1991 Fiscal Year Final Research Report Summary
Study on the biological properties of nitroimidazole nucleoside analogs as a new hypoxic cell radiosensitizer.
| Project/Area Number |
01480277
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Radiation science
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| Research Institution | Tokai University |
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Principal Investigator |
MORI Tomoyuki Tokai Univ., School of Med., Prof., 医学部, 教授 (70055896)
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| Co-Investigator(Kenkyū-buntansha) |
FUKUHARA Noboru Tokai Univ., School of Med., Assist, 医学部, 助手 (70218949)
TAMAI Yoshifumi Tokai Univ., School of Med., Assist, 医学部, 助手 (90207225)
MAEZAWA Hiroshi Tokai Univ., School of Med., Lect., 医学部, 講師 (00138653)
OHIZUMI Yukio Tokai Univ., School of Med., Lect., 医学部, 講師 (30024813)
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| Project Period (FY) |
1989 – 1991
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| Keywords | Radiosensitizer / Hypoxic cells / EMT6 tumor / SCCVII tumor / Nitroimidazoles / Misonidazole / Etanidazole / RP-170 |
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| Research Abstract |
A goal for a new hypoxic cell radiosensitizer would be for it to be more effective than, and/or less toxic than, etanidazole (SR2508) or clinically more useful than etanidazole. A potent sensitizer has been synthesized ; this is 2-nitroimidazole nucleoside analog having methoxyglycerol as a sugar moiety at the N-1 position of the imidazole ring (RP-170). Its radiosensitizing activities in vitro and in vivo were investigated and compared with those of etanidazole. As might be expected from the almost identical electron affinities of the two compounds, there were equally effective against hypoxic EMT6 cells in vitro. An intravenous administration (i. v.) of 100mg/kg of RP-170 or the same dose of etanidazole showed an equal sensitizer enhancement ratio (SER) of about 1.4 to solid FMT6 tumor under in vivo-invitro assay and a virtually equal SER of 1.4-1.5 to solid SCCVII tumor under both tumor growth delay assay and TCD50 assay. As predicted from the low partition coefficient, lower drug levels in neural tissue and more rapid serum elimination of RP-170 and etanidazole produced lower acute toxicity than lipophilic sensitizers (e. g. misonidazole). The major advantage of RP-170 over etanidazole is that it has a second route of administration. In contrast to etanidazole, in which the administration route is limited to intravenous injection, with RP170 oral administration also exhibited effective distribution to tumors, sensitizing radiation activity to solid EMT6 and SCCVII tumors. Moreover, LD50 in mice of RP-170 (4.3g/kg on i. v.) was increased to 5.2g/kg by oral administration. This availability of two routes of administration indicates RP-170 as a promising hypoxic cell radiosensitizer for clinical use.
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