INT199563

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Context Info
Confidence 0.46
First Reported 2006
Last Reported 2010
Negated 0
Speculated 0
Reported most in Body
Documents 38
Total Number 38
Disease Relevance 21.50
Pain Relevance 0.87

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

mitochondrion (Abl1) DNA binding (Abl1) cytoplasm (Abl1)
cytosol (Abl1) nucleolus (Abl1) cell adhesion (Abl1)
Anatomy Link Frequency
arm 1
brain 1
platelet 1
Abl1 (Mus musculus)
Abl1 - H396P (1)
Pain Link Frequency Relevance Heat
Kinase C 4 98.94 Very High Very High Very High
fibrosis 139 97.64 Very High Very High Very High
Potency 60 95.44 Very High Very High Very High
cytokine 36 85.24 High High
antagonist 8 79.28 Quite High
adenocard 7 77.84 Quite High
cINOD 13 72.72 Quite High
headache 27 48.80 Quite Low
Bioavailability 45 46.16 Quite Low
palliative 10 44.36 Quite Low
Disease Link Frequency Relevance Heat
Myeloid Leukemia 1902 99.68 Very High Very High Very High
Leukemia 324 99.40 Very High Very High Very High
Fibromyalgia 16 99.32 Very High Very High Very High
Myelodysplastic Syndromes 298 99.20 Very High Very High Very High
Chromosome Aberrations 18 98.92 Very High Very High Very High
Erythrocytosis 49 98.08 Very High Very High Very High
Gastrointestinal Stromal Tumor 256 98.04 Very High Very High Very High
Philadelphia Chromosome 103 98.00 Very High Very High Very High
Pulmonary Fibrosis 76 97.64 Very High Very High Very High
Reticulocytosis 5 97.40 Very High Very High Very High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
Imatinib mesylate, a BCR-ABL TK inhibitor, is the frontline therapy for CML.
Negative_regulation (inhibitor) of ABL associated with myeloid leukemia
1) Confidence 0.46 Published 2009 Journal Therapeutics and Clinical Risk Management Section Abstract Doc Link PMC2697539 Disease Relevance 0.45 Pain Relevance 0
Novel Bcr-Abl inhibitors
Negative_regulation (inhibitors) of Abl
2) Confidence 0.42 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.17 Pain Relevance 0
CML: chronic myeloid leukemia; CP: chronic phase; AP: accelerated phase; BP: blast phase; TKI: tyrosine kinase inhibitor; IRIS: International Randomized Study of Interferon and STI571; CCyR: complete cytogenetic response; START: SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of dasatinib; Ph+ ALL: Philadelphia chromosome-positive acute lymphoblastic leukemia; MCyR: major cytogenetic response; AE: adverse event; CHR: complete hematologic response.


Negative_regulation (inhibition) of ABL associated with leukemia, myeloid leukemia, philadelphia chromosome and blast crisis
3) Confidence 0.42 Published 2008 Journal J Hematol Oncol Section Body Doc Link PMC2567340 Disease Relevance 0.58 Pain Relevance 0
Initial approval of dasatinib was based on data from the START (SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of dasatinib) program, a series of multicenter, open-label phase 2 clinical trials in imatinib-resistant or -intolerant patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
Negative_regulation (inhibition) of ABL associated with leukemia, myeloid leukemia and philadelphia chromosome
4) Confidence 0.42 Published 2008 Journal J Hematol Oncol Section Body Doc Link PMC2567340 Disease Relevance 0.96 Pain Relevance 0
Alternatively, it is also important to explore the potential for synergy between nilotinib and other classes of inhibitors that work through mechanisms not involving inhibition of Abl tyrosine kinase activity.37,38
Negative_regulation (inhibition) of Abl tyrosine kinase
5) Confidence 0.34 Published 2010 Journal Core evidence Section Body Doc Link PMC2899790 Disease Relevance 0.31 Pain Relevance 0
Dasatinib was initially developed as an inhibitor of the Src family of kinases such as Fyn, Yes, Src, and Lyk, but it also inhibits BCR-ABL, EphA2, platelet-derived growth factor receptor, and c-Kit.
Negative_regulation (inhibits) of ABL in platelet
6) Confidence 0.34 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.08 Pain Relevance 0
A suboptimal response was defined as an incomplete hematologic response at 3 months, less than a partial cytogenetic response at 6 months, less than a complete cytogenetic response at 12 months, less than a major molecular response at 18 months, and, in the case of a major molecular response, loss of BCR-ABL, other mutations or other chromosomal abnormalities.11
Negative_regulation (loss) of ABL associated with chromosome aberrations
7) Confidence 0.34 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.27 Pain Relevance 0
Imatinib mesylate (Gleevec®; Novartis Pharma, East Hanover, NJ, USA) is a very specific inhibitor of BCR-ABL tyrosine kinase activity of the 2-phenylamino pyrimidine class, and it is approved by the Food and Drug Administration as frontline therapy for patients with CML.6 Imatinib acts by binding and stabilizing the inactive form of BCR-ABL, thereby inhibiting its autophosphorylation and the phosphorylation of its substrate, abrogating proliferation and inducing apoptosis of BCR-ABL–positive cells.4,7 The superiority of imatinib for successful clinical outcomes of patients with CML was confirmed by the International Randomized Study of Interferon plus low-dose cytarabine, the previous standard of care, vs STI571, or the imatinib (IRIS) trial, in which 553 patients were randomized to each arm.8 Imatinib induced high rates of complete hematologic response (96% at 1 year, which increased to 98% at 5 years),8 a major cytogenetic response (86% at 1 year, which increased to 92% at 5 years), a complete cytogenetic response (69% at 1 year and 87% at 5 years), a progression-free survival rate without accelerated or blast crisis (93% at 6 years), overall progression-free survival (83% at 6 years) and overall survival (95% at 6 years, taking into consideration only CML-related deaths; and 88% at 6 years when deaths from any cause were included).8–10
Negative_regulation (inhibitor) of ABL in arm associated with myeloid leukemia, blast crisis and apoptosis
8) Confidence 0.34 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 1.07 Pain Relevance 0
M.15,20 Nilotinib also potently inhibited tyrosine autophosphorylation of the E255K, E255V, F317L, M351T, and F486S Bcr-Abl mutants, and these effects were not associated with decreases in Abl or Bcr-Abl protein levels.
Negative_regulation (decreases) of Abl
9) Confidence 0.34 Published 2010 Journal Core evidence Section Body Doc Link PMC2899790 Disease Relevance 0.07 Pain Relevance 0.04
Recently, dasatinib-induced BCR-ABL inhibition was shown to be sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis and suggested that in patients with CML receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy.31
Negative_regulation (inhibition) of ABL associated with leukemia, myeloid leukemia and apoptosis
10) Confidence 0.34 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.83 Pain Relevance 0
Bcr-Abl positive cells cultured in the continuous presence of imatinib show a reduced Bcr-Abl protein level and an increase of expression of Src kinases (Donato et al 2003).
Negative_regulation (reduced) of Abl
11) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.52 Pain Relevance 0
However, MK-0457 has also been shown to bind to and inhibit the Abl kinase (Young et al 2006; Buser et al 2007; Cheetham et al 2007) in a mode that accommodates the substitution of the bulkier isoleucine for threonine at residue 315 (Figure 3, left panel), but the relative contributions of AK, JAK-2, and Bcr-Abl inhibition in the activity of MK-0457 have not been elucidated (Giles et al 2007b).
Negative_regulation (inhibition) of Abl
12) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.56 Pain Relevance 0
In contrast, patients with late stage CML more frequently exhibit primary resistance to Bcr-Abl inhibition.
Negative_regulation (inhibition) of Abl associated with myeloid leukemia
13) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.78 Pain Relevance 0
It functions as a competitive inhibitor of the Bcr-Abl tyrosine kinase leading to inhibition of proliferation, restoration of cell cycle control, induction of apoptosis and reversal of genetic instability in Bcr-Abl dependent cells in vitro (Gambacorti-Passerini et al 1997; Oetzel et al 2000; Jonuleit et al 1998; Jonuleit et al 2000; van der Kuip et al 2004).
Negative_regulation (inhibitor) of Abl associated with apoptosis
14) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.57 Pain Relevance 0
Unlike imatinib this new Abl inhibitor appears to cross the blood–brain barrier in a murine model system (Yokota et al 2007).


Negative_regulation (inhibitor) of Abl in brain
15) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.06 Pain Relevance 0
These include imatinib dose escalation, combining imatinib with other agents, and novel Bcr-Abl inhibitors.
Negative_regulation (inhibitors) of Abl
16) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.17 Pain Relevance 0
The pyridol [2,3-d] pyrimidine dasatinib (Sprycel™, BMS-354825, Figure 1) is another novel Abl-targeted kinase inhibitor, which additionally displays an inhibitory activity against Src kinases.
Negative_regulation (inhibitor) of Abl-targeted kinase
17) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.07 Pain Relevance 0
Cure of CML is not yet achieved by blocking the Bcr-Abl kinase.
Negative_regulation (blocking) of Bcr-Abl kinase associated with myeloid leukemia
18) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.66 Pain Relevance 0
In vitro experiments demonstrated that cells expressing the His396Pro variant of Bcr-Abl reverted to an imatinib sensitive state upon reduction of the Bcr-abl protein content with breakpoint specific siRNAs (Wohlbold et al 2003).



Negative_regulation (reduction) of abl (H396P)
19) Confidence 0.31 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.20 Pain Relevance 0
Substitution of one of these can result in reduced affinity of imatinib to Bcr-Abl or in steric inhibition of the binding.
Negative_regulation (reduced) of Abl
20) Confidence 0.30 Published 2008 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2503652 Disease Relevance 0.07 Pain Relevance 0

General Comments

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