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 Blood, 1 May 2007, Vol. 109, No. 9, pp. 4016-4019.
Prepublished online as a Blood First Edition Paper on January 9, 2007; DOI 10.1182/blood-2006-11-057521.

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Submitted November 13, 2006
Accepted December 26, 2006

Nilotinib exerts equipotent anti-proliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells

Heather G Jorgensen, Elaine K Allan, Niove E Jordanides, Joanne C. Mountford, and Tessa L. Holyoake*

Section of Experimental Haematology, Division of Cancer Sciences & Molecular Pathology, University of Glasgow, Glasgow, United Kingdom
Academic Transfusion Medicine Unit, Scottish National Blood Transfusion Service, Glasgow, United Kingdom

* Corresponding author; email: tlh1g{at}clinmed.gla.ac.uk.

CML stem and progenitor cells over-express BcrAbl and are insensitive to imatinib mesylate (IM). We therefore investigated whether these cells were efficiently targeted by nilotinib. In K562, the IC50 of nilotinib was 30nM versus 600nM for IM, consistent with its reported 20-fold higher potency. However, in primary CD34+ CML cells, nilotinib and IM were equipotent for inhibition of BcrAbl activity, producing equivalent but incomplete reduction in CrkL phosphorylation at 5µM. CML CD34+ cells were still able to expand over 72h with 5µM of either drug, although there was a concentration dependent restriction of amplification. As for IM, the most primitive cells(CFSEmax), persisted and accumulated over 72h with nilotinib and remained caspase-3 negative. Furthermore, nilotinib with IM led to further accumulation of this population, suggesting at least additive anti-proliferative effects. These results confirmed that like IM the predominant effect of nilotinib is anti-proliferative rather than pro-apoptotic.


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