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Takanori Ueda – One of the best experts on this subject based on the ideXlab platform.

  • Overcoming imatinib resistance using Src inhibitor CGP76030, ABL inhibitor nilotinib and ABL/Lyn inhibitor INNO-406 in newly estABLished K562 variants with BCR-ABL Gene amplification.
    International Journal of Cancer, 2008
    Co-Authors: Koji Morinaga, Takahiro Yamauchi, Shinya Kimura, Taira Maekawa, Takanori Ueda

    Abstract:

    Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-estABLishment of ABL kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL Gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL Gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-ABL, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the ABL kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new ABL kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual ABL/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL Gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients’ leukemia. © 2008 Wiley-Liss, Inc.

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  • overcoming imatinib resistance using src inhibitor cgp76030 ABL inhibitor nilotinib and ABL lyn inhibitor inno 406 in newly estABLished k562 variants with bcr ABL Gene amplification
    International Journal of Cancer, 2008
    Co-Authors: Koji Morinaga, Takahiro Yamauchi, Shinya Kimura, Taira Maekawa, Takanori Ueda

    Abstract:

    Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-estABLishment of ABL kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL Gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL Gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-ABL, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the ABL kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new ABL kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual ABL/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL Gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients’ leukemia. © 2008 Wiley-Liss, Inc.

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  • overcoming imatinib resistance using src inhibitor cgp76030 ABL inhibitor nilotinib and ABL lyn inhibitor inno 406 in newly estABLished k562 variants with bcr ABL Gene amplification
    Cancer Research, 2007
    Co-Authors: Koji Morinaga, Takahiro Yamauchi, Shinya Kimura, Taira Maekawa, Takanori Ueda

    Abstract:

    3246 The treatment of chronic myeloid leukemia has recently been revolutionized by the introduction of imatinib mesylate (IM), a selective inhibitor of Bcr-ABL tyrosine kinase. Although IM is effective against chronic-phase chronic myeloid leukemia, only a half of blast-crisis patients respond to IM, and the majority relapses due to acquired drug resistance. Because IM resistance is primarily caused by the re-estABLishment of ABL kinase activity, new inhibitors need to be developed. Here, we evaluated three new agents, the Src kinase inhibitor CGP76030, the highly specific ABL kinase inhibitor nilotinib, and the dual ABL/Lyn inhibitor INNO-406 (formerly NS-187) against IM resistance. Two new K562 cell lines, IM-R1 and IM-R2 cells, were developed having 7- and 27-fold more resistance towards IM, respectively than the parental K562 cells, determined using the XTT assay. These variants were also refractory to IM-induced apoptosis, which were evaluated using Hoechst 33342 staining of nuclei. CytoGenetic and fluorescence in situ hybridization analyses demonstrated that in both cell lines bcr-ABL Gene was amplified, although to a greater extent in IM-R2 cells than IM-R1 cells. Real-time RT-PCR and Western blot analyses revealed that transcript and protein levels were elevated and ABL kinase were enhanced to a greater extent in IM-R2 cells than MI-R1 cells. Mutation was not found in the kinase domain of both resistant variants. P-glycoprotein was not overexpressed, although the increased efflux of IM by this protein was reported in clinic. The degree of bcr-ABL Gene amplification appeared to be associated with the extent of IM-resistance. IM-resistant variants did not acquire Lyn overexpression, which also was reported to be associated with IM resistance of CML in some patients. Nevertheless, CGP76030 showed positive cooperability with IM in enhancing growth inhibition. Nilotinib inhibited the growth of IM-R2 cells much more potently than IM, but the combination of nilotinib with CGP76030 showed little additivity. The growth-inhibitory effect of INNO-406 was a little more potent than nilotinib against K562 and IM-R1 cells, and as potent as nilotinib against IM-R2 cells. Because Bcr-ABL overexpression is found in blast crisis, the present findings suggest that these new inhibitors might have potential to overcome IM resistance.

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Koji Morinaga – One of the best experts on this subject based on the ideXlab platform.

  • Overcoming imatinib resistance using Src inhibitor CGP76030, ABL inhibitor nilotinib and ABL/Lyn inhibitor INNO-406 in newly estABLished K562 variants with BCR-ABL Gene amplification.
    International Journal of Cancer, 2008
    Co-Authors: Koji Morinaga, Takahiro Yamauchi, Shinya Kimura, Taira Maekawa, Takanori Ueda

    Abstract:

    Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-estABLishment of ABL kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL Gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL Gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-ABL, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the ABL kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new ABL kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual ABL/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL Gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients’ leukemia. © 2008 Wiley-Liss, Inc.

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  • overcoming imatinib resistance using src inhibitor cgp76030 ABL inhibitor nilotinib and ABL lyn inhibitor inno 406 in newly estABLished k562 variants with bcr ABL Gene amplification
    International Journal of Cancer, 2008
    Co-Authors: Koji Morinaga, Takahiro Yamauchi, Shinya Kimura, Taira Maekawa, Takanori Ueda

    Abstract:

    Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-estABLishment of ABL kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL Gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL Gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-ABL, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the ABL kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new ABL kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual ABL/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL Gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients’ leukemia. © 2008 Wiley-Liss, Inc.

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  • overcoming imatinib resistance using src inhibitor cgp76030 ABL inhibitor nilotinib and ABL lyn inhibitor inno 406 in newly estABLished k562 variants with bcr ABL Gene amplification
    Cancer Research, 2007
    Co-Authors: Koji Morinaga, Takahiro Yamauchi, Shinya Kimura, Taira Maekawa, Takanori Ueda

    Abstract:

    3246 The treatment of chronic myeloid leukemia has recently been revolutionized by the introduction of imatinib mesylate (IM), a selective inhibitor of Bcr-ABL tyrosine kinase. Although IM is effective against chronic-phase chronic myeloid leukemia, only a half of blast-crisis patients respond to IM, and the majority relapses due to acquired drug resistance. Because IM resistance is primarily caused by the re-estABLishment of ABL kinase activity, new inhibitors need to be developed. Here, we evaluated three new agents, the Src kinase inhibitor CGP76030, the highly specific ABL kinase inhibitor nilotinib, and the dual ABL/Lyn inhibitor INNO-406 (formerly NS-187) against IM resistance. Two new K562 cell lines, IM-R1 and IM-R2 cells, were developed having 7- and 27-fold more resistance towards IM, respectively than the parental K562 cells, determined using the XTT assay. These variants were also refractory to IM-induced apoptosis, which were evaluated using Hoechst 33342 staining of nuclei. CytoGenetic and fluorescence in situ hybridization analyses demonstrated that in both cell lines bcr-ABL Gene was amplified, although to a greater extent in IM-R2 cells than IM-R1 cells. Real-time RT-PCR and Western blot analyses revealed that transcript and protein levels were elevated and ABL kinase were enhanced to a greater extent in IM-R2 cells than MI-R1 cells. Mutation was not found in the kinase domain of both resistant variants. P-glycoprotein was not overexpressed, although the increased efflux of IM by this protein was reported in clinic. The degree of bcr-ABL Gene amplification appeared to be associated with the extent of IM-resistance. IM-resistant variants did not acquire Lyn overexpression, which also was reported to be associated with IM resistance of CML in some patients. Nevertheless, CGP76030 showed positive cooperability with IM in enhancing growth inhibition. Nilotinib inhibited the growth of IM-R2 cells much more potently than IM, but the combination of nilotinib with CGP76030 showed little additivity. The growth-inhibitory effect of INNO-406 was a little more potent than nilotinib against K562 and IM-R1 cells, and as potent as nilotinib against IM-R2 cells. Because Bcr-ABL overexpression is found in blast crisis, the present findings suggest that these new inhibitors might have potential to overcome IM resistance.

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H. Yoshino – One of the best experts on this subject based on the ideXlab platform.

  • in vitro drug resistance to imatinib and mutation of ABL Gene in childhood philadelphia chromosome positive ph acute lymphoblastic leukemia
    Leukemia & Lymphoma, 2005
    Co-Authors: Hiroyuki Kawaguchi, Takeshi Taketani, Teruaki Hongo, Myoung-ja Park, Katsuyoshi Koh, Kohmei Ida, Miyuki Kobayashi, Junko Takita, Tomohiko Taki, H. Yoshino

    Abstract:

    Imatinib, the ABL kinase inhibitor, is used not only for Philadelphia chromosome-positive (Ph + ) chronic myelogenous leukemia, but also for Ph + acute lymphoblastic leukemia (ALL), although resistance to the drug tends to develop in an early stage of the clinical course. We describe a childhood refractory Ph + ALL patient in whom progressive resistance to imatinib was correlated with the appearance of a mutation in the BCR-ABL kinase domain and in vitro drug resistance to imatinib as determined by the methyl-thiazol-tetrazolium (MTT) assay. A missense mutation of T to C (Y253H) of the ABL Gene was identified in the resistant clone, suggesting that this mutation may play an etiological role in the rapid loss of drug sensitivity.

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  • In vitro drug resistance to imatinib and mutation of ABL Gene in childhood Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia.
    Leukemia & Lymphoma, 2005
    Co-Authors: Hiroyuki Kawaguchi, Takeshi Taketani, Teruaki Hongo, Myoung-ja Park, Katsuyoshi Koh, Kohmei Ida, Miyuki Kobayashi, Junko Takita, Tomohiko Taki, H. Yoshino

    Abstract:

    Imatinib, the ABL kinase inhibitor, is used not only for Philadelphia chromosome-positive (Ph + ) chronic myelogenous leukemia, but also for Ph + acute lymphoblastic leukemia (ALL), although resistance to the drug tends to develop in an early stage of the clinical course. We describe a childhood refractory Ph + ALL patient in whom progressive resistance to imatinib was correlated with the appearance of a mutation in the BCR-ABL kinase domain and in vitro drug resistance to imatinib as determined by the methyl-thiazol-tetrazolium (MTT) assay. A missense mutation of T to C (Y253H) of the ABL Gene was identified in the resistant clone, suggesting that this mutation may play an etiological role in the rapid loss of drug sensitivity.

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