| Project/Area Number |
07671214
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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 | Nagasaki University |
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Principal Investigator |
YAMADA Yasuaki Nagasaki University, School of Medicine, Associate professor., 医学部, 助教授 (60145232)
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| Co-Investigator(Kenkyū-buntansha) |
KONDO Takahito Nagasaki University, School of Medicine, Professor., 医学部, 教授 (00158908)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1997: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
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| Keywords | ATL / APOPTOSIS / CD95 / FAS / OXIDANT / ANTIOXIDANT / GLUTATHIONE / 8-OHdG / GSH / ceramide / γ-GCS |
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| Research Abstract |
The mechanism of Fsa (CD95)-mediated apoptosis of ATL cells was studied in the context of oxidant and antioxidant system. We established several ATL cell lines, which were sensitive or resistant to anti-Fas IgM monoclonal antibody.
Although the addition of anti-Fas resulted in formation of oxygen radical species in the sensitive ce11s, no oxygen radical was produced from the resistant cells. The oxygen radical induced DNA damage as determined by formation of 8-hydroxydeoxyguanosine (8-OHdG), which showed a mutual relation with oxygen radical production. The resistant cells had two to three times higher amounts of intracellular glutathione (GSH) as antioxidant and gamma-glutamylcysteine synthetase (gamma-GCS) as the key enzyme for GSH synthesis than the sensitive cells. Interestingly, Fas-resistant cells showed cross resistance to antineoplastic drugs. Moreover, the urine samples from ATL patients showed transient increase of 8-OHdG after chemotherapy suggesting that antineoplastic agents also use oxidant for cell killing.
However, since the addition of exogenous GSH did not abrogate the Fas-induced apoptosis, the involvement of protective machanism other than antioxidant was suggested. By the molecular analysis of Fas genes of resistant cells, we found that one of the cell line had a deletion of the gene for death domain.
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