INT199553

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Context Info
Confidence 0.76
First Reported 2006
Last Reported 2010
Negated 0
Speculated 0
Reported most in Body
Documents 25
Total Number 32
Disease Relevance 13.83
Pain Relevance 0.48

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

cytosol (Bcr) signal transduction (Bcr) plasma membrane (Bcr)
intracellular (Bcr) enzyme binding (Bcr) kinase activity (Bcr)
Anatomy Link Frequency
32D 2
plasma 1
Bcr (Mus musculus)
Bcr - T315I (1)
Pain Link Frequency Relevance Heat
Potency 140 94.48 High High
Kinase C 1 83.44 Quite High
adenocard 1 49.08 Quite Low
abdominal pain 6 35.68 Quite Low
cytokine 22 29.28 Quite Low
headache 49 17.92 Low Low
pruritus 42 17.52 Low Low
Central nervous system 19 5.00 Very Low Very Low Very Low
tolerance 13 5.00 Very Low Very Low Very Low
Pain 8 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Cancer 113 99.98 Very High Very High Very High
Myeloid Leukemia 1476 99.84 Very High Very High Very High
Philadelphia Chromosome 288 99.84 Very High Very High Very High
Leukemia 330 99.68 Very High Very High Very High
Genetic Translocation 4 99.28 Very High Very High Very High
Toxicity 116 98.88 Very High Very High Very High
Chronic Myeloid Leukemia 37 96.44 Very High Very High Very High
Apoptosis 99 96.28 Very High Very High Very High
Recurrence 72 95.76 Very High Very High Very High
Malignant Neoplastic Disease 35 89.24 High High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
Experimental models of in vitro drug sensitivity exposing Bcr-Abl-expressing cells to nilotinib or dasatinib under conditions that favor the development of mutations have shown that although their mutagenic potential is lower than that of imatinib, mutations may still emerge (Table 3).
Gene_expression (expressing) of Bcr-Abl
1) Confidence 0.76 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.15 Pain Relevance 0
Other mechanisms of imatinib resistance may include: increased expression of Bcr-Abl through genomic amplification (Nicolini et al 2006), overexpression of Lyn or other Src-family tyrosine kinases (Donato et al 2003; Dai et al 2004), or overexpression of drug efflux proteins such as P-glycoprotein, which may decrease the intracellular concentration of imatinib in leukemic cells (Thomas et al 2004).
Gene_expression (expression) of Bcr-Abl
2) Confidence 0.76 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.05 Pain Relevance 0
Although over expression of Bcr-Abl is a possible resistance mechanism for nilotinib (Mahon et al 2004), resistance is more likely to arise through the emergence of clones expressing nilotinib-resistant mutant forms of Bcr-Abl.
Gene_expression (expression) of Bcr-Abl
3) Confidence 0.76 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.32 Pain Relevance 0
The 210 kDa Bcr-Abl protein is expressed in CML patients, whereas a 190 kDa Bcr-Abl protein, resulting from an alternative breakpoint in the BCR gene, is expressed in Ph+ acute lymphoblastic leukaemia (ALL) patients (Chan et al 1987).
Gene_expression (expressed) of Bcr-Abl associated with leukemia, myeloid leukemia and philadelphia chromosome
4) Confidence 0.76 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 1.63 Pain Relevance 0
Although over expression of Bcr-Abl is a possible resistance mechanism for nilotinib (Mahon et al 2004), resistance is more likely to arise through the emergence of clones expressing nilotinib-resistant mutant forms of Bcr-Abl.
Gene_expression (expressing) of Bcr-Abl
5) Confidence 0.76 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.29 Pain Relevance 0
The 210 kDa Bcr-Abl protein is expressed in CML patients, whereas a 190 kDa Bcr-Abl protein, resulting from an alternative breakpoint in the BCR gene, is expressed in Ph+ acute lymphoblastic leukaemia (ALL) patients (Chan et al 1987).
Gene_expression (expressed) of Bcr-Abl associated with leukemia, myeloid leukemia and philadelphia chromosome
6) Confidence 0.76 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 1.68 Pain Relevance 0
This better fit between nilotinib and the kinase binding site, as well as differences in interactions with specific amino acid residues, led to the development of a high-affinity ATP-competitive inhibitor, 10 to 30 times more potent than imatinib, which decreases proliferation and viability of wild-type Bcr-Abl- and imatinib-resistant Bcr-Abl mutant-expressing cells in vitro by selectively inhibiting Bcr-Abl autophosphorylation (Schindler et al 2000; Nagar et al 2002; Manley et al 2005; Weisberg et al 2005).
Gene_expression (expressing) of imatinib-resistant Bcr-Abl mutant
7) Confidence 0.66 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0 Pain Relevance 0.03
Dasatinib is well tolerated and has broad efficacy, resulting in durable responses in patients with any BCR-ABL mutation except for T3151 and mutations in codon 317 – most commonly F317L – including mutations that were highly resistant to imatinib, such as L248, Y253, E255, F359, and H396.
Gene_expression (mutation) of BCR
8) Confidence 0.66 Published 2009 Journal Therapeutics and Clinical Risk Management Section Abstract Doc Link PMC2697539 Disease Relevance 0.58 Pain Relevance 0
A model of nilotinib in complex with Abl kinase mutant M351T showed that the sensitivity of Bcr-Abl mutants to nilotinib segregates into 4 categories: high (IC50 < 70 nmol/L: M244V, G250E, Q252H, F3llL, F317L, M351T, V379I, L387M, H396P, H396R), medium (IC50 < 200 nmol/L: Y253F, E255K, F359V), low (IC50 < 450 nmol/L: Y253H, E255V), and insensitive (IC50 > 2 ?
Gene_expression (sensitivity) of Bcr-Abl
9) Confidence 0.66 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0 Pain Relevance 0.09
Imatinib, a small-molecule tyrosine kinase ihibitor (TKI), was the first drug to be developed that targets Bcr-Abl (Deininger et al 2005).
Gene_expression (targets) of Bcr-Abl
10) Confidence 0.66 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.65 Pain Relevance 0
This better fit between nilotinib and the kinase binding site, as well as differences in interactions with specific amino acid residues, led to the development of a high-affinity ATP-competitive inhibitor, 10 to 30 times more potent than imatinib, which decreases proliferation and viability of wild-type Bcr-Abl- and imatinib-resistant Bcr-Abl mutant-expressing cells in vitro by selectively inhibiting Bcr-Abl autophosphorylation (Schindler et al 2000; Nagar et al 2002; Manley et al 2005; Weisberg et al 2005).
Gene_expression (expressing) of Bcr-Abl
11) Confidence 0.66 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0 Pain Relevance 0.03
Based on previously a described interaction between imatinib and nilotinib in mouse expressing p210 positive cells, Weisberg et al showed positive cooperative effects of combination of nilotinib with imatinib in a panel of imatinib-sensitive and imatinib-resistant BCR-ABL expressing cells in vitro: the result was a synergistic/additive effect against Ba/F3 cells carrying multiple point mutations, such as E255V, E255K, F317L, M351T, and F486S, but not against Y253H or T315I (Weisberg et al 2007).
Gene_expression (expressing) of BCR-ABL
12) Confidence 0.64 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 0 Pain Relevance 0
This translocation fuses the genes encoding BCR and ABL, resulting in expression of the constitutively active protein tyrosine kinase, BCR-ABL.
Gene_expression (expression) of BCR
13) Confidence 0.64 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 1.46 Pain Relevance 0
Several mechanisms may contribute to imatinib resistance, including increased expression of BCR-ABL kinase through gene amplification, decreased intracellular drug concentrations caused by drug efflux proteins (OCT1), clonal evolution, or over-expression of Src kinases (Lyn, Hck) involved in BCR-ABL independent activation of alternative pathways (Apperley 2007).
Gene_expression (expression) of BCR-ABL
14) Confidence 0.64 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 0.08 Pain Relevance 0
This translocation fuses the genes encoding BCR and ABL, resulting in expression of the constitutively active protein tyrosine kinase, BCR-ABL.
Gene_expression (expression) of BCR-ABL
15) Confidence 0.64 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 1.51 Pain Relevance 0
Nilotinib has superior potency compared with imatinib as an inhibitor of BCR-ABL in vitro and in vivo: it is 10- to 30-fold more potent, as assessed by its ability to block proliferation of BCR-ABL dependent cell lines derived from CML patients (K562, Ku-812F) and cell lines (32D or Ba/F3) transfected to express the BCR-ABL protein (Figure 2; Weisberg et al 2005).
Gene_expression (express) of BCR-ABL in 32D associated with myeloid leukemia and potency
16) Confidence 0.64 Published 2008 Journal OncoTargets and therapy Section Body Doc Link PMC2994207 Disease Relevance 0.16 Pain Relevance 0.08
Dasatinib (BMS-354825, Sprycel®; Bristol Myers Squibb, New York, NY, USA) is a potent, second-generation, small-molecule, multitarget kinase inhibitor of BCR-ABL.
Gene_expression (generation) of BCR
17) Confidence 0.59 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.09 Pain Relevance 0
Other mechanisms of resistance to imatinib include alteration of the balance favoring the active state of ABL kinase, shifting the equilibrium between active and inactive states;15 a change in the conformation of the BCR-ABL protein, preventing imatinib from directly binding to its binding site;16 amplification of the BCR-ABL gene, leading to over-expression of BCR-ABL protein, as detected by FISH;13,16 or over-expression of the P-glycoprotein efflux pump, for which imatinib is the substrate.17,18 Additional mechanisms include the binding of the A1 acid glycoprotein (AGP) to imatinib in plasma, reducing its intracellular concentrations,19 or a less understood mechanism, the inhibition of ABCG2 protein functionality by imatinib.20
Gene_expression (expression) of BCR in plasma
18) Confidence 0.59 Published 2009 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2697539 Disease Relevance 0.21 Pain Relevance 0
The 210 kDa Bcr-Abl protein is expressed in CML patients, whereas a 190 kDa Bcr-Abl protein, resulting from an alternative breakpoint in the BCR gene, is expressed in Ph+ acute lymphoblastic leukaemia (ALL) patients (Chan et al 1987).
Gene_expression (expressed) of BCR associated with leukemia, myeloid leukemia and philadelphia chromosome
19) Confidence 0.59 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 1.44 Pain Relevance 0
Nilotinib was also shown to inhibit cell proliferation of the KBM5 line, which over expressed Bcr-Abl, with IC50 values of 480 nM (Golemovic et al 2005), and to revert the expression of the pre-apoptotic protein BCL-2- interacting mediator both in vivo and ex vivo (Aichberger et al 2005).
Gene_expression (expressed) of Bcr-Abl associated with apoptosis
20) Confidence 0.59 Published 2008 Journal Drug design, development and therapy Section Body Doc Link PMC2761189 Disease Relevance 0.24 Pain Relevance 0.04

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