients on imatinib therapy. QRT-PCR studies may be able to identify degrees of molecular response that predict both complete cytogenetic response and long term stability, as well as patterns of response that provide an early indication of relapse and imatinib resistance.
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PMID:Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. 1640 13