1999 Fiscal Year Final Research Report Summary
Study of Resistance Mechanisms of All-trans Retinoic Acid in Acute Promyelocytic Leukemia
| Project/Area Number |
10670939
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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 | Hamamatsu University School of Medicine |
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Principal Investigator |
TAKESHITA Akihiro Hamamatsu University School of Medicine, the Attached Hospital, Research Associate, 医学部・附属病院, 助手 (00242769)
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| Co-Investigator(Kenkyū-buntansha) |
OHNISHI Kazunori Hamamatsu University School of Medicine III, the Attached Hospital, Assistant Professor, 医学部・附属病院, 講師 (80252170)
OHNO Ryuzo Hamamatsu University School of Medicine III, Professor, 医学部, 教授 (70093002)
TAKESHITA Kaori Hamamatsu University School of Medicine, the Attached Hospital, Medical Stuff
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| Project Period (FY) |
1998 – 1999
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| Keywords | Acute Promyelocytic Leukemia / All-trans Retinoic Acid (ATRA)-Resistance / P-glycoprotein / NB4 |
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| Research Abstract |
We present here the relationship between all-trans retinoic acid (ATRA)-resistance and P-glycoprotein (P-gp)-associated multidrug resistance (MDR) in acute promyelocytic leukemia (APL). Cells used in this study were NB4 (negative for MDR1, MDR related protein and lung resistant protein), ATRA-resistant NB4 (NB4/RA), MDR1 cDNA-transduced NB4 (NB4/MDR) and MDR1 cDNA-transduced NB4/RA (NB4/RA/MDR), and blast cells from 10 patients with APL. Intracellular ATRA accumulation was determined by the characteristic emission curve of ATRA, which was excited by ultra violet in multi-laser-equipped flow cytometer. The apoptosis- and differentiation-introducing effects of ATRA were determined by CD11b, NBT reduction activity, cell cycle distribution and morphology.
While NB4/MDR and NB4/RA/MDR cells accumulated less Rhodamine-123 (Rh123) than NB4 and NB4/RA cells, respectively, there is no difference in the intracellular ATRA concentration between them. PSC833, a MDR modifier, increased the intracellular accumulation of Rh123 in NB4/MDR and NB4/RA/MDR cells, but not of ATRA. The expression of CD11b, the NBT reduction activity, the proportion of apoptotic cells and the morphology were not different between NB4 and NB4/MDR cells and between NB4/RA and NB4/RA/MDR cells. Similar results were obtained in the analysis of APL cells from patients relapsed after ATRA-induced complete remission.
Although there are a few reports that ATRA-resistant APL cells expressed more P-gp than ATRA-sensitive ones, we here directly show that the expression of P-gp does not influence the intracellular concentration of ATRA and that P-gp and ATRA-resistance independently exist.
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[Publications] Takeshita, K., Shinjo, K., Naito, K., Ohnishi, Y., Sugimoto, Y., Yamakawa, M., Tanimoto, K., Kitamura, T., Naoe and R. Ohno: "Role of P-glycoprotein in all-trans retinoic acid (ATRA) resistance in acute promyelocytic leukaemia cells : analysis of intracellular concentration of ATRA."Br J Haematol. 108. 90-92 (2000)
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