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 cytotoxic metabolites by cellular reductases via a process known as bioreductive drug activation. The identification of key enzymes responsible for drug activation has been investigated extensively with the ultimate aim of tailoring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable interest has been centered upon the enzyme DT-diaphorase (DTD) although conflicting reports of good and poor correlations between enzyme activity and response 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 sensitivity 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 activity and antitumor activity in vitro as well as in vivo was obtained. This study also assessed the predictive value of an alternative approach based upon the ability of tumor homogenates to metabolize MMC. This approach is based on the premise that the overall rate of MMC metabolism may provide a better 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 control tumors)] and resistant (T/C >50%) tumors, the mean half life of MMC was 75+/-48.3 and 280+/-129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005). In conclusion, these results unequivocally demonstrate that response to MMC in vivo cannot 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 tumor response, and further studies are required to determine whether this approach has real clinical potential in terms of individualizing patient chemotherapy.
Phillips
R M
RM
Cancer Research Unit, University of Bradford, United Kingdom. r.m.phillips@bradford.ac.uk
Burger
A M
AM
Loadman
P M
PM
Jarrett
C M
CM
Swaine
D J
DJ
Fiebig
H H
HH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011237:Predictive Value of Tests; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D016685:Mitomycin; D016660:NAD(P)H Dehydrogenase (Quinone)