2005 Fiscal Year Final Research Report Summary
Establishment of taylor-made therapy of acute leukemia by means of pharmacogenetics
| Project/Area Number |
15590999
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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 | University of Fukui (2004-2005)
福井医科大学 (2003) |
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Principal Investigator |
UEDA Takanori University of Fukui, University of Fukui Hospital, Professor, 医学部附属病院, 教授 (40160171)
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| Co-Investigator(Kenkyū-buntansha) |
URASAKI Yoshimasa University of Fukui, University of Fukui Hospital, lecturer, 医学部附属病院, 講師 (10281031)
YAMAUCHI Takahiro University of Fukui, Faculty of Medical Sciences, Assistant, 医学部, 助手 (90291377)
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| Project Period (FY) |
2003 – 2005
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| Keywords | cytarabine / DNA / acute leukemia / Tailor-made / TDM (therapeutic drug monitoring) / Drug resistance / Microarray |
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| Research Abstract |
Two strategies for taylor-made therapy with a major antileukemic agent cytarabine (Ara-C) by means of pharmacogenetics were studied.
(1) The crucial metabolite for ara-C is the DNA-incorporared ara-C in leukemic cells. Therapeutic drug monitoring at the DNA level in leukemic cells may optimize the chemotherapy for acute leukemia and improve clinical outcome. We presently developed a sensitive new method for monitoring ara-C incorporated into DNA in vivo. Accuracy, precision, and coefficient of variation of the method were excellent. The method was found to determine ara-C incorporation into DNA of ara-C-treated HL60 cells in vitro, the values of which were compatible with those measured by scintillation counting in parallel experiments using tritiated ara-C. Our method could monitor DNA-incorporated ara-C concentrations during intermediate-dose ara-C therapy, together with plasma ara-C and intracellular ara-C triphosphate concentrations. ara-C incorporation into DNA appeared to be assoc
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iated with the intracellular retention of ara-C triphosphate or persistence of the plasma ara-C. Thus, the present method is sensitive, accurate, precise, and may permit therapeutic drug monitoring at the DNA level for better individualization of antileukemic regimens.
(2) cDNA microarray was used to examine the comprehensive expression levels of genes in hematologic cell lines in relation to resistance to Ara-C. We isolated five Ara-C resistant cell lines from its parent cell lines (THP-1, K562, HL60, CEM, U937), and conducted molecular cytogenetic analysis of them. Using a quantitative analysis of mRNA expression within these Ara-C reisistant cell lines, we showed no common gene expression to determine resistantce to Ara-C. Each cell lines demonstrated different cross-resistance, despite employment of the common method to induce resistance to Ara-C. These findings suggest the mechanism of resistance of hematological cell lines to Ara-C was varied among each cell lines, which was useful information for the taylor-made therapy with Ara-C. Less
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Research Products
(8 results)
