2002 Fiscal Year Final Research Report Summary
Investigations of mechanisms of drug-resistance in leukemia cells
| Project/Area Number |
13671076
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Jichi Medical School |
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Principal Investigator |
NAGAI Tadashi Jichi Medical School, Faculty of Medicine, Assistant Professor, 医学部, 講師 (40237483)
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| Co-Investigator(Kenkyū-buntansha) |
OHMINA Ken Jichi Medical School, Faculty of Medicine, Research Associate, 医学部, 助手 (90316521)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Chronic Myelogeneous leukemia / Drug resistance / imatinib / R115777 / RAS / KCL22 / SR / K562 / SR / KU812 / SR |
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| Research Abstract |
Drug resistance is a major problem for patients with chronic myelogeneous leukemia in blast crisis who are being treated with the BCR/ABL tyrosine kinase inhibitor imatinib. To determine the mechanisms of imatinib-resistance and to examine the cytotoxic effect of a combination of a farnesyltransferase inhibitor, R115777, and imatinib on the imatinib-resistant cells, we have cloned three imatinib-resistant BCR/ABL-positive cell lines, KCL22/SR, K562/SR and KU812/SR. The level of phosphorylated BCR/ABL protein in these cells was suppressed by imatinib treatment, suggesting that deregulation of douwnstream of BCR/ABL kinase is involved in the resistance. DNA microarray analyses demonstrated that the RAS-MAPK signaling-related molecules RAS RASAP1 and RhoA, were up-regulated in KCL22/SR cells. Furthermore, the level of phospho-ERK1/2 was significantly suppressed in imatinib-sensitive parental KCL22 cells but was not changed in KCL22/SR cells by imatinib treatment. These results suggested that the aberrant activation of Ras-MAPK signaling is involved in the acquisition of resistance to imatinib. Treatment of KCL22/SR, K562/SR and KU812/SR cells with a combination of imatinib and R115777 resulted in synergistic inhibition of cell growth assessed by Isobologram of Steel and Peckham. This cell growth inhibition was, at least in part, due to the induction of apoptosis, while the treatment had no effect on the cell cycle. Furthermore, combined treatment with imatinib and a MEK1/2 inhibitor, U0126, also suppressed cell growth synergistically. These results suggest that the inhibition of RAS-MAPK signaling may restore the sensitivity to imatinib in some of imatinib-resistant cells.
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