Comparison of radiosensitizing effect of KU-2285 and SR-2508 at low drug concentrations and doses.
OBJECTIVE
Since the radiosensitizing effect of KU-2285 at relatively low dose levels is not known, we investigated its efficacy at such low concentrations or doses achievable in humans with oral administration of 0.3-1.0 g/m2.


METHODS
KU-2285 was tested in comparison with SR-2508 at low concentrations (0.05-0.25 mM) in vitro by the cytokinesis-block micronucleus assay and by the colony formation assay, and at low drug doses (12.5-50 mg/kg) in vivo by the in vivo-in vitro assay and by the growth delay assay using SCC VII tumors in C3H/He mice.


RESULTS
In the cytokinesis-block micronucleus assay, the sensitizer enhancement ratio (SER) for KU-2285 and SR-2508 was 1.43 and 1.17 at 0.05 mM, 1.75 and 1.27 at 0.10 mM, and 2.14 and 1.69 at 0.25 mM, respectively. In the colony formation assay, the SER for KU-2285 was also greater than that for SR-2508. In the in vivo-in vitro assay, the SER for KU-2285 and SR-2508 was 1.11 and 1.04 at 12.5 mg/kg, 1.21 and 1.04 at 25 mg/kg, and 1.26 and 1.18 at 50 mg/kg, respectively. In the growth delay assay at 50 mg/kg, no tumor regrowth was observed in four of the 18 mice treated with KU-2285 + 25 Gy, although the growth delay time for the remaining mice was similar to that for SR-2508 + 25 Gy.


CONCLUSIONS
KU-2285 was more effective than SR-2508 both at low drug concentrations in vitro and at low drug doses in vivo. These promising findings suggest the potential superiority of KU-2285 over SR-2508 as a radiosensitizer for clinical use.
Shibata
T
T
Department of Radiology, Faculty of Medicine, Kyoto University, Japan.
Shibamoto
Y
Y
Oya
N
N
Sasai
K
K
Murata
R
R
Ishigaki
T
T
Abe
M
M
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D017341:Etanidazole / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D015162:Micronucleus Tests; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C069296:KU 2285; D017341:Etanidazole