Predicting tumor responses to mitomycin C on the basis of DT-diaphorase activity or drug metabolism by tumor homogenates: Implications for enzyme-directed bioreductive drug development

Mitomycin C (MMC) is a clinically used anticancer drug that is reduced to c ytotoxic metabolites by cellular reductases via a process known as bioreduc tive drug activation. The identification of key enzymes responsible fur dru g activation has been investigated extensively with the ultimate aim of tai loring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable i nterest has been centered upon the enzyme DT-diaphorase (DTD) although conf licting reports of good and poor correlations between enzyme activity and r esponse in vitro and in vivo have been published. The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts, DTD levels were measured in 45 human tumor xenografts that had been characterized previously in terms of their sensit ivity to MMC in vitro and in vivo (the in vivo response profile to MMC was taken from work published previously). A poor correlation between DTD activ ity and antitumor activity in vitro as well as in, vivo was obtained. This study also assessed the predictive value of an alternative approach based u pon the ability of tumor homogenates to metabolize MMC, This approach is ba sed on the premise that the overall rate of MMC metabolism may provide a be tter indicator of response than single enzyme measurements, MMC metabolism was evaluated in tumor homogenates (clarified by centrifugation at 1000 x g for 1 min) by measuring the disappearance of the parent compound by HPLC. In responsive [T/C <10% (T/C defined as the relative size of treated and co ntrol tumors)] and resistant (T/C >50%) tumors, the mean half life of MMC w as 75 +/- 48.3 and 280 +/- 129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005), In conclusion, th ese results unequivocally demonstrate that response to Mlr;IC in vivo canno t be predicted on the basis of DTD activity. Measurement of MMC metabolism by tumor homogenates on the other hand may provide a better indicator of tu mor response, and further studies are required to determine whether this ap proach has real clinical potential in terms of individualizing patient chem otherapy.