| Project/Area Number |
14370276
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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 | 一般 |
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| Research Field |
Radiation science
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| Research Institution | Nagoya City University |
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Principal Investigator |
SHIBAMOTO Yuta Nagoya City University, Graduate School of Medical Science, Professor, 大学院・医学研究科, 教授 (20144719)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIMOTO Sei-ichi Kyoto University, Graduate School of Engineering, Professor, 大学院・工学研究科, 教授 (10115909)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | Prodrug / Radiation-activated / Bioreduction / FdUrd / Mitomycin C / 低酸素細胞 / マイトマイシン / 放射線増加剤 |
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| Research Abstract |
As a novel method of targeting hypoxic tumor cells, we have investigated antitumor prodrugs that are activated by hypoxic irradiation through capturing of hydrated electrons. Since hypoxia exists almost exclusively in tumors and radiation is focused on the tumor, this prodrug activation occurs only in tumors. In this research programwe first investigated the effects of prodrugs of 5- fluoro-2'-deoxyuridine (FdUrd) with 2-oxoalkyl substituents at the N(3) position. The prodrugs released FdUrd at G-values of 1.6-2.0 x 10^<-7> mol/J following hypoxic irradiation. The G-values for FdUrd release with hypoxic irradiation were about 100-fold higher than those with aerobic irradiation. Among the prodrugs tested, OFU106 bearing a 2-oxocyclopentyl substituent released the highest amount of FdUrd in the culture medium, and it was subjected to further in vitro a in vivo assays. Although OFU106 administered alone showed no cytotoxicity up to a concentration of 0.2 mM, it produced an enhanced cytotoxic effect when admiistered before hypoxic irradiation and kept with the cells for 24 h. The enhancement ratios calculated at the surviving fraction of 1% were 1.35-1.4 at 0.04 mM and 1.45-1.5 at 0.2 mM. In vivo, however administration of OFU106 (100 or 300 mg/kg) before 20 Gy of irradiation did not produce marked growth delays compared with 20 Gy of radiation alone. In view of this result, we then tried to apply this strategy of prodrug design to mitomycin C. We synthesized a prodrug of mitomycin C with a 2-oxopropyl substituent and investigated its in vitro effects. However, preferential toxicity towards hypoxic cells was not observed. We will try to apply this strategy to other more potent anticancer agents.
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