In vivo antiproliferative effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on leukemic cells harbouring Abl kinase domain mutations

Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho Mongucgi-Cho, Minami-Ku, Kyoto 601-8550, Japan.
Leukemia Research (Impact Factor: 2.69). 12/2006; 30(11):1443-6. DOI: 10.1016/j.leukres.2006.01.006
Source: PubMed

ABSTRACT Advanced-phase chronic myeloid leukemia patients treated with imatinib often relapse due to point mutations in the Abl kinase domain. We herein examine the in vitro and in vivo effects of a Bcr-Abl/Lyn dual tyrosine kinase inhibitor, NS-187, on seven mutated Bcr-Abl proteins. NS-187 inhibited both Tyr393-phosphorylated and Tyr393-unphosphorylated Abl, resulting in significant in vitro growth inhibition of cells expressing six of seven mutated Bcr-Abl kinases, though not T315I. Furthermore, NS-187 prolonged the survival of mice injected with leukemic cells expressing all mutated Bcr-Abl tested except T315I, and its efficacy correlated well with its in vitro effects.

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    • "Cell lines and reagents BV173, KT-1, KCL22, MYL, K562 and MEG-01 are cell lines derived from CML patients in blast crisis phase. Generation of multidrug resistant K562/D1-9, K562 subclones artificially overexpressing FLAG-tagged Bcl-2 (K562/Bcl-2) or Bcl-X L (K562/Bcl-X L ), transformed Ba/F3-derived haematopoietic cell lines Ba/F3/wt (bearing wild-type Bcr-Abl), Ba/F3/ E255K (mutated Bcr-Abl E255K ) and Ba/F3/T315I (Bcr-Ab- l T315I ) were described elsewhere (Urasaki et al, 1996; Kimura et al, 2005; Kuroda et al, 2006; Naito et al, 2006). IMresistant K562/IMR and MYL-R, expressing higher levels of Bcr-Abl protein, were generated by continuously exposing K562 and MYL, respectively, to 1 lmol/l IM (Ito et al, 2007). "
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