Assessment of micronucleus induction in SCCVII cells treated with bioreductive agents, WIN 59075 (SR 4233) and mitomycin C, under aerobic and hypoxic conditions.
WIN 59075 (SR4233, tirapazamine) is a promising bioreductive antitumor agent preferentially more toxic to hypoxic cells and presently undergoing phase I clinical trials. In this investigation, we have examined the applicability of the cytokinesis-block micronucleus assay to assess the effects of bioreductive agents. SCCVII tumor cells were treated with WIN 59075 or mitomycin C at various concentrations under aerobic and hypoxic conditions. Significant induction of micronuclei in binucleate cells was demonstrated in a dose-dependent fashion and it appeared to be strongly correlated with the loss of clonogenicity in the colony assay. Both agents showed selectively higher toxicity to hypoxic cells than to aerobic cells and the ratios of the concentrations required to obtain the equivalent effects under aerobic and hypoxic conditions could be also estimated by this method as follows: the hypoxic toxicity ratios were 120-130 for WIN 59075 and 3.0-3.3 for mitomycin C. For several favorable characteristics, the cytokinesis-block micronucleus assay can provide an alternative, rapid, and reproducible means for evaluation of antitumor activities from chromosomal breakage caused by the bioreductive agents.
Shibata
T
T
Department of Radiology, Faculty of Medicine, Kyoto University, Japan.
Shibamoto
Y
Y
Sasai
K
K
Oya
N
N
Takagi
T
T
Murata
R
R
Abe
M
M
D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D006801:Humans; D015162:Micronucleus Tests / Q000379:methods*; D016685:Mitomycin / Q000633:toxicity*; D010100:Oxygen; D011838:Radiation-Sensitizing Agents / Q000633:toxicity; D000077704:Tirapazamine; D014227:Triazines / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D016685:Mitomycin; D010100:Oxygen