Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice.
OBJECTIVE
In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined.


METHODS
The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions x three fractions/48 h or 5 Gy/fractions x five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three or four times at 2-h intervals.


RESULTS
At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter.


CONCLUSIONS
Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity.
Iwai
H
H
Chemical Division, Daikin Industries, Ltd., Settsu, Osaka, Japan.
Matsuno
E
E
Sasai
K
K
Shibamoto
Y
Y
Abe
M
M
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy; D017341:Etanidazole / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D008920:Misonidazole / Q000494:pharmacology; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C069296:KU 2285; D017341:Etanidazole; D008920:Misonidazole