Effects of Bleomycin with Iododeoxyuridine, 5′-Amino-5′-Deoxythymidine, and Radiation in a Human Bladder Cancer Cell Line

In vitro bleomycin cytotoxicity in 647V, a human bladder cancer cell line, is enhanced when the cells are preincubated for one cell cycle (24 h) with clinically relevant concentrations (2 μM) of iododeoxyuridine (IdUrd). Bleomycin cytotoxcity after a 1-h exposure is further enhanced by a 24-h preincubation with 2 μM IdUrd plus 30 μM 5′-amino-5′-deoxythymidine (5′-AdThd). Chemosensitization of clinically achievable plasma levels of bleomycin (1-10 mU/ml for 1 h) by IdUrd (± 5′-AdThd) is associated with the level of DNA incorporation of IdUrd in 647V cells and with enhanced bleomycin-induced damage in IdUrd-substituted DNA compared to control DNA, as measured by rapid alkaline elution. We also studied the in vitro effects of bleomycin (± IdUrd) treatment on the subsequent radiation response of 647V cells. We found that a 1-h preirradiation exposure of 647V cells to low concentrations of bleomycin (1 mU/ml) can radiosensitize the cells with an even greater interaction exhibited by pretreatment with 2 μM IdUrd (24 h) plus bleomycin (1 h) vs control. Since the principal normal tissue toxicities of IdUrd (involving bone marrow and gut) and bleomycin (involving lung) do not overlap, these in vitro data suggest that chemosensitization of bleomycin by IdUrd may provide a new therapeutic regimen for chemotherapy and a significant enhancement for radiotherapy in human bladder cancer and possibly other epithelial cancers.