| Project/Area Number |
11671015
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Keio University |
|---|
Principal Investigator |
KIZAKI Masahiro Keio Univ.School of Medicine, Dept.Internal Medicine, Assistant Profess, 医学部, 講師 (20161432)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
IKEDA Yasuo Keio Univ.School of Medicine, Dept.Internal Medicine, Professor, 医学部, 教授 (00110883)
FUKUCHI Yumi Keio Univ.School of Medicine, Dept.Internal Medicine, Research Associate, 医学部, 助手 (40250237)
|
|---|
| Project Period (FY) |
1999 – 2000
|
| Project Status |
Completed (Fiscal Year 2000)
|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
|
|---|
| Keywords | arsenic trioxide / leukemia / apoptosis / differentiation / retinoic acid / GM-CSF / SCID mice / PML / RARα / 細胞周期 / SCIDマウス / Bcl-2 / Bax |
|---|
| Research Abstract |
Arsenic trioxide effectively induces clinical remission via apoptosis in relapsed acute promyelocytic leukemia (APL). However, its molecular mechniams od inducing apoptosis is still unclear. In addition, this new anti-leukemic drug is considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. Arsenic trioxide can induce apoptosis of both retinoic acid-sensitive NB4 and-resistant UF-1 cells with down-regulation of Bcl-2 and up-regulation of Bax proteins, respectively. Also, arsenic trioxide degrades APL-specific PML/RARα fusion protein. Interestingly, a combination of arsenic trioxide and GM-CSF induces differentiation, but not apoptosis of APL cells. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in both NB4 and UF-1 cells. A specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of arsenic trioxide-treated APL cells, suggesting that Jak/STAT pathway is dritical for the anti-apoptotic activity of GM-CSF in APL cells treated with both agents. These results are also observed in vivo by using human GM-CSF-producing transgenic SCID mice model. In conclusion, a combination of arsenic trioxide and GM-CSF appears to be a novel differentiation-inducing therapy in patients with APL.Further molecular studies to determine the target molecules of arsenic trioxide will be needed.
|
