1999 Fiscal Year Final Research Report Summary
Molcular-target chemotherapy in ATL using MTAP-gene deficiency
| Project/Area Number |
10670956
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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 School of Medicine |
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Principal Investigator |
YAMADA Yasuaki Nagasaki University School of Medicine, Department of Laboratory Medicine, Assistant professor, 医学部, 助教授 (60145232)
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| Project Period (FY) |
1998 – 1999
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| Keywords | ATL / HTLV-I / MTAP / p16 / 1-alanosine / 1-methioninase / methionine / real-time PCR |
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| Research Abstract |
Adult T-cell leukemia (ATL) is one of the most aggressive lymphoproliferative diseases and there is no standard chemotherapy regimen to achieve cure of this disease. Since methylthioadenosine phosphorylase (MTAP) is an important enzyme for the salvage of adenine and methionine, cells deficient for MTAP gene is expected to become more sensitive to methonine starvation or de novo purine synthesis inhibitors. Southern blot and real-time PCR analyses of the primary ATL samples showed that more than 20% of ATL cases have homozygous deletion of the MTAP gene. Using ATL cell lines established in our laboratory, we investigated whether MTAP-gene targetted therapy is applicable to ATL. MTAP- negative cell lines (SO4, ST1, KK1) showed higher sensitivities to methionine starvation than MTAP-positive cell lines (KOB, OMT). Similarly, 1-alanosine, an inhibitor of adenosine monophosphate (AMP) synthesis, showed stronger cytotoxic activity to MTAP-negative cell lines compared with MTAP-positive cell lines. Although normal lymphocytes were resistant to 1-alanosine treatment, primary ATL cells showed high sensitivity to 1-alanosine irrespective of MTAP-gene status. These results support the use of 1-alanosine alone or in combination with 1-methioninase, a methionine cleaving enzyme which is now under clinical trials, for the treatment of MTAP-negative ATL.
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Research Products
(4 results)
