The relationship between cytotoxic drug exposure and tumour cell kill, in vitro and in vivo.

Doxorubicin has been shown to be more effective against MGH-U1 bladder carcinoma cells grown in monolayer than spheroid. In vitro clonogenic cell survival curves have been replotted against the area under the concentration-time curve (AUC) for drug exposure and fitted to a Hill plot to derive the parameters E max (maximum possible cell kill) and C50 (drug exposure resulting in half the maximum cell kill). The plasma AUC following intraperitoneal administration of doxorubicin to nude mice was measured using a sensitive and specific HPLC assay and combined with the in vitro cell survival parameters to predict the clonogenic cell survival in MGH-U1 xenografts. The Hill parameters from the spheroid model are better predictors of xenograft clonogenic cell survival than the monolayer parameters. It is possible to predict clonogenic cell survival in solid tumours on the basis of the pharmacokinetics of cytotoxic drug exposure, using a mathematical model based on clonogenic cell kill in vitro.