Radiation-chemical properties of the hypoxic cell radiosensitizer doranidazole (PR-350).
This study was performed to confirm the radiation-chemical properties of the 2-nitroimidazole derivative doranidazole, (+/-)-(2RS,3SR)-3-[(2-nitroimdazol-1-yl)-methoxy]butane-1,2,4-triol [CAS 137339-64-1], PR-350, which was synthesized as a hypoxic cell radiosensitizer with low toxicity. Radiation-chemical experiments using doranidazole showed that (1) unlike O2, it had high reactivity toward not only hydrated electrons (eaq-), but also hydroxyl radicals (.OH), (2) the reduced intermediates of doranidasole had no ability to induce immediate strand breaks of colE1 plasmid DNA, (3) doranidazole enhanced radiation-induced DNA strand breaks of colE1 plasmid DNA in the aqueous state, whereas it did not enhance the base alteration, such as 8-oxo-deoxyguanosine, (4) it enhanced the radiation-induced formation of strand breaks with 3'-phosophate and 3'-phosphoglycolate termini, and (5) it was bound to DNA after irradiation. These facts revealed that the majority of radiation-chemical properties of doranidazole, except for the high reactivity toward OH, were similar to those of oxygen.
Kuwabara
Mikinori
M
Laboratory of Radiation Biology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. kuwabara@vetmed.hokudai.ac.jp
Iida
Yoshiharu
Y
Inanami
Osamu
O
Sawamura
Sadashi
S
Yokoyama
Kouji
K
Tsujitani
Michihiko
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA / Q000737:chemistry / Q000528:radiation effects; D018736:DNA Adducts / Q000737:chemistry / Q000528:radiation effects; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000528:radiation effects; D017665:Hydroxyl Radical / Q000633:toxicity; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects; D066298:In Vitro Techniques; D011675:Pulse Radiolysis; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology* / Q000528:radiation effects; D011854:Radiochemistry
D018736:DNA Adducts; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; D017665:Hydroxyl Radical; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C106738:doranidazole; D003849:Deoxyguanosine