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

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

The optimization of conventional treatment approaches, such as chemotherapy, stem cell transplantation (SCT), and supportive care, and the exploration of new approaches will hopefully further improve the outcome of adults with acute lymphoblastic leukemia (ALL). Subgroup-adjusted treatment has already greatly improved treatment outcomes in T- and mature B-cell ALL. These approaches should be further refined, for example, in T-ALL with cyclophosphamide and cytarabine, in pro-B ALL with high-dose cytarabine (HdAC), in B-precursor ALL with high-dose methotrexate (HdM) and 6-mercaptopurine (6-MP), and in mature B-ALL with HdM and HdAC. The indications for SCT will be extended to include elderly patients undergoing allogeneic mini-transplants, and tumor eradication will be improved by better conditioning regimens such as radioimmunoconjugates and methods to induce the graft-versus-leukemia (GvL) effect, such as donor leukocyte infusions (DLI) or allogeneic mini-transplants applied after autologous transplants. Molecular therapeutic approaches, for example, those directed against the fusion protein BCR-ABL with ABL-tyrosine kinase inhibitor, are on the way to creating a new avenue for the treatment of ALL. In the future, drug resistance should be exploited as a pretherapeutic test for treatment strategies, but whether multidrug resistance modulation with available drugs will be used in ALL remains open. Evaluation of the pharmacokinetics of cytostatic drugs and the pharmacogenomics of cytostatic agents in adult ALL may contribute to the development of individualized treatment strategies with higher efficacy and lower toxicity. Minimal residual disease (MRD) evaluation is attractive in adult ALL, because it can be determined in a very high percentage of patients. It has been shown to be predictive for relapse and might be of benefit for redefinition of complete remission (CR), for determination of the efficacy of single treatment elements, and for treatment tailoring during the course of disease. New treatment approaches include also several forms of immunotherapy for B- as well as T-lineage ALL; after the demonstration that such approaches are also effective in ALL, their optimal place in the treatment strategy for adult ALL can be determined.
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PMID:New approaches to acute lymphoblastic leukemia in adults: where do we go? 1104 22

Persistence of BCR-ABL rearrangements was demonstrated by D-FISH technique in chronic myeloid leukemia (CML) patients in complete cytogenetic response (CCR) after allogeneic bone marrow transplantation (BMT) or interferon-alpha therapy (IFN-alpha). Samples from bone marrow aspirate or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, fluorescent interphase in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement remains unexpressed in a small percentage of cells whatever the treatment (IFN-alpha or BMT), and this in spite of the negativity of the RT-PCR-based classical molecular remission criterion. These data corroborate those obtained by other investigators and point to the need for follow-up of CML patients in CCR over an extensive period, at the DNA level to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse and guide the therapeutic decision. Experimental models suggesting the persistence of positive BCR-ABL cells are discussed and tentative explanations of tumor "dormancy" are proposed.
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PMID:Persistence of transcriptionally silent BCR-ABL rearrangements in chronic myeloid leukemia patients in sustained complete cytogenetic remission. 1169 48

The detection of BCR-ABL specific RNA by RT-PCR has been shown to predict relapse when positive 6 months after allogeneic stem cell transplantation (SCT) for chronic myelogenous leukemia (CML). In the present study, the focus was on evaluation of residual disease during the first weeks following SCT. In this study, 177 blood or marrow samples were obtained from 33 patients who received allogeneic (20 patients) or autologous (13 patients) SCT on day 0, day 30 and every 3 months for 1 year. T-cell depletion (TCD) was performed in 4 cases. On day 0 (day of graft infusion), 10/30 evaluable patients had negative RT-PCR (33%) regardless of pretransplant characteristics. On day 30, 14/18 patients (77%) from the allogeneic group had negative RT-PCR versus 0% in the autologous group. 2/4 patients who received TCD allogeneic grafts had day 30-positive PCR. Five patients in the allogeneic group had at least one positive RT-PCR sample between day 30 and day 90: 3 of them subsequently relapsed suggesting possible correlation between early positivity and relapse. Our results show that disappearance of MRD can be achieved within 3 months after transplantation in the majority of patients treated with allogeneic but not after autologous SCT. This suggests that the GVL effect might be operational early during the first weeks following transplantation.
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PMID:Survey of early disapearance of BCR/ABL fusion transcript after allogeneic or autologous stem cell transplantation for chronic myelogenous leukemia. 1169 49

Detection of BCR-ABL transcripts in chronic myeloid leukaemia (CML) is used to confirm the diagnosis and to monitor residual disease. Quantitative techniques are required to predict response to therapy or early relapse. We have evaluated an assay in which transcription-mediated amplification (TMA) of BCR-ABL and ABL transcripts is achieved using reverse transcriptase and RNA polymerase. The products are quantified in the hybridisation protection assay (HPA) using acridinium ester-labelled DNA probes and chemiluminescence. The method is a single tube procedure which uses small amounts of RNA (<500 ng/triplicate analysis), is technically simple (requiring just two waterbaths and a luminometer), rapid (total assay time <4 h) and sensitive (capable of detecting one BCR-ABL-positive K562 cell in the presence of 10(4)-10(5) BCR-ABL-negative cells). BCR-ABL signals from patient RNA samples were quantified relative to known amounts of K562 RNA and normalised to levels of ABL. BCR-ABL/ABL ratios ranged from 0.15 to 1.59 (median 0.65) in RNA from diagnostic blood or bone marrow of 18 CML patients and were < or =0.0001 in 20 normal controls. Sequential samples analysed from six CML patients post-allogeneic bone marrow transplantation who relapsed and received donor lymphocyte infusions showed BCR-ABL/ABL ratios which reflected patient status or treatment. A BCR-ABL/ABL ratio of 0.01 served as a useful arbitrary indicator value, with results above and below this value generally correlating with relapse or remission, respectively.
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PMID:Transcription-mediated amplification and hybridisation protection assay to determine BCR-ABL transcript levels in patients with chronic myeloid leukaemia. 1189 44

The degree of tumor load reduction as measured by cytogenetic response is an important prognostic factor for chronic myelogenous leukemia (CML) patients on therapy. We sought to determine whether BCR-ABL transcript levels can predict chromosomal response. Residual disease was evaluated in 120 CML patients in chronic phase (CP) treated with the selective tyrosine kinase inhibitor imatinib after resistance or intolerance to interferon alpha (IFN). Median time of therapy was 401 days (range 111-704). BCR-ABL and total ABL transcripts were measured in 486 peripheral blood (PB) specimens with a real time RT-PCR approach using fluorescent-labeled hybridization probes (LightCycler technology) and results were expressed as the ratio BCR-ABL/ABL. Cytogenetic response was determined in 3-monthly intervals: From 101 evaluable patients, 42 achieved a complete (CR, 0% Philadelphia chromosome (Ph)- positive metaphases), 18 a partial (PR, 1-34% Ph+), 13 a minor (MR, 35-94% Ph+), and 26 no response (NR, >94% Ph+). All PB samples were RT-PCR positive. The proportion of Ph+ metaphases and simultaneous BCR-ABL/ABL ratios correlated with r = 0.74, P < 0.0001. In order to investigate whether early molecular analysis may predict cytogenetic response, quantitative RT-PCR data obtained after 1 and 2 months of therapy were compared with cytogenetic response at 6 months. BCR-ABL/ABL ratios after 1 month were not predictive, but results after 2 months correlated with the consecutive cytogenetic response (P = 0.0008). The probability for a major cytogenetic response was significantly higher in patients with a BCR-ABL/ABL ratio <20% after 2 months of imatinib therapy. We conclude that: (1) quantitative determination of residual disease with real time RT-PCR is a reliable and sensitive method to monitor CML patients on imatinib therapy; (2) BCR-ABL/ABL ratios correlate well with cytogenetic response; (3) in IFN-pretreated patients all complete responders to imatinib have evidence of residual disease with the limited follow-up available; and (4) cytogenetic response at 6 months of therapy in CP patients is predictable with real time RT-PCR at 2 months.
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PMID:Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. 1220 Jun 66

Recent advances in molecular genetics impact the health care and outcome of patients with acute lymphoblastic leukemia (ALL). BCR-ABL, a common molecular defect in adult ALL, is a valuable tumor marker whose detection influences prognosis and clinical management decisions. Molecular methods such as fluorescence in situ hybridization (FISH), reverse-transcriptase polymerase chain reaction (rtPCR), and real-time quantitative rtPCR can be used to detect the chimeric BCR-ABL gene or its transcripts. These molecular assays improve our ability to measure residual disease and to estimate risk of relapse. On the horizon are gene expression profiles that will likely provide additional information beyond what is obtainable with current clinical and laboratory approaches.
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PMID:Clinical applications of BCR-ABL molecular testing in acute leukemia. 1270 70

Minimal residual disease (MRD) can be detected in the marrows of children undergoing chemotherapy either by flow cytometry or polymerase chain reaction. In this study, we used four-color flow cytometry to detect MRD in 1016 children undergoing therapy on Children's Oncology Group therapeutic protocols for precursor-B-cell ALL. Compliance was excellent, with follow-up samples received at the end of induction on nearly 95% of cases; sensitivity of detection at this time point was at least 1/10,000 in more than 90% of cases. Overall, 28.6% of patients had detectable MRD at the end of induction. Patients with M3 marrows at day 8 were much more likely to be MRD positive (MRD+) than those with M2 or M1 marrows. Different genetically defined groups of patients varied in their prevalence of MRD. Specifically, almost all patients with BCR-ABL had high levels of end-of-induction MRD. Only 8.4% of patients with TEL-AML1 were MRD+>0.01% compared with 20.3% of patients with trisomies of chromosomes 4 and 10. Our results show that MRD correlates with conventional measures of slow early response. However, the high frequency of MRD positivity in favorable trisomy patients suggests that the clinical significance of MRD positivity at the end of induction may not be the same in all patient groups.
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PMID:Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children's Oncology Group study. 1288 44

A significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) alpha-based protocols. We sought to determine levels of residual disease in patients with MCR using various molecular methods and to establish a relation between residual BCR-ABL transcript levels and rate of relapse in complete cytogenetic remission (CCR). Response was measured by conventional cytogenetic analysis, hypermetaphase and interphase fluorescence in situ hybridization (HM-FISH, IP-FISH) of bone marrow (BM) cells, qualitative nested and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. We investigated 323 peripheral blood (PB) and BM samples from 48 CML patients who achieved a complete (Ph+ 0%; n=41) or partial (Ph+ 1-34%; n=7) cytogenetic remission after 3-20 months of imatinib therapy. Prior to imatinib, 35 patients were in chronic phase (CP), eight in accelerated phase (AP), four in myeloid and one in lymphoid blast crisis. HM-FISH results correlated with ratios BCR-ABL/ABL in PB and BM. In patients with CCR, residual disease was detectable by HM-FISH (31%), IP-FISH (18%), and RT-PCR (100%). During follow-up, BCR-ABL became undetectable in two patients (one CP, one AP) by both nested and quantitative RT-PCR. CCR is ongoing in 30 evaluable patients, 11 patients have relapsed. At the time of best response, median ratios BCR-ABL/ABL were 2.1% (range 0.82-7.8) in patients with subsequent relapse and 0.075% (range 0-3.9) in patients with ongoing remission (P=0.0011). All 16 CP patients, who achieved ratios BCR-ABL/ABL <0.1% as best molecular response are in continuous remission, while 6/13 patients (46%) with ratios >/=0.1% have relapsed (P=0.0036). We conclude that: (i) in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; (ii) RT-PCR results derived from PB and BM are comparable in CP CML; and (iii) low levels of residual disease with ratios BCR-ABL/ABL &<0.1% are associated with continuous remission.
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PMID:Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission. 1297 Jul 65

We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.
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PMID:Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C. 1452 62

Residual disease in chronic myeloid leukemia patients may be assessed by various molecular methods. After imatinib treatment a significant proportion of patients achieve complete cytogenetic remission (CCR) and a sensitive method is necessary to monitor treatment response and to detect early signs of relapse. Reverse-transcriptase polymerase chain reaction (RT-PCR) is by far the most sensitive approach to assess residual disease in this group of patients. Qualitative PCR methods give only limited information about the residual leukemic mass. Quantitative RT-PCR (Q-PCR) assays enable to monitor the kinetics of residual BCR-ABL transcripts over time in patients with a good response to imatinib. Early Q-PCR results on imatinib treatment can help to identify individuals who are likely to have a good response. In chronic phase patients after CCR, Q-PCR may identify patients who are likely to continue with their CCR or to relapse and may help to optimize treatment for this group of patients. The definition of molecular surrogate endpoints beyond CCR for studies which are currently planned demands standardization of the nomenclature and of technologies to measure these targets.
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PMID:Molecular surveillance of chronic myeloid leukemia patients in the imatinib era - evaluation of response and resistance. 1517 8


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