The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR-ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents.
Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR-ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC(50) on day 5 of 4.6 microg ml(-1) and 3.4 microg ml(-1) for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 microg ml(-1): 55.5+/-8.7 vs 96.4+/-3.7%). STI571 also appeared to specifically target bcr-abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34(+) chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+/-11.3 vs 44.5+/-8.7 and 17.8+/-7.0% in cultures with STI571 and etoposide alone respectively; P<0.001). This study confirms the central oncogenic role of BCR-ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease.
Liu
W M
WM
Barry Reed Oncology Laboratory, 4th Floor, 38 Little Britain, St. Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK. w.a.i.liu@qmul.ac.uk
Stimson
L A
LA
Joel
S P
SP
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D016923:Cell Death; D003561:Cytarabine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010879:Piperazines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D005047:Etoposide; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl