7-N -(2-([2-(Gamma-L-glutamylamino)-ethyl]-dithio)-ethyl)-mitomycin C (KW-2149) is more active than mitomycin C on chemonaive and drug-resistant urothelial carcinoma cells

Abstract

This in vitro study aimed to investigate the cytotoxic activity of 7-N-(2-([2-(gamma-l-glutamylamino)ethyl]dithio)ethyl)-mitomycin C (KW-2149) versus mitomycin C (MMC) against cell lines from human transitional cell carcinoma (TCC). Direct cytotoxicity of the two drugs was measured employing a colorimetric cytotoxicity assay on chemonaive and chemoresistant cancer cell populations. The results revealed that all cell lines (n= 19) were significantly more inhibited by treatment (2 h, 96 h) with KW-2149 than by MMC (P < 0.03–0.001). pH 6.0 decreased the stronger activity of KW-2149 (P < 0.013–0.004). Creatinine ≥10 mmol/l and nitrosourea ≥100 mg/l also inhibited the activity of KW-2149 significantly. Tumor cells with relative drug-resistance against MMC (RT112-MMC: 55-fold) exerted minor cross-resistance to KW-2149 (fourfold). In conclusion, the present in vitro data suggest KW-2149 to be a superior drug for intravesical therapy of patients with primary or recurrent superficial bladder carcinoma. Since pH and concentrations of creatinine and nitrosourea influence the activity of KW-2149, patients are supposed to profit from neutralizing the urinary pH and enhanced diureses.