1991 Fiscal Year Final Research Report Summary
Studies on the mechanism of leukemia cell differentiation and its clinical application
| Project/Area Number |
02807232
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | Kagawa Medical School |
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Principal Investigator |
IRINO Shozo Kagawa Medical School, School of Medicine, President, 学長 (50033056)
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| Co-Investigator(Kenkyū-buntansha) |
TAOKA Teruhisa Kagawa Medical School, School Hospital, Associate, 医学部附属病院, 助手 (40154728)
YAMAJI Yasufumi Kagawa Medical, School School Hospital, Associate, 医学部附属病院, 助手 (00191297)
TANAKA Terukazu Kagawa Medical, School School Hospital, Assistant Professor, 医学部附属病院, 講師 (20155146)
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| Project Period (FY) |
1990 – 1991
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| Keywords | Differentiation / Calcium / TPA / calcium antagonist / C-kinase / dehydrothymine dehydrogenase / 1, 25(OH)_2D_3 / Nucleic acid metabolism |
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| Research Abstract |
1. The role of second messenger (1) The iricrease of intracellular free calcium concentration ([Ca^<2+>]i) was observed in the HL-60 cells which were treated with 1, 25(OH)_2D_3 or TPA for short (within 1 min) or long term (3 days). This transient increase of[Ca^<2+>]i caused by short term treatment with TPA was inhibited by the calcium channel blockers(diltiazem, verapamil)or inhibitor of protein kinase C (PK-C), staurosporine. On the other hand, the differentiation into granulocyte lineage by retinoic acid did not affect the[Ca^<2+>]i. (2) The results from the experiments using the subclones of HL-60 cells suggested not only the relation between 1, 25(OH)_2D_3 receptor (VDR) level and differentiative events, but also the linkage between c-myc and cell proliferation but not cell differentiation. (3) K252a, a inhibitor of PK-C, inhibited the cell proliferation and DNA synthesis dose dependently and enhanced the differentiation by various inducers. (4) TI-1 cell. a myeloid leukemia cell
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line which we established, was differentiated into the monocytoid lineage and erythroid one by TPA and hemin, respectively.
2. The study of the metabolism of nucleic acid : Exposure of HL-60 and U-937 cells to TPA resulted in specific alterations in thymidine metabolism. Within 24h after treatment with TPA, the reciprocal alteration in the activities of opposing enzymes of thymidine metabolism observed during normal cell culture growth was reserved. In TPA treated cells, the activities of anabolic enzymes, thymidine kinase and thymidylate synthase declined. In contrast, the activities of catabolic enzymes, thymidine phosphorylase and dehydrothymine dehydrogenase (DHTDH) increased. Northern blot analysis and immunotitration of DHTDH with DNA probe and monoclonal antibody against this enzyme showed that the rise in the activity in the differentiated cells was due to the increase in the amount of mRNA and enzyme protein. These observations indicate that the differentiation of HL-60 and U-937 cells results in a reversal of the enzymic phenotype of thymidine metabolic imbalance may serve as an early marker of differentiation of these cells. Less
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Research Products
(10 results)
