2001 Fiscal Year Final Research Report Summary
Development of local drug disposition analysis and delivery methods in human solid tumors
| Project/Area Number |
12557212
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
TAKAKURA Yoshinobu Kyoto University, Grad. Sch. Pharm. Sci., Professor, 薬学研究科, 教授 (30171432)
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| Co-Investigator(Kenkyū-buntansha) |
YAMASHITA Fumiyoshi Kyoto University, Grad. Sch. Pharm. Sci., Associate Professor, 薬学研究科, 助教授 (30243041)
YAMAOKA Kiyoshi Kyoto University, Grad. Sch. Pharm. Sci., Associate Professor, 薬学研究科, 助教授 (50109013)
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| Project Period (FY) |
2000 – 2001
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| Keywords | solid tumors / drug delivery system / local administration / gene therapy / antisense oligonucleotide / plasmid DNA |
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| Research Abstract |
To construct a strategy for developing efficient and safe in vivo drug delivery systems to solid tumors, a series of pharmacokinetic studies following local administration were carried out. The intratumoral pharmacokinetics of a second-generation antisense oligonucleotid were studied in rat Walker 256 tissue-isolated tumor preparations using an in situ single-pass vascular perfusion technique. Some first-generation oligonucleotides were also used for comparison. These oligonucleotides were administrated directly into the tumor in two ways : constant arterial infusion and direct intratumoral injection. The results suggested that the oligonucleotide may be useful for direct local injection into solid tumors. On the other hand, the intratumoral pharmacokinetics of naked plasmid DNA and gene expression were examined in mice bearing solid tumors. Plasmid DNA was rapidly eliminated from the injection site and lymphatic transfer was observed. Intratumoral injection of naked naked plasmid DNA encoding the luciferase gene into subcutaneously inoculated mouse colon tumor resulted in significant gene expression. The gene expression was inhibited when defined polyanions were injected simultaneously, implying the involvement of a specific mechanism in cellular uptake of plasmid DNA These results demonstrated that tumor tissue might be a promising target for direct gene transfer.with naked plasmid DNA. Thus, the present study provides useful information about the basic disposition characteristics of gene drugs, such as antisense oligonucleotides and plasmid DNA in solid tumors.
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