Enzymology of tirapazamine metabolism: a review

The enzymology of tirapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benz otriazene 1,4-dioxide, Tirazone(TM)) has been extensively studied in rodent s and to a lesser extent in human systems. While it is clear that the initi al reductive step in TPZ activation is enzyme-mediated, there is limited co nsensus in the published literature as to the relative contributions of the cellular reductases involved. Moreover, not only is the importance of subc ellullar localization for these putative activating reductase(s)far from cl ear but their activity profiles in vivo are poorly defined. The same might also be said of the potential detoxifying enzymes This review will attempt to establish what common ground exists regarding the enzymology of TPZ meta bolism, and will relate the available evidence to the enzyme profiles found in human cell lines in vitro, as well as in xenograft models and human sol id tumours.