Reduced bisantrene-induced cytotoxicity and protein-associated DNA strand breaks under hypoxic condition

The effect of hypoxia on bisantrene-induced cytotoxicity and protein-associated DNA strand breaks was studied in mouse L1210 leukemia cells, human T47D breast cancer cell line, and fresh samples of human tumor cells. For each cell type, there was enhanced cell killing under oxic versus hypoxic conditions (1-hour drug treatment at 37 degrees C). Likewise, in L1210 cells, the frequency of bisantrene (10 micrograms/ml for 1 hour)-induced protein-associated DNA strand breaks was reduced by 70% under hypoxic versus oxic conditions. The reason for enhanced cytotoxicity and DNA strand breakage in L1210 cells under oxic conditions could not be attributed to oxygen-enhanced cellular uptake of the drug. The clinical implication of these data is that bisantrene may be relatively ineffective against large tumors containing hypoxic cell populations.