In vivo radiosensitizing effect of nitroimidazole derivative KIN-804.
OBJECTIVE
In vivo characteristics of 2-nitroimidazole-1-methylacetohydroxamate (KIN-804), which is a newly developed hypoxic cell radiosensitizer, are presented.


METHODS
The toxicity, pharmacokinetics, and radiosensitizing effect of KIN-804 were studied by in vivo experiments using C3H/He mice bearing the SCC-VII tumor. Results were compared with misonidazole (MISO).


RESULTS
LD50(7) of KIN-804 and MISO were 3200 mg/kg and 2000 mg/kg, respectively. The peak of concentrations of KIN-804 in the tumor occurred 20 min after intraperitoneal injection and reached about 62% of the maximum concentration in the blood. The concentrations in brain and sciatic nerve were very low and clearance from sciatic nerve was rapid. Enhancement ratios of KIN-804 calculated using the growth delay method were 1.22, 1.50 and 1.71 at doses of 50, 100, and 200 mg/kg, respectively, compared with 1.36 for MISO at a dose of 100 mg/kg. In the TCD50 assay, enhancement ratios at a dose of 200 mg/kg were 1.69 for KIN-804 and 1.52 for MISO, respectively.


CONCLUSIONS
KIN-804 is a promising radiosensitizer since it shows less toxicity and higher radiosensitizing activity than MISO.
Tada
T
T
Department of Radiology, Osaka-Prefectural Habikino Hospital, Japan.
Nakajima
T
T
Onoyama
Y
Y
Murayama
C
C
Mori
T
T
Nagasawa
H
H
Hori
H
H
Inayama
S
S
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy; D004305:Dose-Response Relationship, Drug; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007928:Lethal Dose 50; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000494:pharmacology; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D006877:Hydroxamic Acids; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C076264:2-nitroimidazole-1-methylacetohydroxamate; D008920:Misonidazole