This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jørgensen, H. G. Articles by Holyoake, T. L. Search for Related Content PubMed PubMed Citation Articles by Jørgensen, H. G. Articles by Holyoake, T. L.

Intermittent Exposure of Primitive Quiescent Chronic Myeloid Leukemia Cells to Granulocyte-Colony Stimulating Factor In vitro Promotes their Elimination by Imatinib Mesylate

Authors' Affiliations: ¹ Section of Experimental Haematology, Division of Cancer Sciences and Molecular Pathology, University of Glasgow; ² Academic Transfusion Medicine Unit, Scottish National Blood Transfusion Service, Glasgow, United Kingdom; and ³ Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

Requests for reprints: Tessa L. Holyoake, Section of Experimental Haematology, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Level 3, Queen Elizabeth Building, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, United Kingdom. Phone: 44-141-211-1202; Fax: 44-141-211-0414; E-mail: tlh1g{at}clinmed.gla.ac.uk.

Purpose: Primitive quiescent chronic myeloid leukemia (CML) cells are biologically resistant to imatinib mesylate, an inhibitor of the p210^BCR-ABL kinase. The present study was designed to investigate whether either continuous or intermittent exposure of these cells to granulocyte-colony stimulating factor (G-CSF) in vitro can overcome this limitation to the effectiveness of imatinib mesylate therapy.

Experimental Design: CD34⁺ leukemic cells were isolated from six newly diagnosed chronic phase CML patients and cultured for 12 days in serum-free medium with or without G-CSF and/or imatinib mesylate present either continuously or intermittently (three cycles of G-CSF for 0, 1, or 4 days ± imatinib mesylate for 0, 3, or 4 days). Every 4 days, the number of residual undivided viable cells and the total number of viable cells present were measured.

Results: Intermittent but not continuous exposure to G-CSF significantly accelerated the disappearance in vitro of initially quiescent CD34⁺ CML cells. This resulted in 3- and 5-fold fewer of these cells remaining after 8 and 12 days, respectively, relative to continuous imatinib mesylate alone (P < 0.04). Cultures containing imatinib mesylate and intermittently added G-CSF also showed the greatest reduction in the total number of cells present after 12 days (5-fold more than imatinib mesylate alone).

Conclusion: Intermittent exposure to G-CSF can enhance the effect of imatinib mesylate on CML cells by specifically targeting the primitive quiescent leukemic elements. A protocol for treating chronic-phase CML patients with imatinib mesylate that incorporates intermittent G-CSF exposure may offer a novel strategy for obtaining improved responses in vivo.

This article has been cited by other articles:

				E. Kavalerchik, D. Goff, and C. H.M. Jamieson Chronic Myeloid Leukemia Stem Cells J. Clin. Oncol., June 10, 2008; 26(17): 2911 - 2915. [Abstract] [Full Text] [PDF]

				L. Rink, A. Slupianek, T. Stoklosa, M. Nieborowska-Skorska, K. Urbanska, I. Seferynska, K. Reiss, and T. Skorski Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells Blood, July 15, 2007; 110(2): 651 - 660. [Abstract] [Full Text] [PDF]

				H. G. Jorgensen, E. K. Allan, N. E. Jordanides, J. C. Mountford, and T. L. Holyoake Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells Blood, May 1, 2007; 109(9): 4016 - 4019. [Abstract] [Full Text] [PDF]

				M. Holtz, S. J. Forman, and R. Bhatia Growth Factor Stimulation Reduces Residual Quiescent Chronic Myelogenous Leukemia Progenitors Remaining after Imatinib Treatment Cancer Res., February 1, 2007; 67(3): 1113 - 1120. [Abstract] [Full Text] [PDF]